Linkage modified oligomeric compounds and uses thereof

[0001] The present application is being filed along with a Sequence Listing in electronic format. The Sequence Listing is provided as a file entitled CHEM0101USC1SEQ_ST25.txt created Feb. 11, 2022 which is 593 kb in size. The information in the electronic format of the sequence listing is incorporated herein by reference in its entirety.

[0002] The present disclosure provides oligomeric compounds (including oligomeric compounds that are antisense agents or portions thereof) comprising a modified oligonucleotide having at least one modified internucleoside linking group.

[0003] The principle behind antisense technology is that an antisense compound hybridizes to a target nucleic acid and modulates the amount, activity, and/or function of the target nucleic acid. For example, in certain instances, antisense compounds result in altered transcription or translation of a target. Such modulation of expression can be achieved by, for example, target RNA degradation or occupancy-based inhibition. An example of modulation of RNA target function by degradation is RNase H-based degradation of the target RNA upon hybridization with a DNA-like antisense compound.

[0004] Another example of modulation of gene expression by target degradation is RNA interference (RNAi). RNAi refers to antisense-mediated gene silencing through a mechanism that utilizes the RNA-induced silencing complex (RISC). An additional example of modulation of RNA target function is by an occupancy-based mechanism such as is employed naturally by microRNA. MicroRNAs are small non-coding RNAs that regulate the expression of protein-coding RNAs. The binding of an antisense compound to a microRNA prevents that microRNA from binding to its messenger RNA targets, and thus interferes with the function of the microRNA. MicroRNA mimics can enhance native microRNA function. Certain antisense compounds alter splicing of pre-mRNA. Another example of modulation of gene expression is the use of antisense compounds in a CRISPR system. Regardless of the specific mechanism, sequence-specificity makes antisense compounds attractive as tools for target validation and gene functionalization, as well as therapeutics to selectively modulate the expression of genes involved in the pathogenesis of disease.

[0005] Antisense technology is an effective means for modulating the expression of one or more specific gene products and can therefore prove to be uniquely useful in a number of therapeutic, diagnostic, and research applications. Chemically modified nucleosides may be incorporated into antisense compounds to enhance one or more properties, such as nuclease resistance, tolerability, pharmacokinetics, or affinity for a target nucleic acid.

[0006] The present disclosure provides oligomeric compounds (including oligomeric compounds that are antisense agents or portions thereof) comprising modified oligonucleotides consisting of linked nucleosides linked through internucleoside linking groups, wherein at least one of the internucleoside linking groups has Formula VIII:

[0007]

[0008] wherein independently for each internucleoside linking group of the modified oligonucleotide having Formula VIII:

[0009] R₁ is selected from H, C₁-C₆ alkyl, and substituted C₁-C₆ alkyl; and

[0010] T is selected from SO₂R₂, C(═O)R₃, and P(═O)R₄R₅, wherein:

• • [0011] R₂ is selected from an aryl, a substituted aryl, a heterocycle, a substituted heterocycle, an aromatic heterocycle, a substituted aromatic heterocycle, a diazole, a substituted diazole, a C₁-C₆ alkoxy, C₁-C₆ alkyl, and substituted C₁-C₆ alkyl;
  • [0012] R₃ is selected from an aryl, a substituted aryl, CH₃, N(CH₃)₂, and OCH₃;
  • [0013] R₄ is selected from OCH₃, OH, C₁-C₆ alkyl, and substituted C₁-C₆ alkyl; and
  • [0014] R₅ is selected from OCH₃, OH, C₁-C₆ alkyl, and substituted C₁-C₆ alkyl.

[0015] The present disclosure provides oligomeric compounds (including oligomeric compounds that are antisense agents or portions thereof) comprising modified oligonucleotides consisting of linked nucleosides linked through internucleoside linking groups, wherein at least one of the internucleoside linking groups has Formula VIII:

[0016]
wherein independently for each internucleoside linking group of the modified oligonucleotide having Formula VIII:

[0017] R₁ is selected from H, C₁-C₆ alkyl, and substituted C₁-C₆ alkyl; and

[0018] T is selected from SO₂R₂, C(═O)R₃, and P(═O)R₄R₅, wherein:

• • [0019] R₂ is selected from an aryl, a substituted aryl, a heterocycle, a substituted heterocycle, an aromatic heterocycle, a substituted aromatic heterocycle, a diazole, a substituted diazole, a C₁-C₆ alkoxy, a C₁-C₆ alkyl, and a substituted C₁-C₆ alkyl;
  • [0020] R₃ is selected from an aryl, a substituted aryl, CH₃, N(CH₃)₂, and OCH₃;
  • [0021] R₄ is selected from OCH₃, OH, C₁-C₆ alkyl, and substituted C₁-C₆ alkyl; and
  • [0022] R₅ is selected from OCH₃, OH, C₁-C₆ alkyl, and substituted C₁-C₆ alkyl;
    provided that if R₁ is H, then T is not:

[0023]

[0024] The present disclosure provides oligomeric compounds (including oligomeric compounds that are antisense agents or portions thereof) comprising modified oligonucleotides consisting of linked nucleosides linked through internucleoside linking groups, wherein at least one of the internucleoside linking groups has Formula XVII:

[0025]

[0026] wherein independently for each internucleoside linking group of the modified oligonucleotide having Formula XVII:

• • [0027] X is selected from O or S;
  • [0028] R₁ is selected from H, C₁-C₆ alkyl, and substituted C₁-C₆ alkyl; and
  • [0029] T is selected from SO₂R₂, C(═O)R₃, and P(═O)R₄R₅, wherein:
  • [0030] R₂ is selected from an aryl, a substituted aryl, a heterocycle, a substituted heterocycle, an aromatic heterocycle, a substituted aromatic heterocycle, a diazole, a substituted diazole, a C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ alkenyl, C₁-C₆ alkynyl, substituted C₁-C₆ alkyl, substituted C₁-C₆ alkenyl substituted C₁-C₆ alkynyl, and a conjugate group;
  • [0031] R₃ is selected from an aryl, a substituted aryl, CH₃, N(CH₃)₂, OCH₃ and a conjugate group;
  • [0032] R₄ is selected from OCH₃, OH, C₁-C₆ alkyl, substituted C₁-C₆ alkyl and a conjugate group; and
  • [0033] R₅ is selected from OCH₃, OH, C₁-C₆ alkyl, and substituted C₁-C₆ alkyl.

[0034] In certain embodiments, oligomeric compounds (including oligomeric compounds that are antisense agents or portions thereof) having at least one internucleoside linking group of Formula VIII or Formula XVII have an increased maximum tolerated dose when administered to an animal compared to an otherwise identical oligomeric compound, except that the otherwise identical oligomeric compound lacks the internucleoside linking group of Formula VIII or Formula XVII.

[0035] In certain embodiments, the modified oligonucleotides having at least one internucleoside linking group of Formula VIII or Formula XVII have an increased therapeutic index compared to an otherwise identical oligomeric compound, except that the otherwise identical oligomeric compound lacks the at least one internucleoside linking group of Formula VIII or Formula XVII.

[0039] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the embodiments, as claimed. Herein, the use of the singular includes the plural unless specifically stated otherwise. As used herein, the use of “or” means “and/or” unless stated otherwise. Furthermore, the use of the term “including” as well as other forms, such as “includes” and “included”, is not limiting.

[0040] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. All documents, or portions of documents, cited in this application, including, but not limited to, patents, patent applications, articles, books, treatises, and GenBank and NCBI reference sequence records are hereby expressly incorporated by reference for the portions of the document discussed herein, as well as in their entirety.

[0041] It is understood that the sequence set forth in each SEQ ID NO contained herein is independent of any modification to a sugar moiety, an internucleoside linkage, or a nucleobase. As such, compounds defined by a SEQ ID NO may comprise, independently, one or more modifications to a sugar moiety, an internucleoside linkage, or a nucleobase. Although the sequence listing accompanying this filing identifies each sequence as either “RNA” or “DNA” as required, in reality, those sequences may be modified with any combination of chemical modifications. One of skill in the art will readily appreciate that such designation as “RNA” or “DNA” to describe modified oligonucleotides is, in certain instances, arbitrary. For example, an oligonucleotide comprising a nucleoside comprising a 2′-OH(H) sugar moiety and a thymine base could be described as a DNA having a modified sugar (2′-OH in place of one 2′-H of DNA) or as an RNA having a modified base (thymine (methylated uracil) in place of an uracil of RNA). Accordingly, nucleic acid sequences provided herein, including, but not limited to those in the sequence listing, are intended to encompass nucleic acids containing any combination of natural or modified RNA and/or DNA, including, but not limited to such nucleic acids having modified nucleobases. By way of further example and without limitation, a modified oligonucleotide having the nucleobase sequence “ATCGATCG” encompasses any modified oligonucleotides having such nucleobase sequence, whether modified or unmodified, including, but not limited to, such compounds comprising RNA bases, such as those having sequence “AUCGAUCG” and those having some DNA bases and some RNA bases such as “AUCGATCG” and modified oligonucleotides having other modified nucleobases, such as “ATmCGAUCG,” wherein ^mC indicates a cytosine base comprising a methyl group at the 5-position.

[0042] As used herein, “2′-substituted” in reference to a furanosyl sugar moiety or nucleoside comprising a furanosyl sugar moiety means the furanosyl sugar moiety or nucleoside comprising the furanosyl sugar moiety comprises a substituent other than H or OH at the 2′-position and is a non-bicyclic furanosyl sugar moiety. 2′-substituted furanosyl sugar moieties do not comprise additional substituents at other positions of the furanosyl sugar moiety other than a nucleobase and/or internucleoside linkage(s) when in the context of an oligonucleotide.

[0043] As used herein, “4′-substituted” in reference to a furanosyl sugar moiety or nucleoside comprising a furanosyl sugar moiety means the furanosyl sugar moiety or nucleoside comprising the furanosyl sugar moiety comprises a substituent other than H at the 4′-position and is a non-bicyclic furanosyl sugar moiety. 4′-substituted furanosyl sugar moieties do not comprise additional substituents at other positions of the furanosyl sugar moiety other than a nucleobase and/or internucleoside linkage(s) when in the context of an oligonucleotide.

[0044] As used herein, “5′-substituted” in reference to a furanosyl sugar moiety or nucleoside comprising a furanosyl sugar moiety means the furanosyl sugar moiety or nucleoside comprising the furanosyl sugar moiety comprises a substituent other than H at the 5′-position and is a non-bicyclic furanosyl sugar moiety. 5′-substituted furanosyl sugar moieties do not comprise additional substituents at other positions of the furanosyl sugar moiety other than a nucleobase and/or internucleoside linkage(s) when in the context of an oligonucleotide.

[0045] As used herein, “administration” or “administering” refers to routes of introducing a compound or composition provided herein to a subject to perform its intended function. Examples of routes of administration that can be used include, but are not limited to, administration by inhalation, subcutaneous injection, intrathecal injection, and oral administration.

[0046] As used herein, “antisense activity” means any detectable and/or measurable change attributable to the hybridization of an antisense oligonucleotide to its target nucleic acid. In certain embodiments, antisense activity is a decrease in the amount or expression of a target nucleic acid or protein encoded by such target nucleic acid compared to target nucleic acid levels or target protein levels in the absence of the antisense oligonucleotide.

[0047] As used herein, “antisense agent” means an antisense oligonucleotide or an oligonucleotide duplex comprising an antisense oligonucleotide.

[0048] As used herein, “antisense compound” means an antisense oligonucleotide or an oligonucleotide duplex comprising an antisense oligonucleotide.

[0049] As used herein, “antisense oligonucleotide” means an oligonucleotide that is complementary to a target nucleic acid and is capable of achieving at least one antisense activity. Antisense oligonucleotides include but are not limited to RNAi antisense modified oligonucleotides and RNase H antisense modified oligonucleotides. In certain embodiments, an antisense oligonucleotide is paired with a sense oligonucleotide to form an oligonucleotide duplex. In certain embodiments, an antisense oligonucleotide is unpaired and is a single-stranded antisense oligonucleotide. In certain embodiments, an antisense oligonucleotide comprises a conjugate group.

[0050] As used herein, “artificial mRNA compound” is a modified oligonucleotide, or portion thereof, having a nucleobase sequence comprising one or more codons.

[0051] As used herein, “bicyclic nucleoside” or “BNA” means a nucleoside comprising a bicyclic sugar moiety. As used herein, “bicyclic sugar” or “bicyclic sugar moiety” means a modified sugar moiety comprising two rings, wherein the second ring is formed via a bridge connecting two of the atoms in the first ring thereby forming a bicyclic structure. In certain embodiments, the first ring of the bicyclic sugar moiety is a furanosyl moiety, and the bicyclic sugar moiety is a modified bicyclic furanosyl sugar moiety. In certain embodiments, the bicyclic sugar moiety does not comprise a furanosyl moiety.

[0052] As used herein, “cEt” or “constrained ethyl” or “cEt sugar moiety” means a bicyclic sugar moiety, wherein the first ring of the bicyclic sugar moiety is a ribosyl sugar moiety, the second ring of the bicyclic sugar is formed via a bridge connecting the 4′-carbon and the 2′-carbon, the bridge has the formula 4′-CH(CH₃)—O-2′, and the methyl group of the bridge is in the S configuration. A cEt bicyclic sugar moiety is in the β-D configuration.

[0053] As used herein, “complementary” in reference to an oligonucleotide means that at least 70% of the nucleobases of such oligonucleotide or one or more regions thereof and the nucleobases of another nucleic acid or one or more regions thereof are capable of hydrogen bonding with one another when the nucleobase sequence of the oligonucleotide and the other nucleic acid are aligned in opposing directions. Complementary nucleobases are nucleobase pairs that are capable of forming hydrogen bonds with one another. Complementary nucleobase pairs include adenine (A) and thymine (T), adenine (A) and uracil (U), cytosine (C) and guanine (G), 5-methyl cytosine (^mC) and guanine (G). Complementary oligonucleotides and/or nucleic acids need not have nucleobase complementarity at each nucleoside. Rather, some mismatches are tolerated. As used herein, “fully complementary” or “100% complementary” in reference to oligonucleotides means that such oligonucleotides are complementary to another oligonucleotide or nucleic acid at each nucleoside of the oligonucleotide.

[0054] As used herein, “conjugate group” means a group of atoms consisting of a conjugate moiety and a conjugate linker.

[0055] As used herein, “conjugate moiety” means a group of atoms that modifies one or more properties of a molecule compared to the identical molecule lacking the conjugate moiety, including but not limited to pharmacodynamics, pharmacokinetics, stability, binding, absorption, tissue distribution, cellular distribution, cellular uptake, charge and clearance.

[0056] As used herein, “conjugate linker” means a group of atoms comprising at least one bond.

[0057] As used herein, “CRISPR compound” means a modified oligonucleotide that comprises a DNA recognition portion and a tracrRNA recognition portion. As used herein, “DNA recognition portion” is nucleobase sequence that is complementary to a DNA target. As used herein, “tracrRNA recognition portion” is a nucleobase sequence that is bound to or is capable of binding to tracrRNA. The tracrRNA recognition portion of crRNA may bind to tracrRNA via hybridization or covalent attachment.

[0058] As used herein, “cytotoxic” or “cytotoxicity” in the context of an effect of an oligomeric compound or a parent oligomeric compound on cultured cells means an at least 2-fold increase in caspase activation following administration of 10 μM or less of the oligomeric compound or parent oligomeric compound to the cultured cells relative to cells cultured under the same conditions but that are not administered the oligomeric compound or parent oligomeric compound. In certain embodiments, cytotoxicity is measured using a standard in vitro cytotoxicity assay.

[0059] As used herein, “deoxy region” means a region of 5-12 contiguous nucleotides, wherein at least 70% of the nucleosides are stereo-standard DNA nucleosides. In certain embodiments, each nucleoside is selected from a stereo-standard DNA nucleoside (a nucleoside comprising a β-D-2′-deoxyribosyl sugar moiety), a stereo-non-standard nucleoside of Formula I-VII, a bicyclic nucleoside, and a substituted stereo-standard nucleoside. In certain embodiments, a deoxy region supports RNase H activity. In certain embodiments, a deoxy region is the gap of a gapmer.

[0060] As used herein, “double-stranded antisense compound” means an antisense compound comprising two oligomeric compounds that are complementary to each other and form a duplex, and wherein one of the two said oligomeric compounds comprises an antisense oligonucleotide.

[0061] As used herein, “expression” includes all the functions by which a gene's coded information is converted into structures present and operating in a cell. Such structures include, but are not limited to, the products of transcription and translation. As used herein, “modulation of expression” means any change in amount or activity of a product of transcription or translation of a gene. Such a change may be an increase or a reduction of any amount relative to the expression level prior to the modulation.

[0062] As used herein, “gapmer” means an oligonucleotide having a central region comprising a plurality of nucleosides that support RNase H cleavage positioned between a 5′-region and a 3′-region. Herein, the nucleosides of the 5′-region and 3′-region each comprise a 2′-substituted furanosyl sugar moiety or a bicyclic sugar moiety, and the 3′- and 5′-most nucleosides of the central region each comprise a sugar moiety independently selected from a 2′-deoxyfuranosyl sugar moiety or a sugar surrogate. The positions of the central region refer to the order of the nucleosides of the central region and are counted starting from the 5′-end of the central region. Thus, the 5′-most nucleoside of the central region is at position 1 of the central region. The “central region” may be referred to as a “gap”, and the “5′-region” and “3′-region” may be referred to as “wings”. Gaps of gapmers are deoxy regions.

[0063] As used herein, “hepatotoxic” in the context of a mouse means a plasma ALT level that is above 300 units per liter. Hepatotoxicity of an oligomeric compound or parent oligomeric compound that is administered to a mouse is determined by measuring the plasma ALT level of the mouse 24 hours to 2 weeks following at least one dose of 1-150 mg/kg of the compound.

[0064] As used herein, “hepatotoxic” in the context of a human means a plasma ALT level that is above 150 units per liter. Hepatotoxicity of an oligomeric compound or parent oligomeric compound that is administered to a human is determined by measuring the plasma ALT level of the human 24 hours to 2 weeks following at least one dose of 10-300 mg of the compound.

[0065] As used herein, “hybridization” means the pairing or annealing of complementary oligonucleotides and/or nucleic acids. While not limited to a particular mechanism, the most common mechanism of hybridization involves hydrogen bonding, which may be Watson-Crick, Hoogsteen or reversed Hoogsteen hydrogen bonding, between complementary nucleobases.

[0066] As used herein, “inhibiting the expression or activity” refers to a reduction or blockade of the expression or activity relative to the expression or activity in an untreated or control sample and does not necessarily indicate a total elimination of expression or activity.

[0067] As used herein, “internucleoside linkage” or “internucleoside linking group” means a group or bond that forms a covalent linkage between adjacent nucleosides in an oligonucleotide. As used herein “modified internucleoside linkage” means any internucleoside linkage other than a naturally occurring, phosphodiester internucleoside linkage. “Phosphorothioate linkage” means a modified internucleoside linkage in which one of the non-bridging oxygen atoms of a phosphodiester is replaced with a sulfur atom. Modified internucleoside linkages may or may not contain a phosphorus atom. A “neutral internucleoside linkage” is a modified internucleoside linkage that does not have a negatively charged phosphate in a buffered aqueous solution at pH=7.0. A modified internucleoside linkage may optionally comprise a conjugate group.

[0068] As used herein, “linked nucleosides” are nucleosides that are connected in a continuous sequence (i.e. no additional nucleosides are present between those that are linked).

[0069] As used herein, “maximum tolerated dose” means the highest dose of a compound that does not cause unacceptable side effects. In certain embodiments, the maximum tolerated dose is the highest dose of a modified oligonucleotide that does not cause an ALT elevation of three times the upper limit of normal as measured by a standard assay.

[0070] As used herein, “mismatch” or “non-complementary” means a nucleobase of a first oligonucleotide that is not complementary with the corresponding nucleobase of a second oligonucleotide or target nucleic acid when the first and second oligomeric compound are aligned.

[0071] As used herein, “modulating” refers to changing or adjusting a feature in a cell, tissue, organ or organism.

[0072] As used herein, “MOE” means O-methoxyethyl. “2′-MOE” or “2′-O-methoxyethyl” means a 2′-OCH₂CH₂OCH₃ group at the 2′-position of a furanosyl ring. In certain embodiments, the 2′-OCH₂CH₂OCH₃ group is in place of the 2′-OH group of a ribosyl ring or in place of a 2′-H in a 2′-deoxyribosyl ring. A “2′-MOE sugar moiety” is a sugar moiety with a 2′-OCH₂CH₂OCH₃ group in place of the 2′-OH group of a furanosyl sugar moiety. Unless otherwise indicated, a 2′-MOE sugar moiety is in the β-D ribosyl configuration.

[0073] As used herein, a “2′-OMe sugar moiety” is a sugar moiety with a 2′-CH₃ group in place of the 2′-OH group of a furanosyl sugar moiety. Unless otherwise indicated, a 2′-OMe sugar moiety is in the β-D ribosyl configuration and is a “stereo-standard 2′OMe sugar moiety”.

[0074] As used herein, a “2′-F sugar moiety” is a sugar moiety with a 2′-F group in place of the 2′-OH group of a furanosyl sugar moiety. Unless otherwise indicated, a 2′-F sugar moiety is in the β-D ribosyl configuration and is a “stereo-standard 2′-F sugar moiety”.

[0075] As used herein, “motif” means the pattern of unmodified and/or modified sugar moieties, nucleobases, and/or internucleoside linkages, in an oligonucleotide.

[0076] As used herein, “naturally occurring” means found in nature.

[0077] As used herein, “nucleobase” means an unmodified nucleobase or a modified nucleobase. As used herein an “unmodified nucleobase” is adenine (A), thymine (T), cytosine (C), uracil (U), or guanine (G). As used herein, a modified nucleobase is a group of atoms capable of pairing with at least one unmodified nucleobase. A universal base is a nucleobase that can pair with any one of the five unmodified nucleobases. 5-methylcytosine (^mC) is one example of a modified nucleobase.

[0078] As used herein, “nucleobase sequence” means the order of contiguous nucleobases in a nucleic acid or oligonucleotide independent of any sugar moiety or internucleoside linkage modification.

[0079] As used herein, “nucleoside” means a moiety comprising a nucleobase and a sugar moiety. The nucleobase and sugar moiety are each, independently, unmodified or modified. As used herein, “modified nucleoside” means a nucleoside comprising a modified nucleobase and/or a modified sugar moiety. A modified nucleoside may comprise a conjugate group.

[0080] As used herein, “oligomeric compound” means a compound consisting of (1) an oligonucleotide (a single-stranded oligomeric compound) or two oligonucleotides hybridized to one another (a double-stranded oligomeric compound); and (2) optionally one or more additional features, such as a conjugate group or terminal group which may be attached to the oligonucleotide of a single-stranded oligomeric compound or to one or both oligonucleotides of a double-stranded oligomeric compound.

[0081] As used herein, “oligonucleotide” means a strand of linked nucleosides connected via internucleoside linkages, wherein each nucleoside and internucleoside linkage may be modified or unmodified. Unless otherwise indicated, oligonucleotides consist of 12-3000 linked nucleosides, and optionally a conjugate group or terminal group. As used herein, “modified oligonucleotide” means an oligonucleotide, wherein at least one nucleoside or internucleoside linkage is modified. As used herein, “unmodified oligonucleotide” means an oligonucleotide that does not comprise any nucleoside modifications or internucleoside modifications.

[0082] As used herein, “parent antisense agent” means an antisense agent other than an RNAi agent that is identical to an antisense agent having at least one internucleoside linkage of Formula XVII, except that the parent antisense agent has a phosphorothioate internucleoside linkage in place of each internucleoside linkage of Formula XVII in the antisense agent having at least one internucleoside linkage of Formula XVII.

[0083] As used herein, “parent RNAi agent” means an RNAi agent that is identical to an RNAi agent having at least one internucleoside linkage of Formula XVII, except that the parent RNAi agent has a phosphodiester internucleoside linkage in place of each internucleoside linkage of Formula XVII in the RNAi agent having at least one internucleoside linkage of Formula XVII.

[0084] As used herein, “pharmaceutically acceptable carrier or diluent” means any substance suitable for use in administering to an animal. Certain such carriers enable pharmaceutical compositions to be formulated as, for example, liquids, powders, or suspensions that can be aerosolized or otherwise dispersed for inhalation by a subject. In certain embodiments, a pharmaceutically acceptable carrier or diluent is sterile water; sterile saline; or sterile buffer solution.

[0085] As used herein “pharmaceutically acceptable salts” means physiologically and pharmaceutically acceptable salts of compounds, such as oligomeric compounds (including oligomeric compounds that are antisense agents or portions thereof), i.e., salts that retain the desired biological activity of the compound and do not impart undesired toxicological effects thereto.

[0086] As used herein “pharmaceutical composition” means a mixture of substances suitable for administering to a subject. For example, a pharmaceutical composition may comprise an antisense compound and an aqueous solution.

[0087] As used herein, “RNAi agent” means an antisense agent that acts, at least in part, through RISC or Ago2 to modulate a target nucleic acid and/or protein encoded by a target nucleic acid. RNAi agents include, but are not limited to double-stranded siRNA, single-stranded RNA (ssRNA), and microRNA, including microRNA mimics. RNAi agents may comprise conjugate groups and/or terminal groups. In certain embodiments, an RNAi agent modulates the amount, activity, and/or splicing of a target nucleic acid. The term RNAi agent excludes antisense agents that act through RNase H.

[0088] As used herein, “RNAi oligonucleotide” means an RNAi antisense modified oligonucleotide or a RNAi sense modified oligonucleotide.

[0089] As used herein, “RNAi antisense modified oligonucleotide” means an oligonucleotide comprising a region that is complementary to a target sequence, and which includes at least one chemical modification suitable for RNAi.

[0090] As used herein, “RNAi antisense oligomeric compound” means a single-stranded oligomeric compound comprising a region that is complementary to a target sequence, and which includes at least one chemical modification suitable for RNAi.

[0091] As used herein, “RNAi sense modified oligonucleotide” means an oligonucleotide comprising a region that is complementary to a region of an RNAi antisense modified oligonucleotide, and which is capable of forming a duplex with such RNAi antisense modified oligonucleotide.

[0092] As used herein, “RNAi sense oligomeric compound” means a single-stranded oligomeric compound comprising a region that is complementary to a region of an RNAi antisense modified oligonucleotide and/or an RNAi antisense oligomeric compound, and which is capable of forming a duplex with such RNAi antisense modified oligonucleotide and/or RNAi antisense oligomeric compound.

[0093] A duplex formed by an RNAi antisense modified oligonucleotide and/or an RNAi antisense oligomeric compound with a RNAi sense modified oligonucleotide and/or an RNAi sense oligomeric compound is referred to as a double-stranded RNAi compound (dsRNAi) or a short interfering RNA (siRNA).

[0094] As used herein, “RNase H agent” means an antisense agent that acts, at least in part, through RNase H to modulate a target nucleic acid and/or protein encoded by a target nucleic acid. In certain embodiments, RNase H agents are single-stranded. In certain embodiments, RNase H agents are double-stranded. RNase H compounds may comprise conjugate groups and/or terminal groups. In certain embodiments, an RNase H agent modulates the amount or activity of a target nucleic acid. The term RNase H agent excludes antisense agents that act principally through RISC/Ago2.

[0095] As used herein, “RNase H antisense modified oligonucleotide” means an oligonucleotide comprising a region that is complementary to a target sequence, and which includes at least one chemical modification suitable for RNase H-mediated nucleic acid reduction.

[0096] As used herein, “RNAi compound” means an antisense compound that acts, at least in part, through RISC or Ago2 to modulate a target nucleic acid and/or protein encoded by a target nucleic acid. RNAi compounds include, but are not limited to double-stranded siRNA, single-stranded RNA (ssRNA), and microRNA, including microRNA mimics. In certain embodiments, an RNAi compound modulates the amount, activity, and/or splicing of a target nucleic acid. The term RNAi compound excludes antisense oligonucleotides that act through RNase H.

[0097] As used herein, the term “single-stranded” in reference to an antisense compound means such a compound consisting of one oligomeric compound that is not paired with a second oligomeric compound to form a duplex. “Self-complementary” in reference to an oligonucleotide means an oligonucleotide that at least partially hybridizes to itself. A compound consisting of one oligomeric compound, wherein the oligonucleotide of the oligomeric compound is self-complementary, is a single-stranded compound. A single-stranded antisense or oligomeric compound may be capable of binding to a complementary oligomeric compound to form a duplex, in which case the compound would no longer be single-stranded.

[0098] As used herein, “stabilized phosphate group” refers to a 5′-chemical moiety that results in stabilization of a 5′-phosphate moiety of the 5′-terminal nucleoside of an oligonucleotide, relative to the stability of an unmodified 5′-phosphate of an unmodified nucleoside under biologic conditions. Such stabilization of a 5′-phophate group includes but is not limited to resistance to removal by phosphatases. Stabilized phosphate groups include, but are not limited to, 5′-vinyl phosphonates and 5′-cyclopropyl phosphonate.

[0099] As used herein, “stereo-standard nucleoside” means a nucleoside comprising a non-bicyclic furanosyl sugar moiety having the configuration of naturally occurring DNA and RNA as shown below. A “stereo-standard DNA nucleoside” is a nucleoside comprising a β-D-2′-deoxyribosyl sugar moiety. A “stereo-standard RNA nucleoside” is a nucleoside comprising a β-D-ribosyl sugar moiety. A “substituted stereo-standard nucleoside” is a stereo-standard nucleoside other than a stereo-standard DNA or stereo-standard RNA nucleoside. In certain embodiments, R₁ is a 2′-substituent and R₂-R₅ are each H. In certain embodiments, the 2′-substituent is selected from OMe, F, OCH₂CH₂OCH₃, O-alkyl, SMe, or NMA. In certain embodiments, R₁-R₄ are H and R₅ is a 5′-substituent selected from methyl, allyl, or ethyl. In certain embodiments, the heterocyclic base moiety Bx is selected from uracil, thymine, cytosine, 5-methyl cytosine, adenine or guanine. In certain embodiments, the heterocyclic base moiety Bx is other than uracil, thymine, cytosine, 5-methyl cytosine, adenine or guanine.

[0100]

[0101] As used herein, “stereo-non-standard nucleoside” means a nucleoside comprising a non-bicyclic furanosyl sugar moiety having a configuration other than that of a stereo-standard sugar moiety. In certain embodiments, a “stereo-non-standard nucleoside” is represented by formulas I-VII below. In certain embodiments, J₁-J₁₄ are independently selected from H, OH, F, OCH₃, OCH₂CH₂OCH₃, O—C₁-C₆ alkoxy, and SCH₃. A “stereo-non-standard RNA nucleoside” has one of formulas I-VII below, wherein each of J₁, J₃, J₅, J₇, J₉, J₁₁, and J₁₃ is H, and each of J₂, J₄, J₆, J₈, J₁₀, J₁₂, and J₁₄ is OH. A “stereo-non-standard DNA nucleoside” has one of formulas I-VII below, wherein each J is H. A “2′-substituted stereo-non-standard nucleoside” has one of formulas I-VII below, wherein either J₁, J₃, J₅, J₇, J₉, J₁₁, and J₁₃ is other than H and/or or J₂, J₄, J₆, J₈, J₁₀, J₁₂, and J₁₄ is other than H or OH. In certain embodiments, the heterocyclic base moiety Bx is selected from uracil, thymine, cytosine, 5-methyl cytosine, adenine or guanine. In certain embodiments, the heterocyclic base moiety Bx is other than uracil, thymine, cytosine, 5-methyl cytosine, adenine or guanine.

[0102]

[0103] As used herein, “stereo-standard sugar moiety” means the sugar moiety of a stereo-standard nucleoside.

[0104] As used herein, “stereo-non-standard sugar moiety” means the sugar moiety of a stereo-non-standard nucleoside.

[0105] As used herein, “substituted stereo-non-standard nucleoside” means a stereo-non-standard nucleoside comprising a substituent other than the substituent corresponding to natural RNA or DNA. Substituted stereo-non-standard nucleosides include but are not limited to nucleosides of Formula I-VII wherein the J groups are other than: (1) both H or (2) one H and the other OH.

[0106] As used herein, “subject” means a human or non-human animal selected for treatment or therapy.

[0107] As used herein, “sugar moiety” means an unmodified sugar moiety or a modified sugar moiety. As used herein, “unmodified sugar moiety” means a β-D-ribosyl moiety, as found in naturally occurring RNA, or a β-D-2′-deoxyribosyl sugar moiety as found in naturally occurring DNA. As used herein, “modified sugar moiety” or “modified sugar” means a sugar surrogate or a furanosyl sugar moiety other than a β-D-ribosyl or a β-D-2′-deoxyribosyl. Modified furanosyl sugar moieties may be modified or substituted at a certain position(s) of the sugar moiety, or unsubstituted, and they may or may not be stereo-non-standard sugar moieties. Modified furanosyl sugar moieties include bicyclic sugars and non-bicyclic sugars. As used herein, “sugar surrogate” means a modified sugar moiety that does not comprise a furanosyl or tetrahydrofuranyl ring (is not a “furanosyl sugar moiety”) and that can link a nucleobase to another group, such as an internucleoside linkage, conjugate group, or terminal group in an oligonucleotide. Modified nucleosides comprising sugar surrogates can be incorporated into one or more positions within an oligonucleotide and such oligonucleotides are capable of hybridizing to complementary oligomeric compounds or nucleic acids.

[0108] As used herein, “target nucleic acid,” “target RNA,” “target RNA transcript” and “nucleic acid target” means a nucleic acid that an oligomeric compound, such as an antisense compound, is designed to affect. In certain embodiments, an oligomeric compound comprises an oligonucleotide having a nucleobase sequence that is complementary to more than one RNA, only one of which is the target RNA of the oligomeric compound. In certain embodiments, the target RNA is an RNA present in the species to which an oligomeric compound is administered.

[0109] As used herein, “therapeutic index” means a comparison of the amount of a compound that causes a therapeutic effect to the amount that causes toxicity. Compounds having a high therapeutic index have strong efficacy and low toxicity. In certain embodiments, increasing the therapeutic index of a compound increases the amount of the compound that can be safely administered.

[0110] As used herein, “treat” refers to administering a compound or pharmaceutical composition to an animal in order to effect an alteration or improvement of a disease, disorder, or condition in the animal.

[0111] As used herein, “translation suppression element,” means any sequence and/or secondary structure in the 5′-UTR of a target transcript that reduces, inhibits, and/or suppresses translation of the target transcript. In certain embodiments, a translation suppression element comprises a uORF. In certain embodiments, a translation suppression element does not comprise a uORF. In certain embodiments, a translation suppression element comprises one or more stem-loops. In certain embodiments, a translation suppression element comprises greater than 60%, greater than 70%, or greater than 80% GC content. In certain embodiments, the translation suppression element is a uORF. In certain embodiments, the translation suppression element is a stem-loop.

Certain Embodiments

[0112] The present disclosure provides the following non-limiting embodiments:

• [0113] Embodiment 1. An oligomeric compound comprising a modified oligonucleotide consisting of linked nucleosides linked through internucleoside linking groups, wherein at least one of the internucleoside linking groups has Formula VIII:

[0114]

[0115] wherein independently for each internucleoside linking group of the modified oligonucleotide having Formula VIII:

[0116] R₁ is selected from H, C₁-C₆ alkyl, and substituted C₁-C₆ alkyl; and

[0117] T is selected from SO₂R₂, C(═O)R₃, and P(═O)R₄R₅, wherein:

• • [0118] R₂ is selected from an aryl, a substituted aryl, a heterocycle, a substituted heterocycle, an aromatic heterocycle, a substituted aromatic heterocycle, a diazole, a substituted diazole, an amine, a substituted amine, C₁-C₆ alkoxy, C₁-C₆ alkyl, and substituted C₁-C₆ alkyl;
  • [0119] R₃ is selected from an aryl, a substituted aryl, CH₃, N(CH₃)₂, and OCH₃;
  • [0120] R₄ is selected from OCH₃, OH, C₁-C₆ alkyl, and substituted C₁-C₆ alkyl; and
  • [0121] R₅ is selected from OCH₃, OH, C₁-C₆ alkyl, and substituted C₁-C₆ alkyl.
• [0122] Embodiment 2. An oligomeric compound comprising a modified oligonucleotide consisting of linked nucleosides linked through internucleoside linking groups, wherein at least one of the internucleoside linking groups has Formula VIII:

[0123]

[0124] wherein independently for each internucleoside linking group of the modified oligonucleotide having Formula VIII:

[0125] R₁ is selected from H, C₁-C₆ alkyl, and substituted C₁-C₆ alkyl; and

[0126] T is selected from SO₂R₂, C(═O)R₃, and P(═O)R₄R₅, wherein:

• • [0127] R₂ is selected from an aryl, a substituted aryl, a heterocycle, a substituted heterocycle, an aromatic heterocycle, a substituted aromatic heterocycle, a diazole, a substituted diazole, a C₁-C₆ alkoxy, a C₁-C₆ alkyl, and a substituted C₁-C₆ alkyl;
  • [0128] R₃ is selected from an aryl, a substituted aryl, CH₃, N(CH₃)₂, and OCH₃;
  • [0129] R₄ is selected from OCH₃, OH, C₁-C₆ alkyl, and substituted C₁-C₆ alkyl; and
  • [0130] R₅ is selected from OCH₃, OH, C₁-C₆ alkyl, and substituted C₁-C₆ alkyl;
    provided that if R₁ is H, then T is not:

[0131]

• [0132] Embodiment 3. The oligomeric compound of embodiment 1 or 2, wherein R₁ is H.
• [0133] Embodiment 4. The oligomeric compound of embodiment 1 or 2, wherein R₁ is a C₁-C₆ alkyl.
• [0134] Embodiment 5. The oligomeric compound of embodiment 4, wherein R₁ is methyl.
• [0135] Embodiment 6. The oligomeric compound of embodiment 1 or 2, wherein R₁ is a substituted C₁-C₆ alkyl;
• [0136] Embodiment 7. The oligomeric compound of any of embodiments 1-6, wherein T is SO₂R₂.
• [0137] Embodiment 8. The oligomeric compound of embodiment 7, wherein R₂ is an aryl.
• [0138] Embodiment 9. The oligomeric compound of embodiment 7, wherein R₂ is a substituted aryl.
• [0139] Embodiment 10. The oligomeric compound of embodiment 7, wherein R₂ is a heterocycle.
• [0140] Embodiment 11. The oligomeric compound of embodiment 7, wherein R₂ is a substituted heterocycle.
• [0141] Embodiment 12. The oligomeric compound of embodiment 7, wherein R₂ is an aromatic heterocycle.
• [0142] Embodiment 13. The oligomeric compound of embodiment 7, wherein R₂ is a substituted aromatic heterocycle.
• [0143] Embodiment 14. The oligomeric compound of embodiment 7, wherein R₂ is a diazole.
• [0144] Embodiment 15. The oligomeric compound of embodiment 7, wherein R₂ is a substituted diazole.
• [0145] Embodiment 16. The oligomeric compound of embodiment 7, wherein R₂ is an amine.
• [0146] Embodiment 17. The oligomeric compound of embodiment 7, wherein R₂ is a substituted amine.
• [0147] Embodiment 18. The oligomeric compound of embodiment 7, wherein R₂ is a C₁-C₆ alkoxy.
• [0148] Embodiment 19. The oligomeric compound of embodiment 7, wherein R₂ is C₁-C₆ alkyl.
• [0149] Embodiment 20. The oligomeric compound of embodiment 7, wherein R₂ is substituted C₁-C₆ alkyl.
• [0150] Embodiment 21. The oligomeric compound of embodiment 7, wherein T is:

[0151]

• [0152] Embodiment 22. The oligomeric compound of embodiment 7, wherein T is:

[0153]

• [0154] Embodiment 23. The oligomeric compound of embodiment 7, wherein T is:

[0155]

• [0156] Embodiment 24. The oligomeric compound of embodiment 7, wherein T is:

[0157]

• [0158] Embodiment 25. The oligomeric compound of embodiment 7, wherein T is:

[0159]

• [0160] Embodiment 26. The oligomeric compound of embodiment 7, wherein T is:

[0161]

• [0162] Embodiment 27. The oligomeric compound of embodiment 7, wherein T is:

[0163]

• [0164] Embodiment 28. The oligomeric compound of embodiment 7, wherein T is:

[0165]

• [0166] Embodiment 29. The oligomeric compound of embodiment 7, wherein T is:

[0167]

• [0168] Embodiment 30. The oligomeric compound of any of embodiments 1-6, wherein T is C(═O)R₃.
• [0169] Embodiment 31. The oligomeric compound of embodiment 30, wherein R₃ is an aryl.
• [0170] Embodiment 32. The oligomeric compound of embodiment 30, wherein R₃ is a substituted aryl.
• [0171] Embodiment 33. The oligomeric compound of embodiment 30, wherein R₃ is CH₃.
• [0172] Embodiment 34. The oligomeric compound of embodiment 30, wherein R₃ is N(CH₃)₂.
• [0173] Embodiment 35. The oligomeric compound of embodiment 30, wherein R₃ is OCH₃.
• [0174] Embodiment 36. The oligomeric compound of embodiment 30, wherein T is:

[0175]

• [0176] Embodiment 37. The oligomeric compound of embodiment 30, wherein T is:

[0177]

• [0178] Embodiment 38. The oligomeric compound of embodiment 30, wherein T is:

[0179]

• [0180] Embodiment 39. The oligomeric compound of embodiment 30, wherein T is:

[0181]

• [0182] Embodiment 40. The oligomeric compound of any of embodiments 1-6, wherein T is P(═O)R₄R₅
• [0183] Embodiment 41. The oligomeric compound of embodiment 40, wherein R₄ is OCH₃.
• [0184] Embodiment 42. The oligomeric compound of embodiment 40, wherein R₄ is OH.
• [0185] Embodiment 43. The oligomeric compound of embodiment 40, wherein R₄ is C₁-C₆ alkyl.
• [0186] Embodiment 44. The oligomeric compound of embodiment 40, wherein R₄ is substituted C₁-C₆ alkyl.
• [0187] Embodiment 45. The oligomeric compound of any of embodiments 40-42, wherein R₅ is OCH₃.
• [0188] Embodiment 46. The oligomeric compound of any of embodiments 40-42, wherein R₅ is OH.
• [0189] Embodiment 47. The oligomeric compound of any of embodiments 40-42, wherein R₅ is C₁-C₆ alkyl.
• [0190] Embodiment 48. The oligomeric compound of any of embodiments 40-42, wherein R₅ is substituted C₁-C₆ alkyl.
• [0191] Embodiment 49. The oligomeric compound of embodiment 40, wherein T is:

[0192]

• [0193] Embodiment 50. The oligomeric compound of embodiment 40, wherein T is:

[0194]

• [0195] Embodiment 51. The oligomeric compound of any of embodiments 1-50, wherein at least one internucleoside linking group of the modified oligonucleotide is not a linking group of Formula VIII.
• [0196] Embodiment 52. The oligomeric compound of any of embodiments 1-50, wherein exactly one internucleoside linking group of the modified oligonucleotide is an internucleoside linking group of any of embodiments 1-50.
• [0197] Embodiment 53. The oligomeric compound of any of embodiments 1-50, wherein exactly two internucleoside linking groups of the modified oligonucleotide are internucleoside linking groups of any of embodiments 1-50.
• [0198] Embodiment 54. The oligomeric compound of any of embodiments 1-50, wherein exactly three internucleoside linking groups of the modified oligonucleotide are internucleoside linking groups of any of embodiments 1-50.
• [0199] Embodiment 55. The oligomeric compound of any of embodiments 1-50, wherein exactly four internucleoside linking groups of the modified oligonucleotide are internucleoside linking groups of any of embodiments 1-50.
• [0200] Embodiment 56. The oligomeric compound of any of embodiments 1-50, wherein exactly five internucleoside linking groups of the modified oligonucleotide are internucleoside linking groups of any of embodiments 1-50.
• [0201] Embodiment 57. The oligomeric compound of any of embodiments 1-50, wherein at least six internucleoside linking groups of the modified oligonucleotide are internucleoside linking groups of any of embodiments 1-50.
• [0202] Embodiment 58. The oligomeric compound of any of embodiment 1-51 or 53-57 having at least two linking groups of any of embodiments 1-50, wherein at least two of the linking groups of any of embodiments 1-50 are the same as one another.
• [0203] Embodiment 59. The oligomeric compound of any of embodiments 1-58, wherein each internucleoside linking group of the modified oligonucleotide that is not an internucleoside linking group of any of embodiments 1-50 is either a phosphodiester internucleoside linking group or a phosphorothioate internucleoside linking group.
• [0204] Embodiment 60. The oligomeric compound of any of embodiments 1-58, wherein each internucleoside linking group of the modified oligonucleotide is an internucleoside linking group of any of embodiments 1-50.
• [0205] Embodiment 61. The oligomeric compound of any of embodiments 1-60, wherein at least one nucleoside of the modified oligonucleotide is a modified nucleoside.
• [0206] Embodiment 62. The oligomeric compound of embodiment 61, wherein at least one nucleoside of the modified oligonucleotide is a modified nucleoside selected from a bicyclic nucleoside and a non-bicyclic substituted nucleoside.
• [0207] Embodiment 63. The oligomeric compound of any of embodiments 1-62, wherein at least one nucleoside of the modified oligonucleotide is selected from: a β-D-LNA nucleoside, an α-L-LNA nucleoside, an ENA nucleoside, a cEt nucleoside, a 2′-MOE nucleoside, a 2′-OMe nucleoside, a 2′-F nucleoside, a 2′-NMA nucleoside, a 5′-Me nucleoside, a DNA nucleoside, and an RNA nucleoside.
• [0208] Embodiment 64. The oligomeric compound of any of embodiments 1-62, wherein each nucleoside of the modified oligonucleotide is selected from: a β-D-LNA nucleoside, an α-L-LNA nucleoside, an ENA nucleoside, a cEt nucleoside, a 2′-MOE nucleoside, a 2′-OMe nucleoside, a 2′-F nucleoside, a 2′-NMA nucleoside, a 5′-Me nucleoside, a DNA nucleoside, and an RNA nucleoside.
• [0209] Embodiment 65. The oligomeric compound of any of embodiments 1-62, wherein at least one nucleoside of the modified oligonucleotide is selected from: a 2′-OMe nucleoside, a 2′-F nucleoside, and an RNA nucleoside.
• [0210] Embodiment 66. The oligomeric compound of any of embodiments 1-62, wherein at least one nucleoside of the modified oligonucleotide is a 2′-OMe nucleoside, and at least one nucleoside of the modified oligonucleotide is an RNA nucleoside.
• [0211] Embodiment 67. The oligomeric compound of any of embodiments 61-66, wherein the modified oligonucleotide has a region of alternating nucleoside types having the motif ABABA, wherein each A is a stereo-standard nucleoside of a first type and each B is a stereo-standard nucleoside of a second type, wherein the first type and the second type are different from one another.
• [0212] Embodiment 68. The oligomeric compound of embodiment 67, wherein A and B are selected from 2′-F substituted nucleosides, 2′-OMe substituted nucleosides, and stereo-standard RNA nucleosides.
• [0213] Embodiment 69. The oligomeric compound of any of embodiments 1-68, wherein the 5′-end of the modified oligonucleotide comprises a stabilized phosphate group.
• [0214] Embodiment 70. The oligomeric compound of any of embodiments 1-69, wherein the modified oligonucleotide consists of 12-30 linked nucleosides.
• [0215] Embodiment 71. The oligomeric compound of any of embodiments 1-69, wherein the modified oligonucleotide consists of 16-24 linked nucleosides.
• [0216] Embodiment 72. The oligomeric compound of any of embodiments 1-69, wherein the modified oligonucleotide consists of 18-22 linked nucleosides.
• [0217] Embodiment 73. The oligomeric compound of any of embodiments 1-69, wherein the modified oligonucleotide consists of 16 linked nucleosides.
• [0218] Embodiment 74. The oligomeric compound of any of embodiments 1-69, wherein the modified oligonucleotide consists of 17 linked nucleosides.
• [0219] Embodiment 75. The oligomeric compound of any of embodiments 1-69, wherein the modified oligonucleotide consists of 18 linked nucleosides.
• [0220] Embodiment 76. The oligomeric compound of any of embodiments 1-69, wherein the modified oligonucleotide consists of 19 linked nucleosides.
• [0221] Embodiment 77. The oligomeric compound of any of embodiments 1-69, wherein the modified oligonucleotide consists of 20 linked nucleosides.
• [0222] Embodiment 78. The oligomeric compound of any of embodiments 1-69, wherein the modified oligonucleotide consists of 21 linked nucleosides.
• [0223] Embodiment 79. The oligomeric compound of any of embodiments 1-69, wherein the modified oligonucleotide consists of 22 linked nucleosides.
• [0224] Embodiment 80. The oligomeric compound of any of embodiments 1-69, wherein the modified oligonucleotide consists of 23 linked nucleosides.
• [0225] Embodiment 81. The oligomeric compound of any of embodiments 1-80, wherein the oligomeric compound is an RNAi compound.
• [0226] Embodiment 82. The oligomeric compound of embodiment 81, wherein the RNAi compound is a single-stranded RNAi compound comprising an RNAi antisense modified oligonucleotide, wherein the RNAi antisense modified compound is a modified oligonucleotide of any of embodiments 1-78.
• [0227] Embodiment 83. The oligomeric compound of embodiment 81, wherein the RNAi compound is a double-stranded RNAi compound comprising an RNAi antisense modified oligonucleotide and an RNAi sense modified oligonucleotide, wherein the RNAi antisense modified oligonucleotide and/or the RNAi sense modified oligonucleotide is a modified oligonucleotide of any of embodiments 1-78.
• [0228] Embodiment 84. The oligomeric compound of embodiment 82 or 83, wherein at least one internucleoside linking group of the RNAi antisense modified oligonucleotide is an internucleoside linking group of any of embodiments 1-50.
• [0229] Embodiment 85. The oligomeric compound of embodiment 82 or 83, wherein at least two internucleoside linking groups of the RNAi antisense modified oligonucleotide are independently selected internucleoside linking groups of any of embodiments 1-50.
• [0230] Embodiment 86. The oligomeric compound of any of embodiments 82-85, wherein at least one of the five 3′-most internucleoside linking groups of the RNAi antisense modified oligonucleotide is an internucleoside linking group of any of embodiments 1-50.
• [0231] Embodiment 87. The oligomeric compound of any of embodiments 82-86, wherein at least two of the five 3′-most internucleoside linking groups of RNAi antisense modified oligonucleotide is an internucleoside linking group of any of embodiments 1-50.
• [0232] Embodiment 88. The oligomeric compound of any of embodiments 82-87, wherein at least one internucleoside linking group within the seed region of the RNAi antisense modified oligonucleotide is an internucleoside linking group of any of embodiments 1-50.
• [0233] Embodiment 89. The oligomeric compound of embodiment 83-88, wherein at least one internucleoside linking group of the RNAi sense modified oligonucleotide is an internucleoside linking group of any of embodiments 1-50.
• [0234] Embodiment 90. The oligomeric compound of embodiment 89, wherein at least one of the first 5 internucleoside linking groups from the 5′-end of the RNAi sense modified oligonucleotide is an internucleoside linking group of any of embodiments 1-50.
• [0235] Embodiment 91. The oligomeric compound of any of embodiments 89-90, wherein at least one of the five 3′-most 1 internucleoside linking groups of the RNAi sense modified oligonucleotide is an internucleoside linking group of any of embodiments 1-50.
• [0236] Embodiment 92. The oligomeric compound of any of embodiments 89-91, wherein at least one of the first 5 internucleoside linking groups from the 5′-end of the RNAi sense modified oligonucleotide and at least one of the five 3′-most linking groups of the RNAi sense modified oligonucleotide is an internucleoside linking group of any of embodiments 1-50.
• [0237] Embodiment 93. The oligomeric compound of any of embodiments 1-92, wherein at least one nucleoside of the modified oligonucleotide is a stereo-non-standard nucleoside.
• [0238] Embodiment 94. The oligomeric compound of embodiment 93, wherein the internucleoside linking group linking at least one stereo-non-standard nucleoside to an adjacent nucleoside is an internucleoside linking group of any of embodiments 1-50.
• [0239] Embodiment 95. The oligomeric compound of embodiment 93 or 94, wherein at least two nucleosides of the modified oligonucleotide are stereo-non-standard nucleosides.
• [0240] Embodiment 96. The oligomeric compound of embodiment 95, wherein at least two stereo-non-standard nucleosides of the modified oligonucleotide are adjacent to one another.
• [0241] Embodiment 97. The oligomeric compound of embodiment 96, wherein at least two stereo-non-standard nucleosides of the modified oligonucleotide are linked to one another with an internucleoside linking group of any of embodiments 1-50.
• [0242] Embodiment 98. The oligomeric compound of any of embodiments 95-97, wherein at least one stereo-non-standard nucleoside of the modified oligonucleotide is a stereo-non-standard DNA nucleoside.
• [0243] Embodiment 99. The oligomeric compound of any of embodiments 95-97, wherein at least one stereo-non-standard nucleoside of the modified oligonucleotide is a substituted stereo-non-standard nucleoside or a stereo-non-standard RNA nucleoside.
• [0244] Embodiment 100. The oligomeric compound of embodiment 99, wherein the 2′-substituent of the at least one substituted stereo-non-standard nucleoside of the modified oligonucleotide is selected from: 2′-MOE, 2′-OMe, 2′-F, or 2′-OH.
• [0245] Embodiment 101. The oligomeric compound of any of embodiments 1-100, wherein the modified oligonucleotide comprises a deoxy region consisting of 6-11 linked nucleosides wherein each nucleoside of the deoxy region is either a modified nucleoside or a stereo-standard DNA nucleoside and wherein at least 3 contiguous nucleosides of the deoxy region are stereo-standard DNA nucleosides and not more than three nucleosides of the deoxy region are modified nucleosides.
• [0246] Embodiment 102. The oligomeric compound of embodiment 101, wherein at least 4 contiguous nucleosides of the deoxy region are stereo-standard DNA nucleosides.
• [0247] Embodiment 103. The oligomeric compound of embodiment 101, wherein at least 5 contiguous nucleosides of the deoxy region are stereo-standard DNA nucleosides.
• [0248] Embodiment 104. The oligomeric compound of embodiment 101, wherein at least 6 contiguous nucleosides of the deoxy region are stereo-standard DNA nucleosides.
• [0249] Embodiment 105. The oligomeric compound of embodiment 101, wherein at least 7 contiguous nucleosides of the deoxy region are stereo-standard DNA nucleosides.
• [0250] Embodiment 106. The oligomeric compound of embodiment 101, wherein at least 8 contiguous nucleosides of the deoxy region are stereo-standard DNA nucleosides.
• [0251] Embodiment 107. The oligomeric compound of any of embodiments 101-106, wherein the deoxy region consists of 8-10 linked nucleosides.
• [0252] Embodiment 108. The oligomeric compound of any of embodiments 101-106, wherein the deoxy region consists of 9 linked nucleosides.
• [0253] Embodiment 109. The oligomeric compound of any of embodiments 101-106, wherein the deoxy region consists of 10 linked nucleosides.
• [0254] Embodiment 110. The oligomeric compound of any of embodiments 101-106, wherein the deoxy region consists of 11 linked nucleosides.
• [0255] Embodiment 111. The oligomeric compound of any of embodiments 101-110 wherein at least 6 nucleosides of the deoxy region are stereo-standard DNA nucleosides.
• [0256] Embodiment 112. The oligomeric compound of any of embodiments 101-110 wherein at least 7 nucleosides of the deoxy region are stereo-standard DNA nucleosides.
• [0257] Embodiment 113. The oligomeric compound of any of embodiments 101-110 wherein at least 8 nucleosides of the deoxy region are stereo-standard DNA nucleosides.
• [0258] Embodiment 114. The oligomeric compound of any of embodiments 101-110 wherein at least 9 nucleosides of the deoxy region are stereo-standard DNA nucleosides.
• [0259] Embodiment 115. The oligomeric compound of any of embodiments 101-114 wherein two nucleosides of the deoxy region are modified nucleosides.
• [0260] Embodiment 116. The oligomeric compound of any of embodiments 101-114 wherein one nucleoside of the deoxy region is a modified nucleoside.
• [0261] Embodiment 117. The oligomeric compound of any of embodiments 101-116 wherein at least one modified nucleoside of the deoxy region is a stereo-standard modified nucleoside or bicyclic nucleoside selected from a β-D-LNA nucleoside, an α-L-LNA nucleoside, an ENA nucleoside, a cEt nucleoside, a 2′-MOE nucleoside, a 2′-OMe nucleoside, a 2′-F nucleoside, and a 5′-alkyl nucleoside.
• [0262] Embodiment 118. The oligomeric compound of any of embodiments 101-117 wherein at least one modified nucleoside of the deoxy region is stereo-non-standard nucleoside.
• [0263] Embodiment 119. The oligomeric compound of embodiment 118 wherein the at least one is stereo-non-standard isomeric nucleoside of the deoxy region is a stereo-non-standard DNA nucleoside.
• [0264] Embodiment 120. The oligomeric compound of embodiment 119 wherein the stereo-non-standard DNA nucleoside is selected from a stereo-non-standard DNA nucleoside having: Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, and Formula VII.
• [0265] Embodiment 121. The oligomeric compound of embodiment 120 wherein the stereo-non-standard DNA nucleoside is selected from a stereo-non-standard DNA nucleoside having: Formula V and Formula II.
• [0266] Embodiment 122. The oligomeric compound of any of embodiments 118-121 wherein at least one stereo-non-standard nucleoside of the deoxy region is a substituted stereo-non-standard nucleoside.
• [0267] Embodiment 123. The oligomeric compound of embodiment 122 wherein at least one substituted stereo-non-standard nucleoside has a 2′-substituent selected from: 2′-MOE, 2′-OMe, 2′-F, or 2′-OH.
• [0268] Embodiment 124. The oligomeric compound of any of embodiments 101-123, wherein the 2^nd nucleoside from the 5′-end of the deoxy region is a modified nucleoside.
• [0269] Embodiment 125. The oligomeric compound of any of embodiments 101-124, wherein the 3^rd nucleoside from the 5′-end of the deoxy region is a modified nucleoside.
• [0270] Embodiment 126. The oligomeric compound of any of embodiments 101-125, wherein the 4^th nucleoside from the 5′-end of the deoxy region is a modified nucleoside.
• [0271] Embodiment 127. The oligomeric compound of any of embodiments 101-126, wherein each nucleoside of the deoxy region is a stereo-standard DNA nucleoside.
• [0272] Embodiment 128. The oligomeric compound of any of embodiments 101-127 wherein at least one internucleoside linking group within the deoxy region is an internucleoside linking group of any of embodiments 1-50.
• [0273] Embodiment 129. The oligomeric compound of any of embodiments 101-128, wherein the internucleoside linking group linking the 1^st and 2^nd nucleosides of the deoxy region as counted from the 5′-end of the deoxy region is an internucleoside linking group of any of embodiments 1-50.
• [0274] Embodiment 130. The oligomeric compound of any of embodiments 101-129, wherein the internucleoside linking group linking the 2^nd and 3^rd nucleosides of the deoxy region as counted from the 5′-end of the deoxy region is an internucleoside linking group of any of embodiments 1-50.
• [0275] Embodiment 131. The oligomeric compound of any of embodiments 101-130, wherein the internucleoside linking group linking the 3^rd and 4^th nucleosides of the deoxy region as counted from the 5′-end of the deoxy region is an internucleoside linking group of any of embodiments 1-50.
• [0276] Embodiment 132. The oligomeric compound of any of embodiments 101-131, wherein the internucleoside linking group linking the 4^th and 5^th nucleosides of the deoxy region as counted from the 5′-end of the deoxy region is an internucleoside linking group of any of embodiments 1-50.
• [0277] Embodiment 133. The oligomeric compound of any of embodiments 101-132 wherein one internucleoside linking group in the deoxy region is a linking group of any of embodiments 1-50 and the other internucleoside linking groups of the deoxy region are each phosphodiester or phosphorothioate internucleoside linking groups.
• [0278] Embodiment 134. The oligomeric compound of any of embodiments 101-133 wherein two internucleoside linking groups in the deoxy region are linking groups of any of embodiments 1-50 and the other internucleoside linking groups of the deoxy region are each phosphodiester or phosphorothioate internucleoside linking groups.
• [0279] Embodiment 135. The oligomeric compound of any of embodiments 101-134 wherein three internucleoside linking groups in the deoxy region are linking groups of any of embodiments 1-50 and the other internucleoside linking groups of the deoxy region are each phosphodiester or phosphorothioate internucleoside linking groups.
• [0280] Embodiment 136. The oligomeric compound of any of embodiments 101-135 wherein the deoxy region is flanked on the 5′ side by a 5′-region consisting of 1-6 linked 5′-region nucleosides and on the 3′ side by a 3′-region consisting of 1-6 linked 3′-region nucleosides; wherein

[0281] the 3′-most nucleoside of the 5′-region is a modified nucleoside; and

[0282] the 5′-most nucleoside of the 3′-region is a modified nucleoside.

• [0283] Embodiment 137. The oligomeric compound of embodiment 136, wherein at least one 5′-region nucleoside is a stereo-standard DNA nucleoside.
• [0284] Embodiment 138. The oligomeric compound of embodiment 136, wherein each 5′-region nucleoside is a modified nucleoside.
• [0285] Embodiment 139. The oligomeric compound of any of embodiments 136, wherein at least one 5′-region nucleoside is a 2′-substituted nucleoside.
• [0286] Embodiment 140. The oligomeric compound of any of embodiments 136, or 138-139 wherein each 5′-region nucleoside is a 2′-substituted nucleoside.
• [0287] Embodiment 141. The oligomeric compound of any of embodiments 139-140, wherein the 2′-substitutent is selected from among 2′-F, 2′-OCH₃, and 2′-MOE.
• [0288] Embodiment 142. The oligomeric compound of any of embodiments 136-139 or 141, wherein at least one 5′-region nucleoside is a bicyclic nucleoside.
• [0289] Embodiment 143. The oligomeric compound of embodiment 142, wherein each 5′-region nucleoside is a bicyclic nucleoside.
• [0290] Embodiment 144. The oligomeric compound of any of embodiments 142-143, wherein the bicyclic 5′-region nucleoside is selected from among a β-D-LNA nucleoside, an α-L-LNA nucleoside, an ENA nucleoside, and a cEt nucleoside.
• [0291] Embodiment 145. The oligomeric compound of any of embodiments embodiment 136-144, wherein at least one 3′-region nucleoside is a stereo-standard DNA nucleoside.
• [0292] Embodiment 146. The oligomeric compound of any of embodiments 136-144 wherein each 3′-region nucleoside is a modified nucleoside.
• [0293] Embodiment 147. The oligomeric compound of any of embodiments 136-146, wherein at least one 3′-region nucleoside is a 2′-substituted nucleoside.
• [0294] Embodiment 148. The oligomeric compound of any of embodiments 136-144 or 146-147, wherein each 3′-region nucleoside is a 2′-substituted nucleoside.
• [0295] Embodiment 149. The oligomeric compound of embodiment 147 or 148, wherein the 2′-substituent is selected from among 2′-F, 2′-OCH₃, and 2′-MOE.
• [0296] Embodiment 150. The oligomeric compound of any of embodiments 136-147 or 149, wherein at least one 3′-region nucleoside is a bicyclic nucleoside.
• [0297] Embodiment 151. The oligomeric compound of embodiment 150, wherein each 3′-region nucleoside is a bicyclic nucleoside.
• [0298] Embodiment 152. The oligomeric compound of any of embodiments 150-151 wherein the bicyclic 3′-region nucleoside is selected from among a β-D-LNA nucleoside, an α-L-LNA nucleoside, an ENA nucleoside, and a cEt nucleoside.
• [0299] Embodiment 153. The oligomeric compound of any of embodiments 101-152 wherein the modified oligonucleotide is a gapmer.
• [0300] Embodiment 154. The oligomeric compound of any of embodiments 1-80 wherein each nucleoside of the modified oligonucleotide is a modified nucleoside and each modified nucleoside of the modified oligonucleotide comprises the same modification.
• [0301] Embodiment 155. The oligomeric compound of any of embodiments 1-153, wherein the nucleobase sequence of the modified oligonucleotide is complementary to a target nucleic acid.
• [0302] Embodiment 156. The oligomeric compound of embodiment 155, wherein the nucleobase sequence of the modified oligonucleotide is at least 80% complementary to the target nucleic acid.
• [0303] Embodiment 157. The oligomeric compound of embodiment 155, wherein the nucleobase sequence of the modified oligonucleotide is at least 85% complementary to the target nucleic acid.
• [0304] Embodiment 158. The oligomeric compound of embodiment 155, wherein the nucleobase sequence of the modified oligonucleotide is at least 90% complementary to the target nucleic acid.
• [0305] Embodiment 159. The oligomeric compound of embodiment 155, wherein the nucleobase sequence of the modified oligonucleotide is at least 95% complementary to the target nucleic acid.
• [0306] Embodiment 160. The oligomeric compound of embodiment 155, wherein the nucleobase sequence of the modified oligonucleotide is 100% complementary to the target nucleic acid.
• [0307] Embodiment 161. The oligomeric compound of any of embodiments 155-160, wherein the target nucleic acid is a target RNA.
• [0308] Embodiment 162. The oligomeric compound of embodiment 161, wherein the target RNA is selected from: an mRNA, a pre-mRNA, a microRNA, and a non-coding RNA.
• [0309] Embodiment 163. The oligomeric compound of embodiment 161, wherein the target RNA is not a microRNA.
• [0310] Embodiment 164. The oligomeric compound of any of embodiments 1-162, wherein the modified oligonucleotide is not complementary to miR-21.
• [0311] Embodiment 165. The oligomeric compound of any of embodiments 1-163, comprising a conjugate group.
• [0312] Embodiment 166. The oligomeric compound of embodiment 164, wherein the conjugate group comprises at least one GalNAc.
• [0313] Embodiment 167. The oligomeric compound of embodiment 164 or 165, wherein the conjugate group comprises 1-5 linker-nucleosides.
• [0314] Embodiment 168. The oligomeric compound of any of embodiments 1-80, wherein the oligomeric compound is a CRISPR compound.
• [0315] Embodiment 169. The oligomeric compound of embodiment 168, wherein the CRISPR compound consists of 20-50 linked nucleosides.
• [0316] Embodiment 170. The oligomeric compound of embodiment 168, wherein the CRISPR compound consists of 29-32 linked nucleosides.
• [0317] Embodiment 171. A pharmaceutical composition comprising the CRISPR compound of embodiments 169-170 and a pharmaceutically acceptable carrier or diluent.
• [0318] Embodiment 172. A method comprising contacting a cell with the CRISPR compound or composition of any of embodiments 169-170.
• [0319] Embodiment 173. The method of embodiment 172, comprising contacting the cell with a plasmid that encodes Cas9 or Cpf1.
• [0320] Embodiment 174. The method of embodiment 172-173, wherein the plasmid encodes a tracrRNA.
• [0321] Embodiment 175. The method of embodiment 174, comprising contacting the cell with an mRNA that encodes Cas9 or Cpf1.
• [0322] Embodiment 176. The method of any of embodiments 172-175, comprising contacting the cell with a plasmid that encodes a tracrRNA.
• [0323] Embodiment 177. The method of any of embodiments 172-176 wherein a target gene is edited.
• [0324] Embodiment 178. The oligomeric compound of any of embodiments 1-80, wherein the oligomeric compound is an artificial mRNA compound.
• [0325] Embodiment 179. The artificial mRNA compound of embodiment 178, wherein the artificial mRNA oligonucleotide consists of 17-3000 linked nucleosides.
• [0326] Embodiment 180. The artificial mRNA compound of embodiment 178 or 179, wherein the artificial mRNA oligonucleotide encodes a protein.
• [0327] Embodiment 181. A pharmaceutical composition comprising the artificial mRNA compound of any of embodiments 178-180 and a pharmaceutically acceptable carrier or diluent.
• [0328] Embodiment 182. A method comprising contacting a cell with the artificial mRNA compound or composition of any of embodiments 178-181.
• [0329] Embodiment 183. A pharmaceutical composition comprising the oligomeric compound of any of embodiments 1-182 and a pharmaceutically acceptable carrier or diluent.
• [0330] Embodiment 184. A method comprising contacting a cell with the oligomeric compound or pharmaceutical composition of any of embodiments 1-167 or 183.
• [0331] Embodiment 185. A method of modulating the amount or activity of a target nucleic acid in a cell, comprising contacting the cell with the oligomeric compound or pharmaceutical composition of any of embodiments 1-167 or 183, and thereby modulating the amount or activity of the target nucleic acid.
• [0332] Embodiment 186. A method of modulating the amount or activity of a target nucleic acid in a cell, comprising contacting the cell with the oligomeric compound or pharmaceutical composition of any of embodiments 1-167 or 183.
• [0333] Embodiment 187. The method of embodiment 186, wherein the amount or activity of a target nucleic acid is reduced.
• [0334] Embodiment 188. Use of the oligomeric compound or composition of any of embodiments 1-171, 178-181 or 183 for treatment of a disease or condition.
• [0335] Embodiment 189. Use of the oligomeric compound or composition of any of embodiments 1-171, 178-181 or 183 for a preparation of a medicament for treatment of a disease or condition.
• [0336] Embodiment 190. An oligomeric compound comprising a modified oligonucleotide consisting of 12-23 linked nucleosides, wherein the modified oligonucleotide comprises a 5′-region, a central region, and a 3′-region wherein:

[0337] the 5′-region consists of 1-5 linked nucleosides; wherein at least one 5′-region nucleoside is modified;

[0338] the 3′-region consists of 1-5 linked nucleosides; wherein at least one 3′-region nucleoside is modified; and

[0339] the central region consists of/7-11 linked nucleosides, and has the formula:
(N_d1)_L1(N_d2)_L2(N_d3)_L3(N_d4)_L4[(N_d)_L5]_q,

[0340] wherein N_d1, N_d2, N_d3, N_d4 are independently selected from among

[0341] a stereo-standard DNA nucleoside, a stereo-non-standard DNA nucleoside, or a 2′-substituted nucleoside; with

[0342] the proviso that no more than one of N_d1, N_d2, N_d3, or N_d4 is a 2′-substituted nucleoside;

[0343] each N_d is independently selected from among a stereo-standard DNA nucleoside and a stereo-non-standard DNA nucleoside;

[0344] q is from 3-8;

[0345] wherein each of L₁, L₂, L₃, L₄, and each L₅ is an internucleoside linkage;

[0346] wherein at least two of L₁, L₂, L₃, and L₄ are internucleoside linkages having formula VIII:

[0347]

[0348] wherein independently for each internucleoside linking group of the modified oligonucleotide having Formula VIII:

[0349] R₁ is selected from H, C₁-C₆ alkyl, and substituted C₁-C₆ alkyl; and

[0350] T is selected from SO₂R₂, C(═O)R₃, and P(═O)R₄R₅, wherein:

• • [0351] R₂ is selected from an aryl, a substituted aryl, a heterocycle, a substituted heterocycle, an aromatic heterocycle, a substituted aromatic heterocycle, a diazole, a substituted diazole, an amine, a substituted amine, C₁-C₆ alkoxy, C₁-C₆ alkyl, and substituted C₁-C₆ alkyl;
  • [0352] R₃ is selected from an aryl, a substituted aryl, CH₃, N(CH₃)₂, and OCH₃;
  • [0353] R₄ is selected from OCH₃, OH, C₁-C₆ alkyl, and substituted C₁-C₆ alkyl; and
  • [0354] R₅ is selected from OCH₃, OH, C₁-C₆ alkyl, and substituted C₁-C₆ alkyl.
• [0355] Embodiment 191. The oligomeric compound of embodiment 190, wherein one of N_d1, N_d2, N_d3, or N_d4 is a 2′-substituted nucleoside.
• [0356] Embodiment 192. The oligomeric compound of embodiment 191, wherein the 2′-substituted nucleoside is a 2′-OMe nucleoside.
• [0357] Embodiment 193. The oligomeric compound of embodiment 191, wherein the 2′-OMe nucleoside is a stereo-standard 2′-OMe nucleoside.
• [0358] Embodiment 194. The oligomeric compound of any of embodiments 191-193, wherein the 2′-substituted nucleoside is N_d2.
• [0359] Embodiment 195. The oligomeric compound of embodiment 190, wherein each of N_d1, N_d2, N_d3, N_d4 and each N_d is a DNA nucleoside.
• [0360] Embodiment 196. The oligomeric compound of embodiment 195, wherein each DNA nucleoside is a stereo-standard DNA nucleoside.
• [0361] Embodiment 197. The oligomeric compound of any of embodiments 190-196, wherein L₁ and L₂ are internucleoside linkages having formula VIII.
• [0362] Embodiment 198. The oligomeric compound of any of embodiments 190-196, wherein L₂ and L₃ are internucleoside linkages having formula VIII.
• [0363] Embodiment 199. The oligomeric compound of any of embodiments 190-196, wherein L₃ and L₄ are internucleoside linkages having formula VIII.
• [0364] Embodiment 200. The oligomeric compound of any of embodiments 190-196, wherein L₁, L₂, and L₃ are internucleoside linkages having formula VIII.
• [0365] Embodiment 201. The oligomeric compound of any of embodiments 190-196, wherein L₂, L₃, and L₄, are internucleoside linkages having formula VIII.
• [0366] Embodiment 202. The oligomeric compound of any of embodiments 190-196, wherein L₁, L₂, L₃, and L₄ are internucleoside linkages having formula VIII.
• [0367] Embodiment 203. The oligomeric compound of any of embodiments 190-202, wherein R₁ is H.
• [0368] Embodiment 204. The oligomeric compound of any of embodiments 190-202, wherein R₁ is a C₁-C₆ alkyl.
• [0369] Embodiment 205. The oligomeric compound of embodiment 204, wherein R₁ is methyl.
• [0370] Embodiment 206. The oligomeric compound of any of embodiments 190-202, wherein R₁ is a substituted C₁-C₆ alkyl; Embodiment 207. The oligomeric compound of any of embodiments 190-206, wherein T is SO₂R₂.
• [0371] Embodiment 208. The oligomeric compound of embodiment 207, wherein R₂ is an aryl.
• [0372] Embodiment 209. The oligomeric compound of embodiment 207, wherein R₂ is a substituted aryl.
• [0373] Embodiment 210. The oligomeric compound of embodiment 207, wherein R₂ is a heterocycle.
• [0374] Embodiment 211. The oligomeric compound of embodiment 207, wherein R₂ is a substituted heterocycle.
• [0375] Embodiment 212. The oligomeric compound of embodiment 207, wherein R₂ is an aromatic heterocycle.
• [0376] Embodiment 213. The oligomeric compound of embodiment 207, wherein R₂ is a substituted aromatic heterocycle.
• [0377] Embodiment 214. The oligomeric compound of embodiment 207, wherein R₂ is a diazole.
• [0378] Embodiment 215. The oligomeric compound of embodiment 207, wherein R₂ is a substituted diazole.
• [0379] Embodiment 216. The oligomeric compound of embodiment 207, wherein R₂ is an amine.
• [0380] Embodiment 217. The oligomeric compound of embodiment 207, wherein R₂ is a substituted amine.
• [0381] Embodiment 218. The oligomeric compound of embodiment 207, wherein R₂ is a C₁-C₆ alkoxy.
• [0382] Embodiment 219. The oligomeric compound of embodiment 207, wherein R₂ is C₁-C₆ alkyl.
• [0383] Embodiment 220. The oligomeric compound of embodiment 207, wherein R₂ is substituted C₁-C₆ alkyl.
• [0384] Embodiment 221. The oligomeric compound of embodiment 207, wherein T is:

[0385]

• [0386] Embodiment 222. The oligomeric compound of embodiment 207, wherein T is:

[0387]

• [0388] Embodiment 223. The oligomeric compound of embodiment 207, wherein T is:

[0389]

• [0390] Embodiment 224. The oligomeric compound of embodiment 207, wherein T is:

[0391]

• [0392] Embodiment 225. The oligomeric compound of embodiment 207, wherein T is:

[0393]

• [0394] Embodiment 226. The oligomeric compound of embodiment 207, wherein T is:

[0395]

• [0396] Embodiment 227. The oligomeric compound of embodiment 207, wherein T is:

[0397]

• [0398] Embodiment 228. The oligomeric compound of embodiment 207, wherein T is:

[0399]

• [0400] Embodiment 229. The oligomeric compound of embodiment 207, wherein T is:

[0401]

• [0402] Embodiment 230. The oligomeric compound of any of embodiments 190-206, wherein T is C(═O)R₃.
• [0403] Embodiment 231. The oligomeric compound of embodiment 230, wherein R₃ is an aryl.
• [0404] Embodiment 232. The oligomeric compound of embodiment 230, wherein R₃ is a substituted aryl.
• [0405] Embodiment 233. The oligomeric compound of embodiment 230, wherein R₃ is CH₃.
• [0406] Embodiment 234. The oligomeric compound of embodiment 230, wherein R₃ is N(CH₃)₂.
• [0407] Embodiment 235. The oligomeric compound of embodiment 230, wherein R₃ is OCH₃.
• [0408] Embodiment 236. The oligomeric compound of embodiment 230, wherein T is:

[0409]

• [0410] Embodiment 237. The oligomeric compound of embodiment 230, wherein T is:

[0411]

• [0412] Embodiment 238. The oligomeric compound of embodiment 230, wherein T is:

[0413]

• [0414] Embodiment 239. The oligomeric compound of embodiment 230, wherein T is:

[0415]

• [0416] Embodiment 240. The oligomeric compound of any of embodiments 190-206, wherein T is P(═O)R₄R₅.
• [0417] Embodiment 241. The oligomeric compound of embodiment 240, wherein R₄ is OCH₃.
• [0418] Embodiment 242. The oligomeric compound of embodiment 240, wherein R₄ is OH.
• [0419] Embodiment 243. The oligomeric compound of embodiment 240, wherein R₄ is C₁-C₆ alkyl.
• [0420] Embodiment 244. The oligomeric compound of embodiment 240, wherein R₄ is substituted C₁-C₆ alkyl.
• [0421] Embodiment 245. The oligomeric compound of any of embodiments 240-242, wherein R₅ is OCH₃.
• [0422] Embodiment 246. The oligomeric compound of any of embodiments 240-242, wherein R₅ is OH.
• [0423] Embodiment 247. The oligomeric compound of any of embodiments 240-242, wherein R₅ is C₁-C₆ alkyl.
• [0424] Embodiment 248. The oligomeric compound of any of embodiments 240-242, wherein R₅ is substituted C₁-C₆ alkyl.
• [0425] Embodiment 249. The oligomeric compound of embodiment 240, wherein T is:

[0426]

• [0427] Embodiment 250. The oligomeric compound of embodiment 240, wherein T is:

[0428]

• [0429] Embodiment 251. The oligomeric compound of any of embodiments 190-250, wherein at least one internucleoside linking group of the modified oligonucleotide is not a linking group of Formula VIII.
• [0430] Embodiment 252. The oligomeric compound of any of embodiments 190-250, wherein exactly two internucleoside linking groups of the modified oligonucleotide are internucleoside linking groups of any of Formula VIII.
• [0431] Embodiment 253. The oligomeric compound of any of embodiments 190-250, wherein exactly three internucleoside linking groups of the modified oligonucleotide are internucleoside linking groups of any of Formula VIII.
• [0432] Embodiment 254. The oligomeric compound of any of embodiments 190-250, wherein exactly four internucleoside linking groups of the modified oligonucleotide are internucleoside linking groups of any of Formula VIII.
• [0433] Embodiment 255. The oligomeric compound of any of embodiment 190-250 having at least two linking groups of Formula VIII, wherein at least two of the linking groups of Formula VIII are the same as one another.
• [0434] Embodiment 256. The oligomeric compound of any of embodiments 190-255, wherein each internucleoside linking group of the modified oligonucleotide that is not an internucleoside linking group of Formula VIII is either a phosphodiester internucleoside linking group or a phosphorothioate internucleoside linking group.
• [0435] Embodiment 257. The oligomeric compound of any of embodiments 190-256, wherein the 5′-region consists of 2-5 linked nucleosides.
• [0436] Embodiment 258. The oligomeric compound of embodiment 257, wherein the 5′-region consists of 3 linked nucleosides.
• [0437] Embodiment 259. The oligomeric compound of embodiment 257, wherein the 5′-region consists of 5 linked nucleosides.
• [0438] Embodiment 260. The oligomeric compound of any of embodiments 190-259 wherein each nucleoside of the 5′-region is a modified nucleoside.
• [0439] Embodiment 261. The oligomeric compound of any of embodiments 190-259, wherein each nucleoside of the 5′-region is a modified nucleoside comprising a modified sugar.
• [0440] Embodiment 262. The oligomeric compound of any of embodiments 190-261, wherein each nucleoside of the 5′-region comprises a 2′-substituted furanosyl sugar moiety.
• [0441] Embodiment 263. The oligomeric compound of any of embodiments 190-261, wherein at least one nucleoside of the 5′-region comprises a bicyclic furanosyl sugar moiety.
• [0442] Embodiment 264. The oligomeric compound of any of embodiments 190-261, wherein each nucleoside of the 5′-region comprises a bicyclic furanosyl sugar moiety.
• [0443] Embodiment 265. The oligomeric compound of embodiment 263, wherein each bicyclic sugar moiety of the 5′-region is selected from among cEt, LNA, and ENA.
• [0444] Embodiment 266. The oligomeric compound of embodiment 263, wherein each bicyclic sugar moiety of the 5′-region is a cEt sugar moiety.
• [0445] Embodiment 267. The oligomeric compound of embodiment 262, wherein each 2′-substituted furanosyl sugar moiety of the 5′-region is a ribosyl sugar moiety and has a 2′-substituent selected from among 2′-MOE, 2′-OMe, and 2′-NMA.
• [0446] Embodiment 268. The oligomeric compound of any of embodiments 190-267, wherein each nucleobase of the 5′-region is independently selected from among thymine, uracil, guanine, cytosine, 5-methylcytosine, and adenine.
• [0447] Embodiment 269. The oligomeric compound of any of embodiments 190-268, wherein the 3′-region consists of 2-5 linked nucleosides.
• [0448] Embodiment 270. The oligomeric compound of embodiment 269, wherein the 3′-region consists of 3 linked nucleosides.
• [0449] Embodiment 271. The oligomeric compound of embodiment 269, wherein the 3′-region consists of 5 linked nucleosides.
• [0450] Embodiment 272. The oligomeric compound of any of embodiments 190-271 wherein each nucleoside of the 3′-region is a modified nucleoside.
• [0451] Embodiment 273. The oligomeric compound of any of embodiments 190-272, wherein each nucleoside of the 3′-region is a modified nucleoside comprising a modified sugar.
• [0452] Embodiment 274. The oligomeric compound of any of embodiments 190-273, wherein each nucleoside of the 3′-region comprises a 2′-substituted furanosyl sugar moiety.
• [0453] Embodiment 275. The oligomeric compound of any of embodiments 190-273, wherein at least one nucleoside of the 3′-region comprises a bicyclic furanosyl sugar moiety.
• [0454] Embodiment 276. The oligomeric compound of any of embodiments 190-273, wherein each nucleoside of the 3′-region comprises a bicyclic furanosyl sugar moiety.
• [0455] Embodiment 277. The oligomeric compound of embodiment 276, wherein each bicyclic sugar moiety of the 3′-region is selected from among cEt, LNA, and ENA.
• [0456] Embodiment 278. The oligomeric compound of embodiment 276, wherein each bicyclic sugar moiety of the 3′-region is a cEt sugar moiety.
• [0457] Embodiment 279. The oligomeric compound of embodiment 274, wherein each wherein each 2′-substituted furanosyl sugar moiety of the 5′-region is a ribosyl sugar moiety and has a 2′-substituent selected from among 2′-MOE, 2′-OMe, and 2′-NMA.
• [0458] Embodiment 280. The oligomeric compound of any of embodiments 190-279, wherein each nucleobase of the 5′-region is independently selected from among thymine, uracil, guanine, cytosine, 5-methylcytosine, and adenine.
• [0459] Embodiment 281. The oligomeric compound of any of embodiments 1-80, wherein each nucleoside of the modified oligonucleotide is a modified nucleoside comprising a modified sugar moiety.
• [0460] Embodiment 282. The oligomeric compound of embodiment 281, wherein each modified sugar moiety is independently selected from a bicyclic sugar moiety and a 2′-substituted furanosyl sugar moiety.
• [0461] Embodiment 283. The oligomeric compound of embodiment 282, wherein the three 3′-most nucleosides comprise a bicyclic sugar moiety, and the remaining nucleosides comprise a 2′-substituted furanosyl sugar moiety.
• [0462] Embodiment 284. The oligomeric compound of embodiment 282, wherein the four 3′-most nucleosides comprise a bicyclic sugar moiety, and the remaining nucleosides comprise a 2′-substituted furanosyl sugar moiety.
• [0463] Embodiment 285. The oligomeric compound of embodiment 282, wherein the five 3′-most nucleosides comprise a bicyclic sugar moiety, and the remaining nucleosides comprise a 2′-substituted furanosyl sugar moiety.
• [0464] Embodiment 286. The oligomeric compound of embodiment 282, wherein the six 3′-most nucleosides comprise a bicyclic sugar moiety, and the remaining nucleosides comprise a 2′-substituted furanosyl sugar moiety.
• [0465] Embodiment 287. The oligomeric compound of any of embodiments 282-286, wherein each bicyclic sugar moiety is selected from among cEt, LNA, and ENA.
• [0466] Embodiment 288. The oligomeric compound of embodiment 287, wherein the bicyclic sugar moiety is cEt Embodiment 289. The oligomeric compound of any of embodiments 282-289, wherein the 2′-substituted furanosyl sugar moiety is selected from 2′-OMe, 2′-MOE, and 2′-F.
• [0467] Embodiment 290. The oligomeric compound of any of embodiments 281-289, wherein at least one of the first 10 internucleoside linking groups from the 5′-end of the modified oligonucleotide is an internucleoside linking group of any of embodiments 1-50.
• [0468] Embodiment 291. The oligomeric compound of embodiment 289, wherein at least 2 of the first 10 internucleoside linking groups from the 5′-end of the modified oligonucleotide are internucleoside linking groups of any of embodiments 1-50.
• [0469] Embodiment 292. The oligomeric compound of embodiment 289, wherein at least 3 of the first 10 internucleoside linking groups from the 5′-end of the modified oligonucleotide are internucleoside linking groups of any of embodiments 1-50.
• [0470] Embodiment 293. The oligomeric compound of embodiment 289, wherein at least 4 of the first 10 internucleoside linking groups from the 5′-end of the modified oligonucleotide are internucleoside linking groups of any of embodiments 1-50.
• [0471] Embodiment 294. The oligomeric compound of embodiment 289, wherein at least 5 of the first 10 internucleoside linking groups from the 5′-end of the modified oligonucleotide are internucleoside linking groups of any of embodiments 1-50.
• [0472] Embodiment 295. The oligomeric compound of embodiment 289, wherein at least 6 of the first 10 internucleoside linking groups from the 5′-end of the modified oligonucleotide are internucleoside linking groups of any of embodiments 1-50.
• [0473] Embodiment 296. The oligomeric compound of embodiment 289, wherein the first 2 internucleoside linking groups from the 5′-end of the modified oligonucleotide are internucleoside linking groups of any of embodiments 1-50.
• [0474] Embodiment 297. The oligomeric compound of embodiment 289, wherein the first 3 internucleoside linking groups from the 5′-end of the modified oligonucleotide are internucleoside linking groups of any of embodiments 1-50. Embodiment 298. The oligomeric compound of embodiment 289, wherein the first 4 internucleoside linking groups from the 5′-end of the modified oligonucleotide are internucleoside linking groups of any of embodiments 1-50.
• [0475] Embodiment 299. The oligomeric compound of embodiment 289, wherein the first 5 internucleoside linking groups from the 5′-end of the modified oligonucleotide are internucleoside linking groups of any of embodiments 1-50.
• [0476] Embodiment 300. The oligomeric compound of embodiment 289, wherein the first 6 internucleoside linking groups from the 5′-end of the modified oligonucleotide are internucleoside linking groups of any of embodiments 1-50.
• [0477] Embodiment 301. A method of increasing translation of a target protein in a cell, comprising contacting the cell with an oligomeric compound of any of embodiments 281-300.
• [0478] Embodiment 302. The method of embodiment 301, wherein the target protein is encoded by a target nucleic acid comprising at least one translation suppression element and wherein the modified oligonucleotide is complementary to a target site within a translation suppression element region of the target nucleic acid.
• [0479] Embodiment 303. The method of embodiment 302, wherein the translation suppression element region comprises at least one stem-loop structure.
• [0480] Embodiment 304. A pharmaceutical composition comprising the oligomeric compound of any of embodiments 190-300 and a pharmaceutically acceptable carrier or diluent.
• [0481] Embodiment 305. A method comprising contacting a cell with the oligomeric compound or pharmaceutical composition of any of embodiments 190-300.
• [0482] Embodiment 306. A method of modulating the amount or activity of a target nucleic acid in a cell, comprising contacting the cell with the oligomeric compound or pharmaceutical composition of any of embodiments 190-300, and thereby modulating the amount or activity of the target nucleic acid.
• [0483] Embodiment 307. The method of embodiment 306, wherein the amount or activity of a target nucleic acid is reduced.
• [0484] Embodiment 308. The method of embodiment 306, wherein the amount or activity of a target nucleic acid is increased.
• [0485] Embodiment 309. Use of the oligomeric compound or composition of any of embodiments 190-300 for treatment of a disease or condition.
• [0486] Embodiment 310. Use of the oligomeric compound or composition of any of embodiments 190-300 for a preparation of a medicament for treatment of a disease or condition.
• [0487] Embodiment 311. An antisense agent comprising a modified oligonucleotide consisting of linked nucleosides linked through internucleoside linking groups, wherein at least one of the internucleoside linking groups has Formula XVII:

[0488]

[0489] wherein independently for each internucleoside linking group of the modified oligonucleotide having Formula XVII:

[0490] X is selected from O or S;

[0491] R₁ is selected from H, C₁-C₆ alkyl, and substituted C₁-C₆ alkyl; and

[0492] T is selected from SO₂R₂, C(═O)R₃, and P(═O)R₄R₅, wherein:

[0493] R₂ is selected from an aryl, a substituted aryl, a heterocycle, a substituted heterocycle, an aromatic heterocycle, a substituted aromatic heterocycle, a diazole, a substituted diazole, a C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ alkenyl, C₁-C₆ alkynyl, substituted C₁-C₆ alkyl, substituted C₁-C₆ alkenyl substituted C₁-C₆ alkynyl, and a conjugate group;

[0494] R₃ is selected from an aryl, a substituted aryl, CH₃, N(CH₃)₂, OCH₃ and a conjugate group;

[0495] R₄ is selected from OCH₃, OH, C₁-C₆ alkyl, substituted C₁-C₆ alkyl and a conjugate group; and

[0496] R₅ is selected from OCH₃, OH, C₁-C₆ alkyl, and substituted C₁-C₆ alkyl.

• [0497] Embodiment 312. An antisense agent comprising a modified oligonucleotide consisting of linked nucleosides linked through internucleoside linking groups, wherein at least one of the internucleoside linking groups has Formula XVII:

[0498]

[0499] wherein independently for each internucleoside linking group of the modified oligonucleotide having Formula XVII:

[0500] X is selected from O or S;

[0501] R₁ is selected from H, C₁-C₆ alkyl, and substituted C₁-C₆ alkyl; and

[0502] T is selected from SO₂R₂, C(O)R₃, and P(O)R₄R₅, wherein:

[0503] R₂ is selected from an aryl, a substituted aryl, a heterocycle, a substituted heterocycle, an aromatic heterocycle, a substituted aromatic heterocycle, a diazole, a substituted diazole, a C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ alkenyl, C₁-C₆ alkynyl, substituted C₁-C₆ alkyl, substituted C₁-C₆ alkenyl substituted C₁-C₆ alkynyl, and a conjugate group;

[0504] R₃ is selected from an aryl, a substituted aryl, CH₃, N(CH₃)₂, OCH₃ and a conjugate group;

[0505] R₄ is selected from OCH₃, OH, C₁-C₆ alkyl, substituted C₁-C₆ alkyl and a conjugate group; and

[0506] R₅ is selected from OCH₃, OH, C₁-C₆ alkyl, and substituted C₁-C₆ alkyl;

[0507] Provided that if X is O and that if R₁ is H, then T is not:

[0508]

• [0509] Embodiment 313. The modified oligonucleotide of embodiment 311 or 312, wherein for at least one internucleoside linking group of Formula XVII, X is O.
• [0510] Embodiment 314. The modified oligonucleotide of embodiment 311 or 312, wherein for at least one internucleoside linking group of Formula XVII, X is S.
• [0511] Embodiment 315. The modified oligonucleotide of embodiment 311 or 312, wherein for at least one internucleoside linking group of Formula XVII, R₁ is H.
• [0512] Embodiment 316. The modified oligonucleotide of embodiment 311 or 312, wherein for at least one internucleoside linking group of Formula XVII, R₁ is a C₁-C₆ alkyl, C₁-C₆ alkenyl, or C₁-C₆ alkynyl.
• [0513] Embodiment 317. The modified oligonucleotide of embodiment 6, wherein R₁ is methyl.
• [0514] Embodiment 318. The modified oligonucleotide of embodiment 311 or 312, wherein for at least one internucleoside linking group of Formula XVII, R₁ is a substituted C₁-C₆ alkyl.
• [0515] Embodiment 319. The modified oligonucleotide of any of embodiments 311-318, wherein for at least one internucleoside linking group of Formula XVII, T comprises a conjugate group.
• [0516] Embodiment 320. The modified oligonucleotide of embodiment 319, wherein the conjugate group comprises a carbohydrate or carbohydrate cluster.
• [0517] Embodiment 321. The modified oligonucleotide of embodiment 319 or 320, wherein the conjugate group comprises at least one GalNAc.
• [0518] Embodiment 322. The modified oligonucleotide of embodiment 319, wherein the conjugate group comprises a C₁₀-C₂₀ alkyl chain.
• [0519] Embodiment 323. The modified oligonucleotide of embodiment 322, wherein the conjugate group comprises C₁₆ alkyl.
• [0520] Embodiment 324. The modified oligonucleotide of any of embodiments 311-318, wherein for at least one internucleoside linking group of formula XVII, T does not comprise a conjugate group.
• [0521] Embodiment 325. The modified oligonucleotide of any of embodiments 311-324, wherein for at least one internucleoside linking group of Formula XVII, T is SO₂R₂.
• [0522] Embodiment 326. The modified oligonucleotide of embodiment 325, wherein R₂ is an aryl.
• [0523] Embodiment 327. The modified oligonucleotide of embodiment 325, wherein R₂ is a substituted aryl.
• [0524] Embodiment 328. The modified oligonucleotide of embodiment 325, wherein R₂ is a heterocycle.
• [0525] Embodiment 329. The modified oligonucleotide of embodiment 325, wherein R₂ is a substituted heterocycle.
• [0526] Embodiment 330. The modified oligonucleotide of embodiment 325, wherein R₂ is an aromatic heterocycle.
• [0527] Embodiment 331. The modified oligonucleotide of embodiment 325, wherein R₂ is a substituted aromatic heterocycle.
• [0528] Embodiment 332. The modified oligonucleotide of embodiment 325, wherein R₂ is a diazole.
• [0529] Embodiment 333. The modified oligonucleotide of embodiment 325, wherein R₂ is a substituted diazole.
• [0530] Embodiment 334. The modified oligonucleotide of embodiment 325, wherein R₂ is an amine.
• [0531] Embodiment 335. The modified oligonucleotide of embodiment 325, wherein R₂ is a substituted amine.
• [0532] Embodiment 336. The modified oligonucleotide of embodiment 325, wherein R₂ is a C₁-C₆ alkoxy, or C₁-C₆ alkenyl, C₁-C₆ alkynyl.
• [0533] Embodiment 337. The modified oligonucleotide of embodiment 325, wherein R₂ is C₁-C₂₀, C₁-C₆, C₂-C₂₀, C₂-C₆, or C₁₀-C₂₀ alkyl.
• [0534] Embodiment 338. The modified oligonucleotide of embodiment 325, wherein R₂ is substituted C₁-C₂₀, C₁-C₆, C₂-C₂₀, C₂-C₆, or C₁₀-C₂₀ alkyl.
• [0535] Embodiment 339. The modified oligonucleotide of embodiment 325, wherein R₂ comprises a carbohydrate or carbohydrate cluster.
• [0536] Embodiment 340. The modified oligonucleotide of embodiment 325, wherein R₂ comprises at least one GalNAc.
• [0537] Embodiment 341. The modified oligonucleotide of embodiment 325, wherein T is:

[0538]

• [0539] Embodiment 342. The modified oligonucleotide of embodiment 325, wherein T is:

[0540]

• [0541] Embodiment 343. The modified oligonucleotide of embodiment 325, wherein T is:

[0542]

• [0543] Embodiment 344. The modified oligonucleotide of embodiment 325, wherein T is:

[0544]

• [0545] Embodiment 345. The modified oligonucleotide of embodiment 325, wherein T is:

[0546]

• [0547] Embodiment 346. The modified oligonucleotide of embodiment 325, wherein T is:

[0548]

• [0549] Embodiment 347. The modified oligonucleotide of embodiment 325, wherein T is:

[0550]

• [0551] Embodiment 348. The modified oligonucleotide of embodiment 325, wherein T is:

[0552]

• [0553] Embodiment 349. The modified oligonucleotide of embodiment 325, wherein T is:

[0554]

• [0555] Embodiment 350. The modified oligonucleotide of embodiment 325, wherein T is:

[0556]
wherein n is from 2 to 20.

• [0557] Embodiment 351. The modified oligonucleotide of embodiment 350, wherein n is 15.
• [0558] Embodiment 352. The modified oligonucleotide of any of embodiments 311-324, wherein for at least one internucleoside linking group of Formula XVII, T is C(═O)R₃.
• [0559] Embodiment 353. The modified oligonucleotide of embodiment 352, wherein R₃ is an aryl.
• [0560] Embodiment 354. The modified oligonucleotide of embodiment 352, wherein R₃ is a substituted aryl.
• [0561] Embodiment 355. The modified oligonucleotide of embodiment 352, wherein R₃ is CH₃.
• [0562] Embodiment 356. The modified oligonucleotide of embodiment 352, wherein R₃ is N(CH₃)₂.
• [0563] Embodiment 357. The modified oligonucleotide of embodiment 352, wherein R₃ is OCH₃.
• [0564] Embodiment 358. The modified oligonucleotide of embodiment 352, wherein R₃ is a C₁-C₆ alkoxy.
• [0565] Embodiment 359. The modified oligonucleotide of embodiment 352, wherein R₃ is C₁-C₂₀, C₁-C₆, C₂-C₂₀, C₂-C₆, or C₁₀-C₂₀ alkyl.
• [0566] Embodiment 360. The modified oligonucleotide of embodiment 352, wherein R₃ is substituted C₁-C₂₀, C₁-C₆, C₂-C₂₀, C₂-C₆, or C₁₀-C₂₀ alkyl.
• [0567] Embodiment 361. The modified oligonucleotide of embodiment 352, wherein R₃ comprises a carbohydrate or carbohydrate cluster.
• [0568] Embodiment 362. The modified oligonucleotide of embodiment 352, wherein R₂₃ comprises at least one GalNAc.
• [0569] Embodiment 363. The modified oligonucleotide of embodiment 352, wherein T is:

[0570]

• [0571] Embodiment 364. The modified oligonucleotide of embodiment 352, wherein T is:

[0572]

• [0573] Embodiment 365. The modified oligonucleotide of embodiment 352, wherein T is:

[0574]

• [0575] Embodiment 366. The modified oligonucleotide of embodiment 352, wherein T is:

[0576]

• [0577] Embodiment 367. The modified oligonucleotide of embodiment 352, wherein T is:

[0578]
wherein n is from 2 to 20.

• [0579] Embodiment 368. The modified oligonucleotide of embodiment 367, wherein n is 15.
• [0580] Embodiment 369. The modified oligonucleotide of any of embodiments 1-14, wherein for at least one internucleoside linking group of Formula XVII, T is P(═O)R₄R₅.
• [0581] Embodiment 370. The modified oligonucleotide of embodiment 369, wherein R₄ is OCH₃.
• [0582] Embodiment 371. The modified oligonucleotide of embodiment 369, wherein R₄ is OH.
• [0583] Embodiment 372. The modified oligonucleotide of embodiment 369, wherein R₄ is C₁-C₆ alkyl.
• [0584] Embodiment 373. The modified oligonucleotide of embodiment 369, wherein R₄ is substituted C₁-C₆ alkyl.
• [0585] Embodiment 374. The modified oligonucleotide of embodiment 369, wherein R₄ is C₁-C₂₀, C₁-C₆, C₂-C₂₀, C₂-C₆, or C₁₀-C₂₀ alkyl.
• [0586] Embodiment 375. The modified oligonucleotide of embodiment 369, wherein R₄ is substituted C₁-C₂₀, C₁-C₆, C₂-C₂₀, C₂-C₆, or C₁₀-C₂₀ alkyl.
• [0587] Embodiment 376. The modified oligonucleotide of embodiment 369, wherein R₄ comprises a carbohydrate or carbohydrate cluster.
• [0588] Embodiment 377. The modified oligonucleotide of embodiment 369, wherein R₄ comprises at least one GalNAc.
• [0589] Embodiment 378. The modified oligonucleotide of any of embodiments 369-67, wherein R₅ is OCH₃.
• [0590] Embodiment 379. The modified oligonucleotide of any of embodiments 369-67, wherein R₅ is OH.
• [0591] Embodiment 380. The modified oligonucleotide of any of embodiments 369-67, wherein R₅ is C₁-C₆ alkyl.
• [0592] Embodiment 381. The modified oligonucleotide of any of embodiments 369-67, wherein R₅ is substituted C₁-C₆ alkyl.
• [0593] Embodiment 382. The modified oligonucleotide of embodiment 369, wherein T is:

[0594]

• [0595] Embodiment 383. The modified oligonucleotide of embodiment 369, wherein T is:

[0596]

• [0597] Embodiment 384. The modified oligonucleotide of embodiment 369, wherein T is:

[0598]
wherein n is from 2 to 20.

• [0599] Embodiment 385. The modified oligonucleotide of embodiment 384, wherein n is 15.
• [0600] Embodiment 386. The modified oligonucleotide of any of embodiments 311-385, wherein at least one internucleoside linking group of the modified oligonucleotide is not a linking group of Formula XVII.
• [0601] Embodiment 387. The modified oligonucleotide of any of embodiments 311-385, wherein exactly one internucleoside linking group of the modified oligonucleotide is an internucleoside linking group of Formula XVII.
• [0602] Embodiment 388. The modified oligonucleotide of any of embodiments 311-385, wherein exactly two internucleoside linking groups of the modified oligonucleotide are internucleoside linking groups of Formula XVII.
• [0603] Embodiment 389. The modified oligonucleotide of any of embodiments 311-385, wherein exactly three internucleoside linking groups of the modified oligonucleotide are internucleoside linking groups of Formula XVII.
• [0604] Embodiment 390. The modified oligonucleotide of any of embodiments 311-385, wherein exactly four internucleoside linking groups of the modified oligonucleotide are internucleoside linking groups of Formula XVII.
• [0605] Embodiment 391. The modified oligonucleotide of any of embodiments 311-385, wherein exactly five internucleoside linking groups of the modified oligonucleotide are internucleoside linking groups of Formula XVII.
• [0606] Embodiment 392. The modified oligonucleotide of any of embodiments 311-385, wherein at least six internucleoside linking groups of the modified oligonucleotide are internucleoside linking groups of Formula XVII.
• [0607] Embodiment 393. The modified oligonucleotide of any of embodiment 311-386 or 388-392 having at least two linking groups of Formula XVII, wherein at least two of the linking groups of Formula XVII are the same as one another.
• [0608] Embodiment 394. The modified oligonucleotide of any of embodiments 311-393, wherein each internucleoside linking group of the modified oligonucleotide that is not an internucleoside linking group of Formula XVII is either a phosphodiester internucleoside linking group or a phosphorothioate internucleoside linking group.
• [0609] Embodiment 395. The modified oligonucleotide of any of embodiments 311-386 or 393-394, wherein each internucleoside linking group of the modified oligonucleotide is an internucleoside linking group of Formula XVII.
• [0610] Embodiment 396. An antisense agent comprising a modified oligonucleotide, wherein at least one region of the modified oligonucleotide has Structure A:

[0611]

[0612] wherein:

[0613] each Bx is a heterocyclic base moiety;

[0614] X is selected from O or S;

[0615] each of Y₁, and Y₂ is independently selected from OH or SH;

[0616] each of Z¹, Z², and Z³ are independently selected from —(CH₂)_p—X^Z—(CH₂)_q—, wherein p is 0 or 1, q is 0 or 1, and X^Z is O, S, or N(E₁);

[0617] R₁ is selected from H, C₁-C₆ alkyl, and substituted C₁-C₆ alkyl; and

[0618] T is selected from SO₂R₂, C(═O)R₃, and P(═O)R₄R₅, wherein:

[0619] R₂ is selected from an aryl, a substituted aryl, a heterocycle, a substituted heterocycle, an aromatic heterocycle, a substituted aromatic heterocycle, a diazole, a substituted diazole, a C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ alkenyl, C₁-C₆ alkynyl, substituted C₁-C₆ alkyl, substituted C₁-C₆ alkenyl, substituted C₁-C₆ alkynyl, and a conjugate group;

[0620] R₃ is selected from an aryl, a substituted aryl, CH₃, N(CH₃)₂, OCH₃ and a conjugate group;

[0621] R₄ is selected from OCH₃, OH, C₁-C₆ alkyl, substituted C₁-C₆ alkyl and a conjugate group;

[0622] R₅ is selected from OCH₃, OH, C₁-C₆ alkyl, and substituted C₁-C₆ alkyl;

[0623] either J^R1 and G¹ form a J^R1 to G¹ bridge, or J^R1 is H and G¹ is selected from H, OH, halogen or O—[C(R₆)(R₇)]_n—[(C═O)_m—X^G]_j—R₈;

[0624] either J^R1 and G² form a J^R2 and G² bridge, or J^R2 is H and G² is selected from H, OH, halogen or O—[C(R₆)(R₇)]_n—[(C═O)_m—X^G]_j—R₈;

[0625] either J^R3 and G³ form a J^R3 and G³ bridge, or J^R3 is H and G³ is selected from H, OH, halogen or O—[C(R₆)(R₇)]_n—[(C═O)_m—X^G]_j—R₈;

[0626] wherein each J^R to G bridge has a formula independently selected from —CH(CH₃)—O— or —(CH₂)_k—O—, wherein k is from 1 to 3;

[0627] each R₆ and R₇ is, independently, H, halogen, C₁-C₆ alkyl or substituted C₁-C₆ alkyl;

[0628] each X^G is O, S or N(E₁);

[0629] R₈ is H, halogen, C₁-C₆ alkyl, substituted C₁-C₆ alkyl, C₂-C₆ alkenyl, substituted C₂-C₆ alkenyl, C₂-C₆ alkynyl, substituted C₂-C₆ alkynyl or N(E₂)(E₃);

[0630] E₁, E₂ and E₃ are each, independently, H, C₁-C₆ alkyl or substituted C₁-C₆ alkyl;

[0631] n is from 1 to 6;

[0632] m is 0 or 1;

[0633] j is 0 or 1;

[0634] each substituted group comprises one or more optionally protected substituent groups independently selected from halogen, OJ₁, N(J₁)(J₂), NJ₁, SJ₁, N₃, CN, OC(═X₂)J₁, OC(═X₂)N(J₁)(J₂) and C(=Q₂)N(J₁)(J₂);

[0635] Q₂ is O, S or NJ₃;

[0636] each J₁, J₂ and J₃ is, independently, H or C₁-C₆ alkyl.

• [0637] Embodiment 397. An antisense agent comprising a modified olignucleotide, wherein at least one region of the modified oligonucleotide has Structure B:

[0638]

[0639] wherein:

• • [0640] each Bx is a heterocyclic base moiety;

[0641] X is selected from O or S;

[0642] each of Y₁ and Y₂ is independently selected from OH or SH;

[0643] each of Z¹ and Z² are independently selected from —(CH₂)_p—X^Z—(CH₂)_q—, wherein p is 0 or 1, q is 0 or 1, and X^Z is O, S, or N(E₁);

[0644] R₁ is selected from H, C₁-C₆ alkyl, and substituted C₁-C₆ alkyl; and

[0645] T is selected from SO₂R₂, C(═O)R₃, and P(═O)R₄R₅, wherein:

[0646] R₂ is selected from an aryl, a substituted aryl, a heterocycle, a substituted heterocycle, an aromatic heterocycle, a substituted aromatic heterocycle, a diazole, a substituted diazole, a C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ alkenyl, C₁-C₆ alkynyl, substituted C₁-C₆ alkyl, substituted C₁-C₆ alkenyl, substituted C₁-C₆ alkynyl, and a conjugate group;

[0647] R₃ is selected from an aryl, a substituted aryl, CH₃, N(CH₃)₂, OCH₃ and a conjugate group;

[0648] R₄ is selected from OCH₃, OH, C₁-C₆ alkyl, substituted C₁-C₆ alkyl and a conjugate group;

[0649] R₅ is selected from OCH₃, OH, C₁-C₆ alkyl, and substituted C₁-C₆ alkyl;

[0650] either J^R1 and G¹ form a J^R1 to G¹ bridge, or J^R1 is H and G¹ is selected from H, OH, halogen or O—[C(R₆)(R₇)]_n—[(C═O)_m—X^G]_j—R₈;

[0651] either J^R2 and G² form a J^R2 and G² bridge, or J^R2 is H and G² is selected from H, OH, halogen or O—[C(R₆)(R₇)]_n—[(C═O)_m—X^G]_j—R₈;

[0652] wherein each J^R to G bridge has a formula independently selected from —CH(CH₃)—O— or —(CH₂)_k—O—, wherein k is from 1 to 3;

[0653] each R₆ and R₇ is, independently, H, halogen, C₁-C₆ alkyl or substituted C₁-C₆ alkyl;

[0654] each X^G is O, S or N(E₁);

[0655] R₈ is H, halogen, C₁-C₆ alkyl, substituted C₁-C₆ alkyl, C₂-C₆ alkenyl, substituted C₂-C₆ alkenyl, C₂-C₆ alkynyl, substituted C₂-C₆ alkynyl or N(E₂)(E₃);

[0656] E₁, E₂ and E₃ are each, independently, H, C₁-C₆ alkyl or substituted C₁-C₅ alkyl;

[0657] n is from 1 to 6;

[0658] m is 0 or 1;

[0659] j is 0 or 1;

[0660] each substituted group comprises one or more optionally protected substituent groups independently selected from halogen, OJ₁, N(J₁)(J₂), NJ₁, SJ₁, N₃, CN, OC(═X₂)J₁, OC(═X₂)N(J₁)(J₂) and C(=Q₂)N(J₁)(J₂); Q₂ is O, S or NJ₃;

[0661] each J₁, J₂ and J₃ is, independently, H or C₁-C₆ alkyl.

• [0662] Embodiment 398. An antisense agent comprising a modified olignucleotide, wherein at least one region of the modified oligonucleotide has Structure C:

[0663]

[0664] wherein:

[0665] each Bx is a heterocyclic base moiety;

[0666] X is selected from O or S;

[0667] each of Y₁ and Y₂ is independently selected from OH or SH;

[0668] each of Z² and Z³ are independently selected from —(CH₂)_p—X^Z—(CH₂)_q—, wherein p is 0 or 1, q is 0 or 1, and X^Z is O, S, or N(E₁);

[0669] R₁ is selected from H, C₁-C₆ alkyl, and substituted C₁-C₆ alkyl; and

[0670] T is selected from SO₂R₂, C(═O)R₃, and P(═O)R₄R₅, wherein:

[0671] R₂ is selected from an aryl, a substituted aryl, a heterocycle, a substituted heterocycle, an aromatic heterocycle, a substituted aromatic heterocycle, a diazole, a substituted diazole, a C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ alkenyl, C₁-C₆ alkynyl, substituted C₁-C₆ alkyl, substituted C₁-C₆ alkenyl, substituted C₁-C₆ alkynyl, and a conjugate group;

[0672] R₃ is selected from an aryl, a substituted aryl, CH₃, N(CH₃)₂, OCH₃ and a conjugate group;

[0673] R₄ is selected from OCH₃, OH, C₁-C₆ alkyl, substituted C₁-C₆ alkyl and a conjugate group;

[0674] R₅ is selected from OCH₃, OH, C₁-C₆ alkyl, and substituted C₁-C₆ alkyl;

• • [0675] either J^R2 and G² form a J^R2 and Gf bridge, or J^R2 is H and G² is selected from H, OH, halogen or O—[C(R₆)(R₇)]_n—[(C═O)_m—X^G]_j—R₈;

[0676] either J^R3 and G³ form a J^R3 and G³ bridge, or J^R3 is H and G³ is selected from H, OH, halogen or O—[C(R₆)(R₇)]_n—[(C═O)_m—X^G]_j—R₈;

[0677] wherein each J^R to G bridge has a formula independently selected from —CH(CH₃)—O— or —(CH₂)_k—O—, wherein k is from 1 to 3;

[0678] each R₆ and R₇ is, independently, H, halogen, C₁-C₆ alkyl or substituted C₁-C₆ alkyl;

[0679] each X^G is O, S or N(E₁);

[0680] R₈ is H, halogen, C₁-C₆ alkyl, substituted C₁-C₆ alkyl, C₂-C₆ alkenyl, substituted C₂-C₆ alkenyl, C₂-C₆ alkynyl, substituted C₂-C₆ alkynyl or N(E₂)(E₃);

[0681] E₁, E₂ and E₃ are each, independently, H, C₁-C₆ alkyl or substituted C₁-C₆ alkyl;

[0682] n is from 1 to 6;

[0683] m is 0 or 1;

[0684] j is 0 or 1;

[0685] each substituted group comprises one or more optionally protected substituent groups independently selected from halogen, OJ₁, N(J₁)(J₂), NJ₁, SJ₁, N₃, CN, OC(═X₂)J₁, OC(═X₂)N(J₁)(J₂) and C(=Q₂)N(J₁)(J₂);

[0686] Q₂ is O, S or NJ₃;

[0687] each J₁, J₂ and J₃ is, independently, H or C₁-C₆ alkyl.

• [0688] Embodiment 399. An antisense agent comprising a modified olignucleotide, wherein at least one region of the modified oligonucleotide has Structure D:

[0689]

[0690] wherein:

[0691] each Bx is a heterocyclic base moiety;

[0692] X is selected from O or S;

[0693] each of Y₁ and Y₂ is independently selected from OH or SH;

[0694] each of Z² and Z³ are independently selected from —(CH₂)_p—X^Z—(CH₂)_q—, wherein p is 0 or 1, q is 0 or 1, and X^Z is O, S, or N(E₁);

[0695] R₁ is selected from H, C₁-C₆ alkyl, and substituted C₁-C₆ alkyl; and

[0696] T is selected from SO₂R₂, C(═O)R₃, and P(═O)R₄R₅, wherein:

[0697] R₂ is selected from an aryl, a substituted aryl, a heterocycle, a substituted heterocycle, an aromatic heterocycle, a substituted aromatic heterocycle, a diazole, a substituted diazole, a C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ alkenyl, C₁-C₆ alkynyl, substituted C₁-C₆ alkyl, substituted C₁-C₆ alkenyl, substituted C₁-C₆ alkynyl, and a conjugate group;

[0698] R₃ is selected from an aryl, a substituted aryl, CH₃, N(CH₃)₂, OCH₃ and a conjugate group;

[0699] R₄ is selected from OCH₃, OH, C₁-C₆ alkyl, substituted C₁-C₆ alkyl and a conjugate group;

[0700] R₅ is selected from OCH₃, OH, C₁-C₆ alkyl, and substituted C₁-C₆ alkyl;

[0701] either J^R1 and G¹ form a J^R1 to G¹ bridge, or J^R1 is H and G¹ is selected from H, OH, halogen or O—[C(R₆)(R₇)]_n—[(C═O)_m—X^G]_j—R₈;

[0702] either J^R2 and G² form a J^R2 and G² bridge, or J^R2 is H and G² is selected from H, OH, halogen or O—[C(R₆)(R₇)]_n—[(C═O)_m—X^G]_j—R₈;

[0703] either J^R3 and G³ form a J^R3 and G³ bridge, or J^R3 is H and G³ is selected from H, OH, halogen or O—[C(R₆)(R₇)]_n—[(C═O)_m—X^G]_j—R₈;

[0704] wherein each J^R to G bridge has a formula independently selected from —CH(CH₃)—O— or —(CH₂)_k—O—, wherein k is from 1 to 3;

[0705] each R₆ and R₇ is, independently, H, halogen, C₁-C₆ alkyl or substituted C₁-C₆ alkyl;

[0706] each X^G is O, S or N(E₁);

[0707] R₈ is H, halogen, C₁-C₆ alkyl, substituted C₁-C₆ alkyl, C₂-C₆ alkenyl, substituted C₂-C₆ alkenyl, C₂-C₆ alkynyl, substituted C₂-C₆ alkynyl or N(E₂)(E₃);

[0708] E₁, E₂ and E₃ are each, independently, H, C₁-C₆ alkyl or substituted C₁-C₆ alkyl;

[0709] n is from 1 to 6;

[0710] m is 0 or 1;

[0711] j is 0 or 1;

[0712] each substituted group comprises one or more optionally protected substituent groups independently selected from halogen, OJ₁, N(J₁)(J₂), NJ₁, SJ₁, N₃, CN, OC(═X₂)J₁, OC(═X₂)N(J₁)(J₂) and C(=Q₂)N(J₁)(J₂); Q₂ is O, S or NJ₃;

[0713] each J₁, J₂ and J₃ is, independently, H or C₁-C₆ alkyl.

• [0714] Embodiment 400. An antisense agent comprising a modified olignucleotide, wherein at least one region of the modified oligonucleotide has Structure E:

[0715]

[0716] wherein:

[0717] each Bx is a heterocyclic base moiety;

[0718] X is selected from O or S;

[0719] each of Y₁ and Y₂ is independently selected from OH or SH;

[0720] each of Z² and Z³ are independently selected from —(CH₂)_p—X^Z—(CH₂)_q—, wherein p is 0 or 1, q is 0 or 1, and X^Z is O, S, or N(E₁);

[0721] R₁ is selected from H, C₁-C₆ alkyl, and substituted C₁-C₆ alkyl; and

[0722] T is selected from SO₂R₂, C(═O)R₃, and P(═O)R₄R₅, wherein:

[0723] R₂ is selected from an aryl, a substituted aryl, a heterocycle, a substituted heterocycle, an aromatic heterocycle, a substituted aromatic heterocycle, a diazole, a substituted diazole, a C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ alkenyl, C₁-C₆ alkynyl, substituted C₁-C₆ alkyl, substituted C₁-C₆ alkenyl, substituted C₁-C₆ alkynyl, and a conjugate group;

[0724] R₃ is selected from an aryl, a substituted aryl, CH₃, N(CH₃)₂, OCH₃ and a conjugate group;

[0725] R₄ is selected from OCH₃, OH, C₁-C₆ alkyl, substituted C₁-C₆ alkyl and a conjugate group;

[0726] R₅ is selected from OCH₃, OH, C₁-C₆ alkyl, and substituted C₁-C₆ alkyl;

[0727] either J^R1 and G¹ form a J^R1 to G¹ bridge, or J^R1 is H and G¹ is selected from H, OH, halogen or O—[C(R₆)(R₇)]_n—[(C═O)_m—X^G]_j—R₈;

[0728] either J^R2 and G² form a J^R2 and G² bridge, or J^R2 is H and G² is selected from H, OH, halogen or O—[C(R₆)(R₇)]_n—[(C═O)_m—X^G]_j—R₈;

[0729] either J^R3 and G³ form a J^R3 and G³ bridge, or J^R3 is H and G³ is selected from H, OH, halogen or O—[C(R₆)(R₇)]_n—[(C═O)_m—X^G]_j—R₈;

[0730] wherein each J^R to G bridge has a formula independently selected from —CH(CH₃)—O— or —(CH₂)_k—O—, wherein k is from 1 to 3;

[0731] each R₆ and R₇ is, independently, H, halogen, C₁-C₆ alkyl or substituted C₁-C₆ alkyl;

[0732] each X^G is O, S or N(E₁);

[0733] R₈ is H, halogen, C₁-C₆ alkyl, substituted C₁-C₆ alkyl, C₂-C₆ alkenyl, substituted C₂-C₆ alkenyl, C₂-C₆ alkynyl, substituted C₂-C₆ alkynyl or N(E₂)(E₃);

[0734] E₁, E₂ and E₃ are each, independently, H, C₁-C₆ alkyl or substituted C₁-C₆ alkyl;

[0735] n is from 1 to 6;

[0736] m is 0 or 1;

[0737] j is 0 or 1;

[0738] each substituted group comprises one or more optionally protected substituent groups independently selected from halogen, OJ₁, N(J₁)(J₂), NJ₁, SJ₁, N₃, CN, OC(═X₂)J₁, OC(═X₂)N(J₁)(J₂) and C(=Q₂)N(J₁)(J₂); Q₂ is O, S or NJ₃;

[0739] each J₁, J₂ and J₃ is, independently, H or C₁-C₆ alkyl.

• [0740] Embodiment 401. The modified oligonucleotide of any of embodiments 396-400, wherein each Z is O.
• [0741] Embodiment 402. The modified oligonucleotide of any of embodiments 396-401, wherein at least one G is selected from H, OH, halogen, C₁-C₆ alkoxy, —O(CH₂)₂OCH₃, or —OCH₂(C═O)NHCH₃.
• [0742] Embodiment 403. The modified oligonucleotide of any of embodiments 396-401, wherein each G is selected from H, OH, halogen, C₁-C₆ alkoxy, —O(CH₂)₂OCH₃, or —OCH₂(C═O)NHCH₃.
• [0743] Embodiment 404. The modified oligonucleotide of any of embodiments 396-402, wherein at least one JR forms a bridge with at least one G, wherein said J^R to G bridge has a formula selected from 4CH(CH₃)—O— or —(CH₂)_k—O′, wherein k is from 1 to 3.
• [0744] Embodiment 405. The modified oligonucleotide of any of embodiments 396-402, wherein each J^R and G form a bridge, wherein said J^R to G bridge has a formula selected from —CH(CH₃)—O— or —(CH₂)_k—O—, wherein k is from 1 to 3.
• [0745] Embodiment 406. The modified oligonucleotide of any of embodiments 404 or 405, wherein at least one Z is O and the corresponding J^R to G bridge has a formula (CH₂)_k—O—, wherein k is 1.
• [0746] Embodiment 407. The modified oligonucleotide of any of embodiments 396-406 wherein each nucleoside of structure A, B, C, D, or E is a stereo standard nucleoside.
• [0747] Embodiment 408. The modified oligonucleotide of any of embodiments 396-406, wherein at least one nucleoside of structure A, B, C, D, or E is a stereo-non-standard nucleoside.
• [0748] Embodiment 409. The modified oligonucleotide of any of embodiments 404-406 or 408, wherein at least one nucleoside having a J^R to G bridge is in the α-L-ribosyl configuration.
• [0749] Embodiment 410. The modified oligonucleotide of any of embodiments 396-409, wherein the modified oligonucleotide comprises at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 regions having structures A, B, C, D, or E.
• [0750] Embodiment 411. The modified oligonucleotide of any of embodiments 396-410, wherein at least one region having structure A, B, C, D, or E is at the 5′ end of the modified oligonucleotide.
• [0751] Embodiment 412. The modified oligonucleotide of any of embodiments 396-410, wherein at least one region having structure A, B, C, D, or E is at the 3′ end of the modified oligonucleotide.
• [0752] Embodiment 413. The modified oligonucleotide of any of embodiments 396-410, wherein at least one region having structure A, B, C, D, or E is internal to the modified oligonucleotide.
• [0753] Embodiment 414. An antisense agent, comprising a modified oligonucleotide consisting of 10-30 linked nucleosides, wherein a region of the modified oligonucleotide has the formula (N_g1)_L1(N_g2)_L2(N_g3)_L3, wherein each N_g is a nucleoside and each L is an internucleoside linking group; wherein each of L₁, and L₂ is a phosphodiester internucleoside linking group, a phosphorothioate internucleoside linking group, or an internucleoside linking group of Formula XVII:

[0754]
wherein L₃ is absent or is a phosphodiester internucleoside linking group, a phosphorothioate internucleoside linking group, or an internucleoside linking group of Formula XVII;
wherein at least one of L₁, L₂, and L₃ an internucleoside linking group of Formula XVII; and at least one of L₁, L₂, and L₃ is a phosphorothioate or a phosphodiester internucleoside linking group,

[0755] wherein independently for each internucleoside linking group of the modified oligonucleotide having Formula XVII:

[0756] X is selected from O or S;

[0757] R₁ is selected from H, C₁-C₆ alkyl, and substituted C₁-C₆ alkyl; and

[0758] T is selected from SO₂R₂, C(═O)R₃, and P(═O)R₄R₅, wherein:

[0759] R₂ is selected from an aryl, a substituted aryl, a heterocycle, a substituted heterocycle, an aromatic heterocycle, a substituted aromatic heterocycle, a diazole, a substituted diazole, a C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ alkenyl, C₁-C₆ alkynyl, substituted C₁-C₆ alkyl, substituted C₁-C₆ alkenyl, substituted C₁-C₆ alkynyl, and a conjugate group;

[0760] R₃ is selected from an aryl, a substituted aryl, CH₃, N(CH₃)₂, OCH₃ and a conjugate;

[0761] R₄ is selected from OCH₃, OH, C₁-C₆ alkyl, substituted C₁-C₆ alkyl and a conjugate; and

[0762] R₅ is selected from OCH₃, OH, C₁-C₆ alkyl, and substituted C₁-C₆ alkyl.

• [0763] Embodiment 415. The modified oligonucleotide of embodiment 414, wherein the modified oligonucleotide comprises at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 regions having the formula (N_g1)_L1(N_g2)_L2(N_g3)_L3.
• [0764] Embodiment 416. The modified oligonucleotide of embodiment 414, wherein at least one region having the formula (N_g1)_L1(N_g2)_L2(N_g3)_L3 is at the 5′ end of the oligonucleotide
• [0765] Embodiment 417. The modified oligonucleotide of embodiment 414, wherein at least one region having the formula (N_g1)_L1(N_g2)_L2(N_g3)_L3 is internal to the oligonucleotide.
• [0766] Embodiment 418. The modified oligonucleotide of embodiment 414, wherein at least one region having the formula (N_g1)_L1(N_g2)_L2(N_g3)_L3 is at the 3′ end of the oligonucleotide.
• [0767] Embodiment 419. The modified oligonucleotide of any of embodiments 311-418, wherein at least one nucleoside of the modified oligonucleotide is a modified nucleoside.
• [0768] Embodiment 420. The modified oligonucleotide of embodiment 419, wherein at least one nucleoside of the modified oligonucleotide is a modified nucleoside selected from a bicyclic nucleoside and a non-bicyclic substituted nucleoside.
• [0769] Embodiment 421. The modified oligonucleotide of any of embodiments 311-420, wherein at least one nucleoside of the modified oligonucleotide is selected from: a β-D-LNA nucleoside, an α-L-LNA nucleoside, an ENA nucleoside, a cEt nucleoside, a 2′-MOE nucleoside, a 2′-OMe nucleoside, a 2′-F nucleoside, a 2′-NMA nucleoside, a 5′-Me nucleoside, a DNA nucleoside, and an RNA nucleoside.
• [0770] Embodiment 422. The modified oligonucleotide of any of embodiments 311-421, wherein each nucleoside of the modified oligonucleotide is selected from: a β-D-LNA nucleoside, an α-L-LNA nucleoside, an ENA nucleoside, a cEt nucleoside, a 2′-MOE nucleoside, a 2′-OMe nucleoside, a 2′-F nucleoside, a 2′-NMA nucleoside, a 5′-Me nucleoside, a DNA nucleoside, and an RNA nucleoside.
• [0771] Embodiment 423. The modified oligonucleotide of any of embodiments 311-422, wherein at least one nucleoside of the modified oligonucleotide is a stereo-non-standard nucleoside.
• [0772] Embodiment 424. The modified oligonucleotide of embodiment 423, wherein the internucleoside linking group linking at least one stereo-non-standard nucleoside to an adjacent nucleoside is an internucleoside linking group of Formula XVII.
• [0773] Embodiment 425. The modified oligonucleotide of embodiment 423 or 424, wherein at least two nucleosides of the modified oligonucleotide are stereo-non-standard nucleosides.
• [0774] Embodiment 426. The modified oligonucleotide of embodiment 425, wherein at least two stereo-non-standard nucleosides of the modified oligonucleotide are adjacent to one another.
• [0775] Embodiment 427. The modified oligonucleotide of embodiment 426, wherein at least two stereo-non-standard nucleosides of the modified oligonucleotide are linked to one another with an internucleoside linking group of Formula XVII.
• [0776] Embodiment 428. The modified oligonucleotide of any of embodiments 423-427, wherein at least one stereo-non-standard nucleoside of the modified oligonucleotide is a stereo-non-standard DNA nucleoside.
• [0777] Embodiment 429. The modified oligonucleotide of embodiment 428 wherein the stereo-non-standard DNA nucleoside is selected from a stereo-non-standard DNA nucleoside having: Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, and Formula VII.
• [0778] Embodiment 430. The modified oligonucleotide of embodiment 429 wherein the stereo-non-standard DNA nucleoside is selected from a stereo-non-standard DNA nucleoside having: Formula V and Formula II.
• [0779] Embodiment 431. The modified oligonucleotide of any of embodiments 423-427, wherein at least one stereo-non-standard nucleoside of the modified oligonucleotide is a substituted stereo-non-standard nucleoside or a stereo-non-standard RNA nucleoside.
• [0780] Embodiment 432. The modified oligonucleotide of embodiment 431, wherein the 2′-substituent of the at least one substituted stereo-non-standard nucleoside of the modified oligonucleotide is selected from: 2′-MOE, 2′-OMe, 2′-F, or 2′-OH.
• [0781] Embodiment 433. The modified oligonucleotide of any of embodiments 311-432, wherein the modified oligonucleotide consists of 12-30 linked nucleosides.
• [0782] Embodiment 434. The modified oligonucleotide of any of embodiments 311-433, wherein the modified oligonucleotide consists of 16-24 linked nucleosides.
• [0783] Embodiment 435. The modified oligonucleotide of any of embodiments 311-434, wherein the modified oligonucleotide consists of 18-22 linked nucleosides.
• [0784] Embodiment 436. The modified oligonucleotide of any of embodiments 311-434, wherein the modified oligonucleotide consists of 16 linked nucleosides.
• [0785] Embodiment 437. The modified oligonucleotide of any of embodiments 311-434, wherein the modified oligonucleotide consists of 17 linked nucleosides.
• [0786] Embodiment 438. The modified oligonucleotide of any of embodiments 311-435, wherein the modified oligonucleotide consists of 18 linked nucleosides.
• [0787] Embodiment 439. The modified oligonucleotide of any of embodiments 311-435, wherein the modified oligonucleotide consists of 19 linked nucleosides.
• [0788] Embodiment 440. The modified oligonucleotide of any of embodiments 311-435, wherein the modified oligonucleotide consists of 20 linked nucleosides.
• [0789] Embodiment 441. The modified oligonucleotide of any of embodiments 311-435, wherein the modified oligonucleotide consists of 21 linked nucleosides.
• [0790] Embodiment 442. The modified oligonucleotide of any of embodiments 311-435, wherein the modified oligonucleotide consists of 22 linked nucleosides.
• [0791] Embodiment 443. The modified oligonucleotide of any of embodiments 311-434, wherein the modified oligonucleotide consists of 23 linked nucleosides.
• [0792] Embodiment 444. The modified oligonucleotide of any of embodiments 311-443, wherein at least one nucleoside of the modified oligonucleotide is selected from: a 2′-OMe nucleoside, a 2′-F nucleoside, and an RNA nucleoside.
• [0793] Embodiment 445. The modified oligonucleotide of any of embodiments 311-444, wherein at least one nucleoside of the modified oligonucleotide is a 2′-OMe nucleoside, and at least one nucleoside of the modified oligonucleotide is an RNA nucleoside.
• [0794] Embodiment 446. The modified oligonucleotide of any of embodiments 444-445, wherein the modified oligonucleotide has a region of alternating nucleoside types having the motif ABABA, wherein each A is a stereo-standard nucleoside of a first type and each B is a stereo-standard nucleoside of a second type, wherein the first type and the second type are different from one another.
• [0795] Embodiment 447. The modified oligonucleotide of embodiment 446, wherein A and B are selected from 2′-F substituted nucleosides, 2′-OMe substituted nucleosides, and stereo-standard RNA nucleosides.
• [0796] Embodiment 448. The modified oligonucleotide of any of embodiments 311-447, wherein the 5′-end of the modified oligonucleotide comprises a stabilized phosphate group.
• [0797] Embodiment 449. The modified oligonucleotide of embodiment 448, wherein the stabilized phosphate group is a 5′-vinyl phosphonate or a 5′-cyclopropyl phosphonate.
• [0798] Embodiment 450. An RNAi agent, comprising a modified oligonucleotide of any of embodiments 311-449.
• [0799] Embodiment 451. The RNAi agent of embodiment 450, wherein the RNAi agent is a single-stranded RNAi agent comprising an RNAi antisense modified oligonucleotide, wherein the RNAi antisense modified oligonucleotide is a modified oligonucleotide of any of embodiments 311-449.
• [0800] Embodiment 452. The RNAi agent of embodiment 450, wherein the RNAi agent is an oligomeric duplex comprising an RNAi antisense modified oligonucleotide and an RNAi sense modified oligonucleotide, wherein the RNAi antisense modified oligonucleotide and/or the RNAi sense modified oligonucleotide is a modified oligonucleotide of any of embodiments 311-449.
• [0801] Embodiment 453. The RNAi agent of embodiment 451 or 452, wherein at least one internucleoside linking group of the RNAi antisense modified oligonucleotide is an internucleoside linking group of Formula XVII.
• [0802] Embodiment 454. The RNAi agent of embodiment 451 or 452, wherein at least two internucleoside linking groups of the RNAi antisense modified oligonucleotide are independently selected internucleoside linking groups of any of embodiments 311-385.
• [0803] Embodiment 455. The RNAi agent of any of embodiments 450-454, wherein at least one of the five 3′-most internucleoside linking groups of the RNAi antisense modified oligonucleotide is an internucleoside linking group of Formula XVII.
• [0804] Embodiment 456. The RNAi agent of any of embodiments 450-454, wherein at least two of the five 3′-most internucleoside linking groups of RNAi antisense modified oligonucleotide is an internucleoside linking group of Formula XVII.
• [0805] Embodiment 457. The RNAi agent of any of embodiments 450-454, wherein at least one internucleoside linking group within the seed region of the RNAi antisense modified oligonucleotide is an internucleoside linking group of Formula XVII.
• [0806] Embodiment 458. The RNAi agent of any of embodiments 450-457, wherein at least one region of the RNAi antisense modified oligonucleotide has structure A, B, C, D, or E.
• [0807] Embodiment 459. The RNAi agent of embodiment 458, wherein at least one region having structure A, B, C, D, or E is within the seed region of the RNAi antisense modified oligonucleotide.
• [0808] Embodiment 460. The RNAi agent of embodiment 458, wherein at least one region having structure A, B, C, D, or E is at the 3′ end of the RNAi antisense modified oligonucleotide.
• [0809] Embodiment 461. The RNAi agent of any of embodiments 450-457, wherein at least one region of the RNAi antisense modified oligonucleotide has the formula (N_g1)_L1(N_g2)_L2(N_g3)_L3, wherein each N_g is a nucleoside and each L is an internucleoside linking group; wherein each of L₁, and L₂ is a phosphodiester internucleoside linking group, a phosphorothioate internucleoside linking group, or an internucleoside linking group of Formula XVII:

[0810]

[0811] wherein L₃ is absent or is a phosphodiester internucleoside linking group, a phosphorothioate internucleoside linking group, or an internucleoside linking group of Formula XVII;

[0812] wherein at least one of L₁, L₂, and L₃ an internucleoside linking group of Formula XVII; and at least one of L₁, L₂, and L₃ is a phosphorothioate or a phosphodiester internucleoside linking group,

[0813] wherein independently for each internucleoside linking group of the modified oligonucleotide having Formula XVII:

• • [0814] X is selected from O or S;
  • [0815] R₁ is selected from H, C₁-C₆ alkyl, and substituted C₁-C₆ alkyl; and
  • [0816] T is selected from SO₂R₂, C(═O)R₃, and P(═O)R₄R₅, wherein:
  • [0817] R₂ is selected from an aryl, a substituted aryl, a heterocycle, a substituted heterocycle, an aromatic heterocycle, a substituted aromatic heterocycle, a diazole, a substituted diazole, a C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ alkenyl, C₁-C₆ alkynyl, substituted C₁-C₆ alkyl, substituted C₁-C₆ alkenyl, substituted C₁-C₆ alkynyl, and a conjugate group;
  • [0818] R₃ is selected from an aryl, a substituted aryl, CH₃, N(CH₃)₂, OCH₃ and a conjugate;
  • [0819] R₄ is selected from OCH₃, OH, C₁-C₆ alkyl, substituted C₁-C₆ alkyl and a conjugate; and

[0820] R₅ is selected from OCH₃, OH, C₁-C₆ alkyl, and substituted C₁-C₆ alkyl.

• [0821] Embodiment 462. The RNAi agent of embodiment 461, wherein at least one region having the formula (N_g1)_L1(N_g2)_L2(N_g3)_L3 is at the 3′ end of the RNAi antisense modified oligonucleotide.
• [0822] Embodiment 463. The RNAi agent of embodiment 461, wherein at least one region having the formula (N_g1)_L1(N_g2)_L2(N_g3)_L3 is within the seed region of the RNAi antisense modified oligonucleotide.
• [0823] Embodiment 464. The RNAi agent of embodiment 450 or 452-463 wherein at least one internucleoside linking group of the RNAi sense modified oligonucleotide is an internucleoside linking group of Formula XVII.
• [0824] Embodiment 465. The RNAi agent of embodiment 464, wherein at least one of the first 5 internucleoside linking groups from the 5′-end of the RNAi sense modified oligonucleotide is an internucleoside linking group of Formula XVII.
• [0825] Embodiment 466. The RNAi agent of any of embodiments 464-465, wherein at least one of the five 3′-most internucleoside linking groups of the RNAi sense modified oligonucleotide is an internucleoside linking group of Formula XVII.
• [0826] Embodiment 467. The RNAi agent of any of embodiments 464-466, wherein at least one of the first 5 internucleoside linking groups from the 5′-end of the RNAi sense modified oligonucleotide and at least one of the five 3′-most linking groups of the RNAi sense modified oligonucleotide is an internucleoside linking group of Formula XVII.
• [0827] Embodiment 468. The RNAi agent of any of embodiments 464-467, wherein at least one region of the RNAi sense modified oligonucleotide has structure A, B, C, D, or E.
• [0828] Embodiment 469. The RNAi agent of embodiment 468, wherein at least one region having structure A, B, C, D, or E is at the 3′ end of the RNAi sense modified oligonucleotide.
• [0829] Embodiment 470. The RNAi agent of embodiment 468, wherein at least one region having structure A, B, C, D, or E is at the 5′ end of the RNAi sense modified oligonucleotide.
• [0830] Embodiment 471. The RNAi agent of any of embodiments 464-467, wherein at least one region of the RNAi sense modified oligonucleotide has the formula (N_g1)_L1(N_g2)_L2(N_g3)_L3, wherein each N_g is a nucleoside and each L is an internucleoside linking group; wherein each of L₁, and L₂ is a phosphodiester internucleoside linking group, a phosphorothioate internucleoside linking group, or an internucleoside linking group of Formula XVII:

[0831]

[0832] wherein L₃ is absent or is phosphodiester internucleoside linking group, a phosphorothioate internucleoside linking group, or an internucleoside linking group of Formula XVII;

[0833] wherein at least one of L₁, L₂, and L₃ an internucleoside linking group of Formula XVII; and at least one of L₁, L₂, and L₃ is a phosphorothioate or a phosphodiester internucleoside linking group,

• • [0834] wherein independently for each internucleoside linking group of the modified oligonucleotide having Formula XVII:
  • [0835] X is selected from O or S;
  • [0836] R₁ is selected from H, C₁-C₆ alkyl, and substituted C₁-C₆ alkyl; and
  • [0837] T is selected from SO₂R₂, C(═O)R₃, and P(═O)R₄R₅, wherein:
  • [0838] R₂ is selected from an aryl, a substituted aryl, a heterocycle, a substituted heterocycle, an aromatic heterocycle, a substituted aromatic heterocycle, a diazole, a substituted diazole, a C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ alkenyl, C₁-C₆ alkynyl, substituted C₁-C₆ alkyl, substituted C₁-C₆ alkenyl, substituted C₁-C₆ alkynyl, and a conjugate group;
  • [0839] R₃ is selected from an aryl, a substituted aryl, CH₃, N(CH₃)₂, OCH₃ and a conjugate;
  • [0840] R₄ is selected from OCH₃, OH, C₁-C₆ alkyl, substituted C₁-C₆ alkyl and a conjugate; and
  • [0841] R₅ is selected from OCH₃, OH, C₁-C₆ alkyl, and substituted C₁-C₆ alkyl.
• [0842] Embodiment 472. The RNAi agent of embodiment 471, wherein at least one region having the formula (N_g1)_L1(N_g2)_L2(N_g3)_L3 is at the 3′ end of the RNAi sense modified oligonucleotide.
• [0843] Embodiment 473. The RNAi agent of embodiment 471, wherein at least one region having the formula (N_g1)_L1(N_g2)_L2(N_g3)_L3 is at the 5′ end of the RNAi sense modified oligonucleotide.
• [0844] Embodiment 474. The modified oligonucleotide of any of embodiments 311-443, wherein each nucleoside of the modified oligonucleotide is a modified nucleoside comprising a modified sugar moiety.
• [0845] Embodiment 475. The modified oligonucleotide of embodiment 474, wherein each modified sugar moiety is independently selected from a bicyclic sugar moiety and a 2′-substituted furanosyl sugar moiety.
• [0846] Embodiment 476. The modified oligonucleotide of embodiment 474 or 475, wherein each modified sugar moiety comprises the same modification.
• [0847] Embodiment 477. The modified oligonucleotide of any of embodiments 474-476, wherein each modified sugar moiety is selected from a 2′-OMe sugar moiety, a 2′-MOE sugar moiety, and a 2′-NMA sugar moiety.
• [0848] Embodiment 478. The modified oligonucleotide of embodiment 476 or 477, wherein the three 3′-most nucleosides comprise a bicyclic sugar moiety, and the remaining nucleosides comprise a 2′-substituted furanosyl sugar moiety.
• [0849] Embodiment 479. The modified oligonucleotide of embodiment 476 or 477, wherein the four 3′-most nucleosides comprise a bicyclic sugar moiety, and the remaining nucleosides comprise a 2′-substituted furanosyl sugar moiety.
• [0850] Embodiment 480. The modified oligonucleotide of embodiment 476 or 477, wherein the five 3′-most nucleosides comprise a bicyclic sugar moiety, and the remaining nucleosides comprise a 2′-substituted furanosyl sugar moiety.
• [0851] Embodiment 481. The modified oligonucleotide of embodiment 476 or 477, wherein the six 3′-most nucleosides comprise a bicyclic sugar moiety, and the remaining nucleosides comprise a 2′-substituted furanosyl sugar moiety.
• [0852] Embodiment 482. The modified oligonucleotide of any of embodiments 476 or 478-481, wherein each bicyclic sugar moiety is selected from among cEt, LNA, and ENA.
• [0853] Embodiment 483. The modified oligonucleotide of embodiment 482, wherein the bicyclic sugar moiety is cEt.
• [0854] Embodiment 484. The modified oligonucleotide of any of embodiments 476 or 478-481, wherein the 2′-substituted furanosyl sugar moiety is selected from 2′-OMe, 2′-MOE, and 2′-F.
• [0855] Embodiment 485. The modified oligonucleotide of any of embodiments 474-484, wherein at least one of the ten 5′-most linking groups of the modified oligonucleotide is an internucleoside linking group of Formula XVII.
• [0856] Embodiment 486. The modified oligonucleotide of embodiment 485, wherein at least 2 of the ten 5′-most linking groups of the modified oligonucleotide are internucleoside linking groups of Formula XVII.
• [0857] Embodiment 487. The modified oligonucleotide of embodiment 485, wherein at least 3 of the ten 5′-most linking groups of the modified oligonucleotide are internucleoside linking groups of Formula XVII.
• [0858] Embodiment 488. The modified oligonucleotide of embodiment 485, wherein at least 4 of the ten 5′-most linking groups of the modified oligonucleotide are internucleoside linking groups of Formula XVII.
• [0859] Embodiment 489. The modified oligonucleotide of embodiment 485, wherein at least 5 of the ten 5′-most linking groups of the modified oligonucleotide are internucleoside linking groups of Formula XVII.
• [0860] Embodiment 490. The modified oligonucleotide of embodiment 485, wherein at least 6 of the ten 5′-most linking groups of the modified oligonucleotide are internucleoside linking groups of Formula XVII.
• [0861] Embodiment 491. The modified oligonucleotide of embodiment 485, wherein the two 5′-most internucleoside linking groups are internucleoside linking groups of Formula XVII.
• [0862] Embodiment 492. The modified oligonucleotide of any of embodiments 478-491, wherein at least one of the ten 3′-most internucleoside linking groups of the modified oligonucleotide is an internucleoside linking group of Formula XVII.
• [0863] Embodiment 493. The modified oligonucleotide of embodiment 492, wherein at least 2 of the ten 3′-most internucleoside linking groups of the modified oligonucleotide are internucleoside linking groups of Formula XVII.
• [0864] Embodiment 494. The modified oligonucleotide of embodiment 492, wherein at least 3 of the ten 3′-most internucleoside linking groups are internucleoside linking groups of Formula XVII.
• [0865] Embodiment 495. The modified oligonucleotide of embodiment 492, wherein at least 4 of the ten 3′-most internucleoside linking groups are internucleoside linking groups of Formula XVII.
• [0866] Embodiment 496. The modified oligonucleotide of embodiment 492, wherein at least 5 of the ten 3′-most internucleoside linking groups are internucleoside linking groups of Formula XVII.
• [0867] Embodiment 497. The modified oligonucleotide of embodiment 492, wherein at least 6 of the ten 3′-most internucleoside linking groups are internucleoside linking groups of Formula XVII.
• [0868] Embodiment 498. The modified oligonucleotide of embodiment 492, wherein the two 3′-most internucleoside linking groups of the modified oligonucleotide are internucleoside linking groups of Formula XVII.
• [0869] Embodiment 499. The modified oligonucleotide of any of embodiments 474-484, wherein the modified oligonucleotide comprises at least one block of at least 3 consecutive internucleoside linking groups of Formula XVII.
• [0870] Embodiment 500. The modified oligonucleotide of any of embodiments 474-484, wherein the modified oligonucleotide comprises at least one block of at least 4 consecutive internucleoside linking groups of Formula XVII.
• [0871] Embodiment 501. The modified oligonucleotide of any of embodiments 474-484, wherein the modified oligonucleotide comprises at least one block of at least 5 consecutive internucleoside linking groups of Formula XVII.
• [0872] Embodiment 502. The modified oligonucleotide of any of embodiments 474-484, wherein the modified oligonucleotide comprises at least one block of at least 6 consecutive internucleoside linking groups of Formula XVII.
• [0873] Embodiment 503. The modified oligonucleotide of any of embodiments 499-502, wherein at least one block of consecutive internucleoside linking groups of Formula XVII is at the 5′ end of the modified oligonucleotide.
• [0874] Embodiment 504. The modified oligonucleotide of any of embodiments 499-502, wherein at least one block of consecutive internucleoside linking groups of Formula XVII is at the 3′ end of the modified oligonucleotide.
• [0875] Embodiment 505. The modified oligonucleotide of any of embodiments 311-443, wherein the modified oligonucleotide comprises a deoxy region consisting of 6-11 linked nucleosides wherein each nucleoside of the deoxy region is either a modified nucleoside or a stereo-standard DNA nucleoside and wherein at least 3 contiguous nucleosides of the deoxy region are stereo-standard DNA nucleosides and not more than three nucleosides of the deoxy region are modified nucleosides.
• [0876] Embodiment 506. The modified oligonucleotide of embodiment 505, wherein at least 4 contiguous nucleosides of the deoxy region are stereo-standard DNA nucleosides.
• [0877] Embodiment 507. The modified oligonucleotide of embodiment 505, wherein at least 5 contiguous nucleosides of the deoxy region are stereo-standard DNA nucleosides.
• [0878] Embodiment 508. The modified oligonucleotide of embodiment 505, wherein at least 6 contiguous nucleosides of the deoxy region are stereo-standard DNA nucleosides.
• [0879] Embodiment 509. The modified oligonucleotide of embodiment 505, wherein at least 7 contiguous nucleosides of the deoxy region are stereo-standard DNA nucleosides.
• [0880] Embodiment 510. The modified oligonucleotide of embodiment 505, wherein at least 8 contiguous nucleosides of the deoxy region are stereo-standard DNA nucleosides.
• [0881] Embodiment 511. The modified oligonucleotide of any of embodiments 505-510, wherein the deoxy region consists of 8-10 linked nucleosides.
• [0882] Embodiment 512. The modified oligonucleotide of any of embodiments 505-510, wherein the deoxy region consists of 9 linked nucleosides.
• [0883] Embodiment 513. The modified oligonucleotide of any of embodiments 505-510, wherein the deoxy region consists of 10 linked nucleosides.
• [0884] Embodiment 514. The modified oligonucleotide of any of embodiments 505-510, wherein the deoxy region consists of 11 linked nucleosides.
• [0885] Embodiment 515. The modified oligonucleotide of any of embodiments 505-510, wherein at least 6 nucleosides of the deoxy region are stereo-standard DNA nucleosides.
• [0886] Embodiment 516. The modified oligonucleotide of any of embodiments 505-510, wherein at least 7 nucleosides of the deoxy region are stereo-standard DNA nucleosides.
• [0887] Embodiment 517. The modified oligonucleotide of any of embodiments 505-510, wherein at least 8 nucleosides of the deoxy region are stereo-standard DNA nucleosides.
• [0888] Embodiment 518. The modified oligonucleotide of any of embodiments 505-510, wherein at least 9 nucleosides of the deoxy region are stereo-standard DNA nucleosides.
• [0889] Embodiment 519. The modified oligonucleotide of any of embodiments 505-518 wherein two nucleosides of the deoxy region are modified nucleosides.
• [0890] Embodiment 520. The modified oligonucleotide of any of embodiments 505-518 wherein one nucleoside of the deoxy region is a modified nucleoside.
• [0891] Embodiment 521. The modified oligonucleotide of any of embodiments 505-520 wherein at least one modified nucleoside of the deoxy region is a stereo-standard modified nucleoside or bicyclic nucleoside selected from a β-D-LNA nucleoside, an α-L-LNA nucleoside, an ENA nucleoside, a cEt nucleoside, a 2′-MOE nucleoside, a 2′-OMe nucleoside, a 2′-F nucleoside, and a 5′-alkyl nucleoside.
• [0892] Embodiment 522. The modified oligonucleotide of any of embodiments 505-520 wherein at least one modified nucleoside of the deoxy region is stereo-non-standard nucleoside.
• [0893] Embodiment 523. The modified oligonucleotide of embodiment 522 wherein the at least one is stereo-non-standard nucleoside of the deoxy region is a stereo-non-standard DNA nucleoside.
• [0894] Embodiment 524. The modified oligonucleotide of embodiment 523 wherein the stereo-non-standard DNA nucleoside is selected from a stereo-non-standard DNA nucleoside having: Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, and Formula VII.
• [0895] Embodiment 525. The modified oligonucleotide of embodiment 524 wherein the stereo-non-standard DNA nucleoside is selected from a stereo-non-standard DNA nucleoside having: Formula V and Formula II.
• [0896] Embodiment 526. The modified oligonucleotide of embodiment 525 wherein at least one stereo-non-standard nucleoside of the deoxy region is a substituted stereo-non-standard nucleoside.
• [0897] Embodiment 527. The modified oligonucleotide of embodiment 526 wherein at least one substituted stereo-non-standard nucleoside has a 2′-substituent selected from: 2′-MOE, 2′-OMe, 2′-F, or 2′-OH.
• [0898] Embodiment 528. The modified oligonucleotide of any of embodiments 505-527, wherein the 2^nd nucleoside from the 5′-end of the deoxy region is a modified nucleoside.
• [0899] Embodiment 529. The modified oligonucleotide of any of embodiments 505-527, wherein the 3^rd nucleoside from the 5′-end of the deoxy region is a modified nucleoside.
• [0900] Embodiment 530. The modified oligonucleotide of any of embodiments 505-527, wherein the 4′ nucleoside from the 5′-end of the deoxy region is a modified nucleoside.
• [0901] Embodiment 531. The modified oligonucleotide of any of embodiments 528-530, wherein the modified nucleoside in the deoxy region is a 2′-OMe nucleoside.
• [0902] Embodiment 532. The modified oligonucleotide of any of embodiments 505-518, wherein each nucleoside of the deoxy region is a stereo-standard DNA nucleoside.
• [0903] Embodiment 533. The modified oligonucleotide of any of embodiments 505-532 wherein at least one internucleoside linking group within the deoxy region is an internucleoside linking group of Formula XVII.
• [0904] Embodiment 534. The modified oligonucleotide of any of embodiments 505-532, wherein the internucleoside linking group linking the 1^st and 2^nd nucleosides of the deoxy region as counted from the 5′-end of the deoxy region is an internucleoside linking group of Formula XVII.
• [0905] Embodiment 535. The modified oligonucleotide of any of embodiments 505-534, wherein the internucleoside linking group linking the 2^nd and 3^rd nucleosides of the deoxy region as counted from the 5′-end of the deoxy region is an internucleoside linking group of Formula XVII.
• [0906] Embodiment 536. The modified oligonucleotide of any of embodiments 505-535, wherein the internucleoside linking group linking the 3^rd and 4^th nucleosides of the deoxy region as counted from the 5′-end of the deoxy region is an internucleoside linking group of Formula XVII.
• [0907] Embodiment 537. The modified oligonucleotide of any of embodiments 505-536, wherein the internucleoside linking group linking the 4^th and 5^th nucleosides of the deoxy region as counted from the 5′-end of the deoxy region is an internucleoside linking group of Formula XVII.
• [0908] Embodiment 538. The modified oligonucleotide of any of embodiments 505-537, wherein one internucleoside linking group in the deoxy region is a linking group of Formula XVII and the other internucleoside linking groups of the deoxy region are each phosphodiester or phosphorothioate internucleoside linking groups.
• [0909] Embodiment 539. The modified oligonucleotide of any of embodiments 505-537, wherein two internucleoside linking groups in the deoxy region are linking groups of Formula XVII and the other internucleoside linking groups of the deoxy region are each phosphodiester or phosphorothioate internucleoside linking groups.
• [0910] Embodiment 540. The modified oligonucleotide of any of embodiments 505-537, wherein three internucleoside linking groups in the deoxy region are linking groups linking groups of Formula XVII and the other internucleoside linking groups of the deoxy region are each phosphodiester or phosphorothioate internucleoside linking groups.
• [0911] Embodiment 541. The modified oligonucleotide of any of embodiments 505-540, wherein the deoxy region comprises at least one region having structure A, B, C, D, or E.
• [0912] Embodiment 542. The modified oligonucleotide of embodiment 541, wherein the region having structure A, B, C, D, or E is at the 3′ end of the deoxy region.
• [0913] Embodiment 543. The modified oligonucleotide of embodiment 541, wherein the region having structure A, B, C, D, or E is at the 5′ end of the deoxy region.
• [0914] Embodiment 544. The modified oligonucleotide of any of embodiments 505-540, wherein the deoxy region comprises at least one region having the formula (N_g1)_L1(N_g2)_L2(N_g3)_L3, wherein each N_g is a nucleoside and each L is an internucleoside linking group; wherein each of L₁, and L₂ is a phosphodiester internucleoside linking group, a phosphorothioate internucleoside linking group, or an internucleoside linking group of Formula XVII:

[0915]

[0916] wherein L₃ is absent or is a phosphodiester internucleoside linking group, a phosphorothioate internucleoside linking group, or an internucleoside linking group of Formula XVII;

[0917] wherein at least one of L₁, L₂, and L₃ an internucleoside linking group of Formula XVII; and at least one of L₁, L₂,

[0918] and L₃ is a phosphorothioate or a phosphodiester internucleoside linking group,

• • [0919] wherein independently for each internucleoside linking group of the modified oligonucleotide having Formula XVII:
  • [0920] X is selected from O or S;
  • [0921] R₁ is selected from H, C₁-C₆ alkyl, and substituted C₁-C₆ alkyl; and
  • [0922] T is selected from SO₂R₂, C(═O)R₃, and P(═O)R₄R₅, wherein:
  • [0923] R₂ is selected from an aryl, a substituted aryl, a heterocycle, a substituted heterocycle, an aromatic heterocycle, a substituted aromatic heterocycle, a diazole, a substituted diazole, a C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ alkenyl, C₁-C₆ alkynyl, substituted C₁-C₆ alkyl, substituted C₁-C₆ alkenyl, substituted C₁-C₆ alkynyl, and a conjugate group;
  • [0924] R₃ is selected from an aryl, a substituted aryl, CH₃, N(CH₃)₂, OCH₃ and a conjugate;
  • [0925] R₄ is selected from OCH₃, OH, C₁-C₆ alkyl, substituted C₁-C₆ alkyl and a conjugate; and
  • [0926] R₅ is selected from OCH₃, OH, C₁-C₆ alkyl, and substituted C₁-C₆ alkyl.
• [0927] Embodiment 545. The modified oligonucleotide of any of embodiments 544, wherein the region having the formula (N_g1)_L1(N_g2)_L2(N_g3)_L3 is at the 3′ end of the deoxy region.
• [0928] Embodiment 546. The modified oligonucleotide of any of embodiments 544, wherein the region having the formula (N_g1)_L1(N_g2)_L2(N_g3)_L3 is at the 5′ end of the deoxy region.
• [0929] Embodiment 547. The modified oligonucleotide of any of embodiments 505-546 wherein the deoxy region is flanked on the 5′ side by a 5′-region consisting of 1-6 linked 5′-region nucleosides and on the 3′ side by a 3′-region consisting of 1-6 linked 3′-region nucleosides; wherein the 3′-most nucleoside of the 5′-region is a modified nucleoside; and the 5′-most nucleoside of the 3′-region is a modified nucleoside.
• [0930] Embodiment 548. The modified oligonucleotide of embodiment 547, wherein the deoxy region consists of 7-11 linked nucleosides, and has the formula:
  (N_d1)_L1(N_d2)_L2(N_d3)_L3(N_d4)_L4[(N_d)_L5]_q;

[0931] wherein N_d1, N_d2, N_d3, N_d4 are independently selected from among

[0932] a stereo-standard DNA nucleoside, a stereo-non-standard DNA nucleoside, or a 2′-substituted nucleoside; with the proviso that no more than one of N_d1, N_d2, N_d3, or N_d4 is a 2′-substituted nucleoside;

[0933] each N_d is independently selected from among a stereo-standard DNA nucleoside and a stereo-non-standard DNA nucleoside;

[0934] q is from 3-8;

[0935] wherein each of L₁, L₂, L₃, L₄, and each L₅ is an internucleoside linkage;

[0936] wherein at least two of L₁, L₂, L₃, L₄ are internucleoside linkages of Formula XVII.

• [0937] Embodiment 549. The modified oligonucleotide of embodiment 548, wherein one of N_d1, N_dz, N_d3, or N_d4 is a 2′-substituted nucleoside.
• [0938] Embodiment 550. The modified oligonucleotide of embodiment 549, wherein the 2′-substituted nucleoside is a 2′-OMe nucleoside.
• [0939] Embodiment 551. The modified oligonucleotide of embodiment 550, wherein the 2′-OMe nucleoside is a stereo-standard 2′-OMe nucleoside.
• [0940] Embodiment 552. The modified oligonucleotide of any of embodiments 548-551, wherein the 2′-substituted nucleoside is N_d2
• [0941] Embodiment 553. The modified oligonucleotide of embodiment 548, wherein each of N_d1, N_d2, N_d3, N_d4 and each N_d is a DNA nucleoside.
• [0942] Embodiment 554. The modified oligonucleotide of embodiment 553, wherein each DNA nucleoside is a stereo-standard DNA nucleoside.
• [0943] Embodiment 555. The modified oligonucleotide of any of embodiments 548-554, wherein L₁ and L₂ are internucleoside linkages of Formula XVII.
• [0944] Embodiment 556. The modified oligonucleotide of any of embodiments 548-554, wherein L₂ and L₃ are internucleoside linkages of Formula XVII.
• [0945] Embodiment 557. The modified oligonucleotide of any of embodiments 548-554, wherein L₃ and L₄ are internucleoside linkages of Formula XVII.
• [0946] Embodiment 558. The modified oligonucleotide of any of embodiments 548-554, wherein L₁, L₂, and L₃ are internucleoside linkages of Formula XVII.
• [0947] Embodiment 559. The modified oligonucleotide of any of embodiments 548-554, wherein L₂, L₃, and L₄, are internucleoside linkages of Formula XVII.
• [0948] Embodiment 560. The modified oligonucleotide of any of embodiments 548-554, wherein L₁, L₂, L₃, and L₄ are internucleoside linkages of Formula XVII.
• [0949] Embodiment 561. The modified oligonucleotide of any of embodiments 547-560, wherein the 5′-region consists of 2-5 linked nucleosides.
• [0950] Embodiment 562. The modified oligonucleotide of embodiment 561, wherein the 5′-region consists of 3 linked nucleosides.
• [0951] Embodiment 563. The modified oligonucleotide of embodiment 561, wherein the 5′-region consists of 5 linked nucleosides.
• [0952] Embodiment 564. The modified oligonucleotide of any of embodiments 547-563 wherein each nucleoside of the 5′-region is a modified nucleoside.
• [0953] Embodiment 565. The modified oligonucleotide of any of embodiments 547-564, wherein each nucleoside of the 5′-region is a modified nucleoside comprising a modified sugar.
• [0954] Embodiment 566. The modified oligonucleotide of any of embodiments 547-565, wherein at least one nucleoside of the 5′-region comprises a 2′-substituted furanosyl sugar moiety.
• [0955] Embodiment 567. The modified oligonucleotide of any of embodiments 547-566, wherein each nucleoside of the 5′-region comprises a 2′-substituted furanosyl sugar moiety.
• [0956] Embodiment 568. The modified oligonucleotide of any or embodiments 547-567, wherein each 2′-substituted furanosyl sugar moiety of the 5′-region has a 2′-substituent selected from among 2′-MOE, 2′-OMe, and 2′-NMA.
• [0957] Embodiment 569. The modified oligonucleotide of any of embodiments 547-566 or 568, wherein at least one nucleoside of the 5′-region comprises a bicyclic furanosyl sugar moiety.
• [0958] Embodiment 570. The modified oligonucleotide of any of embodiments 547-566 or 568-569, wherein each nucleoside of the 5′-region comprises a bicyclic furanosyl sugar moiety.
• [0959] Embodiment 571. The modified oligonucleotide of embodiment 569 or 570, wherein each bicyclic sugar moiety of the 5′-region is selected from among cEt, LNA, and ENA.
• [0960] Embodiment 572. The modified oligonucleotide of embodiment 571, wherein each bicyclic sugar moiety of the 5′-region is a cEt sugar moiety.
• [0961] Embodiment 573. The modified oligonucleotide of any of embodiments 547-563, 566 or 569, wherein at least one nucleoside of the 5′ region is a stereo-standard DNA nucleoside.
• [0962] Embodiment 574. The modified oligonucleotide of any of embodiments 547-572, wherein at least one nucleoside of the 5′ region is a stereo-non-standard nucleoside.
• [0963] Embodiment 575. The modified oligonucleotide of any of embodiments 547-574, wherein each nucleobase of the 5′-region is independently selected from among thymine, uracil, guanine, cytosine, 5-methylcytosine, and adenine.
• [0964] Embodiment 576. The modified oligonucleotide of any of embodiments 547-575, wherein the 3′-region consists of 2-5 linked nucleosides.
• [0965] Embodiment 577. The modified oligonucleotide of embodiment 576, wherein the 3′-region consists of 3 linked nucleosides.
• [0966] Embodiment 578. The modified oligonucleotide of embodiment 576, wherein the 3′-region consists of 5 linked nucleosides.
• [0967] Embodiment 579. The modified oligonucleotide of any of embodiments 547-578, wherein each nucleoside of the 3′-region is a modified nucleoside.
• [0968] Embodiment 580. The modified oligonucleotide of any of embodiments 547-578, wherein each nucleoside of the 3′-region is a modified nucleoside comprising a modified sugar.
• [0969] Embodiment 581. The modified oligonucleotide of any of embodiments 547-580, wherein at least one nucleoside of the 3′-region comprises a 2′-substituted furanosyl sugar moiety.
• [0970] Embodiment 582. The modified oligonucleotide of any of embodiments 547-581, wherein each nucleoside of the 3′-region comprises a 2′-substituted furanosyl sugar moiety.
• [0971] Embodiment 583. The modified oligonucleotide of any or embodiments 547-582, wherein each 2′-substituted furanosyl sugar moiety of the 3′-region has a 2′-substituent selected from among 2′-MOE, 2′-OMe, and 2′-NMA.
• [0972] Embodiment 584. The modified oligonucleotide of any of embodiments 547-581 or 583, wherein at least one nucleoside of the 3′-region comprises a bicyclic furanosyl sugar moiety.
• [0973] Embodiment 585. The modified oligonucleotide of any of embodiments 547-580 or 584, wherein each nucleoside of the 3′-region comprises a bicyclic furanosyl sugar moiety.
• [0974] Embodiment 586. The modified oligonucleotide of embodiment 584 or 585, wherein each bicyclic sugar moiety of the 3′-region is selected from among cEt, LNA, and ENA.
• [0975] Embodiment 587. The modified oligonucleotide of embodiment 586, wherein each bicyclic sugar moiety of the 3′-region is a cEt sugar moiety.
• [0976] Embodiment 588. The modified oligonucleotide of any of embodiments 547-578, 581 or 584, wherein at least one nucleoside of the 3′ region is a stereo-standard DNA nucleoside.
• [0977] Embodiment 589. The modified oligonucleotide of any of embodiments 547-588, wherein at least one nucleoside of the 3′ region is a stereo-non-standard nucleoside.
• [0978] Embodiment 590. The modified oligonucleotide of any of embodiments 547-589, wherein each nucleobase of the 3′-region is independently selected from among thymine, uracil, guanine, cytosine, 5-methylcytosine, and adenine.
• [0979] Embodiment 591. The modified oligonucleotide of any of embodiments 547-590 wherein the modified oligonucleotide is a gapmer.
• [0980] Embodiment 592. The modified oligonucleotide of any of embodiments 311-432, wherein the modified oligonucleotide is a CRISPR compound.
• [0981] Embodiment 593. The modified oligonucleotide of embodiment 592, wherein the CRISPR compound consists of 20-50 linked nucleosides.
• [0982] Embodiment 594. The modified oligonucleotide of embodiment 592, wherein the CRISPR compound consists of 29-32 linked nucleosides.
• [0983] Embodiment 595. The modified oligonucleotide of any of embodiments 311-432, wherein the modified oligonucleotide is an artificial mRNA compound.
• [0984] Embodiment 596. The artificial mRNA compound of embodiment 595, wherein the artificial mRNA oligonucleotide consists of 17-3000 linked nucleosides.
• [0985] Embodiment 597. The artificial mRNA compound of embodiment 595 or 596, wherein the artificial mRNA oligonucleotide encodes a protein.
• [0986] Embodiment 598. The modified oligonucleotide of any of embodiments 396-597, wherein each X is P.
• [0987] Embodiment 599. The modified oligonucleotide of any of embodiments 396-597, wherein each X is S.
• [0988] Embodiment 600. The modified oligonucleotide of any of embodiments 396-599, wherein at least one R₁ is H.
• [0989] Embodiment 601. The modified oligonucleotide of any of embodiments 396-599, wherein at least one R₁ is a C₁-C₆ alkyl.
• [0990] Embodiment 602. The modified oligonucleotide of embodiment 601, wherein the at least one R₁ is methyl.
• [0991] Embodiment 603. The modified oligonucleotide of any of embodiments 396-602, at least one R₁ is a substituted C₁-C₆ alkyl.
• [0992] Embodiment 604. The modified oligonucleotide of any of embodiments 396-603, wherein at least one T comprises a conjugate group.
• [0993] Embodiment 605. The modified oligonucleotide of embodiment 604, wherein the conjugate group comprises a carbohydrate or carbohydrate cluster.
• [0994] Embodiment 606. The modified oligonucleotide of embodiment 604 or 605, wherein the conjugate group comprises at least one GalNAc.
• [0995] Embodiment 607. The modified oligonucleotide of embodiment 604, wherein the conjugate group comprises a C₁₀-C₂₀ alkyl chain.
• [0996] Embodiment 608. The modified oligonucleotide of embodiment 607, wherein the conjugate group comprises C₁₆ alkyl.
• [0997] Embodiment 609. The modified oligonucleotide of any of embodiments 396-603, wherein at least one T does not comprise a conjugate group.
• [0998] Embodiment 610. The modified oligonucleotide of any of embodiments 396-603, wherein each T does not comprise a conjugate group.
• [0999] Embodiment 611. The modified oligonucleotide of any of embodiments 396-603, wherein at least one T is SO₂R₂.
• [1000] Embodiment 612. The modified oligonucleotide of embodiment 611, wherein R₂ is an aryl.
• [1001] Embodiment 613. The modified oligonucleotide of embodiment 611, wherein R₂ is a substituted aryl.
• [1002] Embodiment 614. The modified oligonucleotide of embodiment 611, wherein R₂ is a heterocycle.
• [1003] Embodiment 615. The modified oligonucleotide of embodiment 611, wherein R₂ is a substituted heterocycle.
• [1004] Embodiment 616. The modified oligonucleotide of embodiment 611, wherein R₂ is an aromatic heterocycle.
• [1005] Embodiment 617. The modified oligonucleotide of embodiment 611, wherein R₂ is a substituted aromatic heterocycle.
• [1006] Embodiment 618. The modified oligonucleotide of embodiment 611, wherein R₂ is a diazole.
• [1007] Embodiment 619. The modified oligonucleotide of embodiment 611, wherein R₂ is a substituted diazole.
• [1008] Embodiment 620. The modified oligonucleotide of embodiment 611, wherein R₂ is an amine.
• [1009] Embodiment 621. The modified oligonucleotide of embodiment 611, wherein R₂ is a substituted amine.
• [1010] Embodiment 622. The modified oligonucleotide of embodiment 611, wherein R₂ is a C₁-C₆ alkoxy, C₁-C₆ alkenyl, or C₁-C₆ alkynyl.
• [1011] Embodiment 623. The modified oligonucleotide of embodiment 611, wherein R₂ is C₁-C₂₀, C₁-C₆, C₂-C₂₀, C₂-C₆, or C₁₀-C₂₀ alkyl.
• [1012] Embodiment 624. The modified oligonucleotide of embodiment 611, wherein R₂ is substituted C₁-C₂₀, C₁-C₆, C₂-C₂₀, C₂-C₆, or C₁₀-C₂₀ alkyl.
• [1013] Embodiment 625. The modified oligonucleotide of embodiment 611, wherein R₂ comprises a carbohydrate or carbohydrate cluster.
• [1014] Embodiment 626. The modified oligonucleotide of embodiment 611, wherein R₂ comprises at least one GalNAc.
• [1015] Embodiment 627. The modified oligonucleotide of embodiment 611, wherein T is:

[1016]

• [1017] Embodiment 628. The modified oligonucleotide of embodiment 611, wherein T is:

[1018]

• [1019] Embodiment 629. The modified oligonucleotide of embodiment 611, wherein T is:

[1020]

• [1021] Embodiment 630. The modified oligonucleotide of embodiment 611, wherein T is:

[1022]

• [1023] Embodiment 631. The modified oligonucleotide of embodiment 611, wherein T is:

[1024]

• [1025] Embodiment 632. The modified oligonucleotide of embodiment 611, wherein T is:

[1026]

• [1027] Embodiment 633. The modified oligonucleotide of embodiment 611, wherein T is:

[1028]

• [1029] Embodiment 634. The modified oligonucleotide of embodiment 611, wherein T is:

[1030]

• [1031] Embodiment 635. The modified oligonucleotide of embodiment 611, wherein T is:

[1032]

• [1033] Embodiment 636. The modified oligonucleotide of embodiment 611, wherein T is:

[1034]
wherein n is from 2 to 20.

• [1035] Embodiment 637. The modified oligonucleotide of embodiment 636, wherein n is 15.
• [1036] Embodiment 638. The modified oligonucleotide of any of embodiments 396-603, wherein at least one T is C(═O)R₃.
• [1037] Embodiment 639. The modified oligonucleotide of embodiment 638, wherein R₃ is an aryl.
• [1038] Embodiment 640. The modified oligonucleotide of embodiment 638, wherein R₃ is a substituted aryl.
• [1039] Embodiment 641. The modified oligonucleotide of embodiment 638, wherein R₃ is CH₃.
• [1040] Embodiment 642. The modified oligonucleotide of embodiment 638, wherein R₃ is N(CH₃)₂.
• [1041] Embodiment 643. The modified oligonucleotide of embodiment 638, wherein R₃ is OCH₃.
• [1042] Embodiment 644. The modified oligonucleotide of embodiment 638, wherein R₃ is a C₁-C₆ alkoxy.
• [1043] Embodiment 645. The modified oligonucleotide of embodiment 638, wherein R₃ is C₁-C₂₀, C₁-C₆, C₂-C₂₀, C₂-C₆, or C₁₀-C₂₀ alkyl.
• [1044] Embodiment 646. The modified oligonucleotide of embodiment 638, wherein R₃ is substituted C₁-C₂₀, C₁-C₆, C₂-C₂₀, C₂-C₆, or C₁₀-C₂₀ alkyl.
• [1045] Embodiment 647. The modified oligonucleotide of embodiment 638, wherein R₃ comprises a carbohydrate or carbohydrate cluster.
• [1046] Embodiment 648. The modified oligonucleotide of embodiment 638, wherein R₂₃ comprises at least one GalNAc.
• [1047] Embodiment 649. The modified oligonucleotide of embodiment 638, wherein T is:

[1048]

• [1049] Embodiment 650. The modified oligonucleotide of embodiment 638, wherein T is:

[1050]

• [1051] Embodiment 651. The modified oligonucleotide of embodiment 638, wherein T is:

[1052]

• [1053] Embodiment 652. The modified oligonucleotide of embodiment 638, wherein T is:

[1054]

• [1055] Embodiment 653. The modified oligonucleotide of embodiment 638, wherein T is:

[1056]
wherein n is from 2 to 20.

• [1057] Embodiment 654. The modified oligonucleotide of embodiment 653, wherein n is 15.
• [1058] Embodiment 655. The modified oligonucleotide of any of embodiments 396-603, wherein at least one T is P(═O)R₄R₅.
• [1059] Embodiment 656. The modified oligonucleotide of embodiment 655, wherein R₄ is OCH₃.
• [1060] Embodiment 657. The modified oligonucleotide of embodiment 655, wherein R₄ is OH.
• [1061] Embodiment 658. The modified oligonucleotide of embodiment 655, wherein R₄ is C₁-C₆ alkyl.
• [1062] Embodiment 659. The modified oligonucleotide of embodiment 655, wherein R₄ is substituted C₁-C₆ alkyl.
• [1063] Embodiment 660. The modified oligonucleotide of embodiment 655, wherein R₄ is C₁-C₂₀, C₁-C₆, C₂-C₂₀, C₂-C₆, or C₁₀-C₂₀ alkyl.
• [1064] Embodiment 661. The modified oligonucleotide of embodiment 655, wherein R₄ is substituted C₁-C₂₀, C₁-C₆, C₂-C₂₀, C₂-C₆, or C₁₀-C₂₀ alkyl.
• [1065] Embodiment 662. The modified oligonucleotide of embodiment 655, wherein R₄ comprises a carbohydrate or carbohydrate cluster.
• [1066] Embodiment 663. The modified oligonucleotide of embodiment 655, wherein R₄ comprises at least one GalNAc.
• [1067] Embodiment 664. The modified oligonucleotide of any of embodiments 655-663, wherein R₅ is OCH₃.
• [1068] Embodiment 665. The modified oligonucleotide of any of embodiments 655-663, wherein R₅ is OH.
• [1069] Embodiment 666. The modified oligonucleotide of any of embodiments 655-663, wherein R₅ is C₁-C₆ alkyl.
• [1070] Embodiment 667. The modified oligonucleotide of any of embodiments 655-663, wherein R₅ is substituted C₁-C₆ alkyl.
• [1071] Embodiment 668. The modified oligonucleotide of embodiment 655, wherein T is:

[1072]

• [1073] Embodiment 669. The modified oligonucleotide of embodiment 655, wherein T is:

[1074]

• [1075] Embodiment 670. The modified oligonucleotide of embodiment 655, wherein T is:

[1076]
n wherein n is from 2 to 20.

• [1077] Embodiment 671. The modified oligonucleotide of embodiment 670, wherein n is 15.
• [1078] Embodiment 672. A chirally enriched population of modified oligonucleotides of any of embodiments 311-671, wherein the population is enriched for modified oligonucleotides comprising at least one particular internucleoside linking group having a particular stereochemical configuration.
• [1079] Embodiment 673. The chirally enriched population of modified oligonucleotides of embodiment 672, wherein the particular internucleoside linking group having a particular stereochemical configuration is an internucleoside linking group of Formula XVIII, as indicated in Formula XVIIIa and XVIIIb below:

[1080]

• [1081] Embodiment 674. The chirally enriched population of modified oligonucleotides of embodiment 672, wherein the particular internucleoside linking group having a particular stereochemical configuration is a phosphorothioate internucleoside linking group.
• [1082] Embodiment 675. The chirally enriched population of any of embodiments 672-674, wherein the population is enriched for modified oligonucleotides comprising at least one particular internucleoside linkage having the (Sp) configuration.
• [1083] Embodiment 676. The chirally enriched population of any of embodiments 672-675, wherein the population is enriched for modified oligonucleotides comprising at least one particular internucleoside linkage having the (Rp) configuration.
• [1084] Embodiment 677. The chirally enriched population of embodiment 672, wherein the population is enriched for modified oligonucleotides having a particular, independently selected stereochemical configuration at each chiral internucleoside linkage.
• [1085] Embodiment 678. The chirally enriched population of any of embodiments 672-677, wherein the population is enriched for modified oligonucleotides having the (Sp) configuration at each chiral internucleoside linkage.
• [1086] Embodiment 679. The chirally enriched population of any of embodiments 672-677, wherein the population is enriched for modified oligonucleotides having the (Rp) configuration at each chiral internucleoside linkage.
• [1087] Embodiment 680. The chirally enriched population of any of embodiments 672-677, wherein the population is enriched for modified oligonucleotides having the (Rp) configuration at one particular chiral internucleoside linkage and the (Sp) configuration at each of the remaining chiral internucleoside linkages.
• [1088] Embodiment 681. The chirally enriched population of embodiment 673, wherein each phosphorothioate internucleoside linkage is stereorandom.
• [1089] Embodiment 682. The modified oligonucleotide of any of embodiments 311-681, wherein the nucleobase sequence of the modified oligonucleotide is complementary to a target nucleic acid.
• [1090] Embodiment 683. The modified oligonucleotide of embodiment 682, wherein the nucleobase sequence of the modified oligonucleotide is at least 80% complementary to the target nucleic acid.
• [1091] Embodiment 684. The modified oligonucleotide of embodiment 682, wherein the nucleobase sequence of the modified oligonucleotide is at least 85% complementary to the target nucleic acid.
• [1092] Embodiment 685. The modified oligonucleotide of embodiment 682, wherein the nucleobase sequence of the modified oligonucleotide is at least 90% complementary to the target nucleic acid.
• [1093] Embodiment 686. The modified oligonucleotide of embodiment 682, wherein the nucleobase sequence of the modified oligonucleotide is at least 95% complementary to the target nucleic acid.
• [1094] Embodiment 687. The modified oligonucleotide of embodiment 682, wherein the nucleobase sequence of the modified oligonucleotide is 100% complementary to the target nucleic acid.
• [1095] Embodiment 688. The modified oligonucleotide of any of embodiments 682-687, wherein the target nucleic acid is a target RNA.
• [1096] Embodiment 689. The modified oligonucleotide of embodiment 688, wherein the target RNA is selected from: an mRNA, a pre-mRNA, a microRNA, and a non-coding RNA.
• [1097] Embodiment 690. The modified oligonucleotide of embodiment 688, wherein the target RNA is not a microRNA.
• [1098] Embodiment 691. The modified oligonucleotide of any of embodiments 311-690, wherein the modified oligonucleotide is not complementary to miR-21.
• [1099] Embodiment 692. The modified oligonucleotide of any of embodiments 311-691, comprising a conjugate group.
• [1100] Embodiment 693. The modified oligonucleotide of embodiment 692, wherein the conjugate group comprises at least one GalNAc.
• [1101] Embodiment 694. The modified oligonucleotide of embodiment 692 or 693, wherein the conjugate group comprises 1-5 linker-nucleosides.
• [1102] Embodiment 695. A pharmaceutical composition comprising the modified oligonucleotide of any of embodiments 311-694 and a pharmaceutically acceptable carrier or diluent.
• [1103] Embodiment 696. A method comprising contacting a cell with the modified oligonucleotide or pharmaceutical composition of any of embodiments 311-695.
• [1104] Embodiment 697. A method of modulating the amount or activity of a target nucleic acid in a cell, comprising contacting the cell with the modified oligonucleotide or pharmaceutical composition of any of embodiments 311-695 and thereby modulating the amount or activity of the target nucleic acid.
• [1105] Embodiment 698. A method of modulating the amount or activity of a target nucleic acid in a cell, comprising contacting the cell with the modified oligonucleotide or pharmaceutical composition of any of embodiments 311-695.
• [1106] Embodiment 699. The method of embodiments 696-698, wherein the amount or activity of a target nucleic acid is reduced.
• [1107] Embodiment 700. The method of embodiments 696-698, wherein the amount or activity of a target nucleic acid is increased.
• [1108] Embodiment 701. The method of embodiment 700, wherein the target protein is encoded by a target nucleic acid comprising at least one translation suppression element and wherein the modified oligonucleotide is complementary to a target site within a translation suppression element region of the target nucleic acid.
• [1109] Embodiment 702. The method of embodiment 701, wherein the translation suppression element region comprises at least one stem-loop structure.
• [1110] Embodiment 703. Use of the modified oligonucleotide or composition of any of embodiments 311-695 for treatment of a disease or condition.
• [1111] Embodiment 704. Use of the modified oligonucleotide or composition of any of embodiments 311-695 for a preparation of a medicament for treatment of a disease or condition.
• [1112] Embodiment 705. An antisense agent comprising a modified oligonucleotide consisting of 12-70 linked nucleosides linked through internucleoside linking groups, wherein at least one nucleoside comprises a modified sugar moiety, and wherein at least one of the internucleoside linking groups has Formula XVII:

[1113]

• • [1114] wherein independently for each internucleoside linking group of the modified oligonucleotide having Formula XVII:
  • [1115] X is selected from O or S;
  • [1116] R₁ is selected from H, C₁-C₆ alkyl, and substituted C₁-C₆ alkyl; and
  • [1117] T is selected from SO₂R₂, C(═O)R₃, and P(═O)R₄R₅, wherein:
  • [1118] R₂ is selected from an aryl, a substituted aryl, a heterocycle, a substituted heterocycle, an aromatic heterocycle, a substituted aromatic heterocycle, a diazole, a substituted diazole, a C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ alkenyl, C₁-C₆ alkynyl, substituted C₁-C₆ alkyl, substituted C₁-C₆ alkenyl substituted C₁-C₆ alkynyl, and a conjugate group;
  • [1119] R₃ is selected from an aryl, a substituted aryl, CH₃, N(CH₃)₂, OCH₃ and a conjugate group;
  • [1120] R₄ is selected from OCH₃, OH, C₁-C₆ alkyl, substituted C₁-C₆ alkyl and a conjugate group; and
  • [1121] R₅ is selected from OCH₃, OH, C₁-C₆ alkyl, and substituted C₁-C₆ alkyl.
• [1122] Embodiment 706. An antisense agent comprising a modified oligonucleotide consisting of 12-70 linked nucleosides linked through internucleoside linking groups, wherein at least one nucleoside comprises a modified sugar moiety, and wherein at least one of the internucleoside linking groups has Formula XVII:

[1123]

• • [1124] wherein independently for each internucleoside linking group of the modified oligonucleotide having Formula XVII:
    • [1125] X is selected from O or S;
    • [1126] R₁ is selected from H, C₁-C₆ alkyl, and substituted C₁-C₆ alkyl; and
    • [1127] T is selected from SO₂R₂, C(═O)R₃, and P(═O)R₄R₅, wherein:
  • [1128] R₂ is selected from an aryl, a substituted aryl, a heterocycle, a substituted heterocycle, an aromatic heterocycle, a substituted aromatic heterocycle, a diazole, a substituted diazole, a C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ alkenyl, C₁-C₆ alkynyl, substituted C₁-C₆ alkyl, substituted C₁-C₆ alkenyl substituted C₁-C₆ alkynyl, and a conjugate group;
  • [1129] R₃ is selected from an aryl, a substituted aryl, CH₃, N(CH₃)₂, OCH₃ and a conjugate group;
  • [1130] R₄ is selected from OCH₃, OH, C₁-C₆ alkyl, substituted C₁-C₆ alkyl and a conjugate group; and
  • [1131] R₅ is selected from OCH₃, OH, C₁-C₆ alkyl, and substituted C₁-C₆ alkyl,
    • [1132] Provided that if X is O and that if R₁ is H then T is not:

[1133]

• [1134] Embodiment 707. The antisense agent of embodiment 705 or embodiment 706, wherein at least one internucleoside linking group is a phosphodiester or a phosphorothioate internucleoside linking group.
• [1135] Embodiment 708. The antisense agent of any of embodiments 705-707, wherein at least one nucleoside comprises a 2′-β-D-deoxyribosyl sugar moiety.
• [1136] Embodiment 709. The modified oligonucleotide of any of embodiments 705-708, wherein for at least one internucleoside linking group of Formula XVII, X is O.
• [1137] Embodiment 710. The modified oligonucleotide of any of embodiments 705-709, wherein for at least one internucleoside linking group of Formula XVII, X is S.
• [1138] Embodiment 711. The modified oligonucleotide of embodiment 705 or 706, wherein for at least one internucleoside linking group of Formula XVII, R₁ is H.
• [1139] Embodiment 712. The modified oligonucleotide of embodiment 705 or 706, wherein for at least one internucleoside linking group of Formula XVII, R₁ is a C₁-C₆ alkyl.
• [1140] Embodiment 713. The modified oligonucleotide of embodiment 710, wherein R₁ is methyl.
• [1141] Embodiment 714. The modified oligonucleotide of embodiment 705 or 706, wherein for at least one internucleoside linking group of Formula XVII, R₁ is a substituted C₁-C₆ alkyl.
• [1142] Embodiment 715. The modified oligonucleotide of any of embodiments 705-714, wherein for at least one internucleoside linking group of Formula XVII, T comprises a conjugate group.
• [1143] Embodiment 716. The modified oligonucleotide of embodiment 715, wherein the conjugate group comprises a cell-targeting moiety.
• [1144] Embodiment 717. The modified oligonucleotide of embodiment 715, wherein the conjugate group comprises a carbohydrate or carbohydrate cluster.
• [1145] Embodiment 718. The modified oligonucleotide of any of embodiments 715-717, wherein the conjugate group comprises at least one GalNAc.
• [1146] Embodiment 719. The modified oligonucleotide of embodiment 715, wherein the conjugate group comprises a C₁-C₂₀ alkyl chain.
• [1147] Embodiment 720. The modified oligonucleotide of embodiment 719, wherein the conjugate group comprises C₁₆ alkyl.
• [1148] Embodiment 721. The modified oligonucleotide of any of embodiments 705-714, wherein for at least one internucleoside linking group of Formula XVII, T does not comprise a conjugate group.
• [1149] Embodiment 722. The modified oligonucleotide of any of embodiments 705-714, wherein for at least one internucleoside linking group of Formula XVII, T does not comprise a cell-targeting moiety.
• [1150] Embodiment 723. The modified oligonucleotide of any of embodiments 705-722, wherein for at least one internucleoside linking group of Formula XVII, T is SO₂R₂.
• [1151] Embodiment 724. The modified oligonucleotide of embodiment 723, wherein R₂ is an aryl.
• [1152] Embodiment 725. The modified oligonucleotide of embodiment 723, wherein R₂ is a substituted aryl.
• [1153] Embodiment 726. The modified oligonucleotide of embodiment 723, wherein R₂ is a heterocycle.
• [1154] Embodiment 727. The modified oligonucleotide of embodiment 723, wherein R₂ is a substituted heterocycle.
• [1155] Embodiment 728. The modified oligonucleotide of embodiment 723, wherein R₂ is an aromatic heterocycle.
• [1156] Embodiment 729. The modified oligonucleotide of embodiment 723, wherein R₂ is a substituted aromatic heterocycle.
• [1157] Embodiment 730. The modified oligonucleotide of embodiment 723, wherein R₂ is a diazole.
• [1158] Embodiment 731. The modified oligonucleotide of embodiment 723, wherein R₂ is a substituted diazole.
• [1159] Embodiment 732. The modified oligonucleotide of embodiment 723, wherein R₂ is an amine.
• [1160] Embodiment 733. The modified oligonucleotide of embodiment 723, wherein R₂ is a substituted amine.
• [1161] Embodiment 734. The modified oligonucleotide of embodiment 723, wherein R₂ is a C₁-C₆ alkoxy, C₁-C₆ alkenyl, or C₁.

[1162] C₆-alkynl.

• [1163] Embodiment 735. The modified oligonucleotide of embodiment 723, wherein R₂ is C₁-C₂₀, C₁-C₆, C₂-C₂₀, C₂-C₆, or C₁₀-C₂₀ alkyl.
• [1164] Embodiment 736. The modified oligonucleotide of embodiment 723, wherein R₂ is substituted C₁-C₂₀, C₁-C₆, C₂-C₂₀, C₂-C₆, or C₁₀-C₂₀ alkyl.
• [1165] Embodiment 737. The modified oligonucleotide of embodiment 723, wherein R₂ comprises a carbohydrate or carbohydrate cluster.
• [1166] Embodiment 738. The modified oligonucleotide of embodiment 723, wherein R₂ comprises at least one GalNAc.
• [1167] Embodiment 739. The modified oligonucleotide of embodiment 723, wherein T is:

[1168]

• [1169] Embodiment 740. The oligomeric compound of embodiment 739, wherein T is:

[1170]

• [1171] Embodiment 741. The modified oligonucleotide of embodiment 723, wherein T is:

[1172]

• [1173] Embodiment 742. The modified oligonucleotide of embodiment 723, wherein T is:

[1174]

• [1175] Embodiment 743. The modified oligonucleotide of embodiment 723, wherein T is:

[1176]

• [1177] Embodiment 744. The modified oligonucleotide of embodiment 723, wherein T is:

[1178]

• [1179] Embodiment 745. The modified oligonucleotide of embodiment 723, wherein T is:

[1180]

• [1181] Embodiment 746. The modified oligonucleotide of embodiment 723, wherein T is:

[1182]

• [1183] Embodiment 747. The modified oligonucleotide of embodiment 723, wherein T is:

[1184]

• [1185] Embodiment 748. The modified oligonucleotide of embodiment 723, wherein T is:

[1186]
wherein n is from 2 to 20.

• [1187] Embodiment 749. The modified oligonucleotide of embodiment 748, wherein n is 15.
• [1188] Embodiment 750. The modified oligonucleotide of any of embodiments 705-722, wherein for at least one internucleoside linking group of Formula XVII, T is C(═O)R₃.
• [1189] Embodiment 751. The modified oligonucleotide of embodiment 750, wherein R₃ is an aryl.
• [1190] Embodiment 752. The modified oligonucleotide of embodiment 750, wherein R₃ is a substituted aryl.
• [1191] Embodiment 753. The modified oligonucleotide of embodiment 750, wherein R₃ is CH₃.
• [1192] Embodiment 754. The modified oligonucleotide of embodiment 750, wherein R₃ is N(CH₃)₂.
• [1193] Embodiment 755. The modified oligonucleotide of embodiment 750, wherein R₃ is OCH₃.
• [1194] Embodiment 756. The modified oligonucleotide of embodiment 750, wherein R₃ is a C₁-C₆ alkoxy.
• [1195] Embodiment 757. The modified oligonucleotide of embodiment 750, wherein R₃ is C₁-C₂₀, C₁-C₆, C₂-C₂₀, C₂-C₆, or C₁₀-C₂₀ alkyl.
• [1196] Embodiment 758. The modified oligonucleotide of embodiment 750, wherein R₃ is substituted C₁-C₂₀, C₁-C₆, C₂-C₂₀, C₂-C₆, or C₁₀-C₂₀ alkyl.
• [1197] Embodiment 759. The modified oligonucleotide of embodiment 750, wherein R₃ comprises a carbohydrate or carbohydrate cluster.
• [1198] Embodiment 760. The modified oligonucleotide of embodiment 750, wherein R₂₃ comprises at least one GalNAc.
• [1199] Embodiment 761. The modified oligonucleotide of embodiment 750, wherein T is:

[1200]

• [1201] Embodiment 762. The modified oligonucleotide of embodiment 750, wherein T is:

[1202]

• [1203] Embodiment 763. The modified oligonucleotide of embodiment 750, wherein T is:

[1204]

• [1205] Embodiment 764. The modified oligonucleotide of embodiment 750, wherein T is:

[1206]

• [1207] Embodiment 765. The modified oligonucleotide of embodiment 750, wherein T is:

[1208]
wherein n is from 2 to 20.

• [1209] Embodiment 766. The modified oligonucleotide of embodiment 765, wherein n is 15.
• [1210] Embodiment 767. The modified oligonucleotide of any of embodiments 705-722, wherein for at least one internucleoside linking group of Formula XVII, T is P(═O)R₄R₅.
• [1211] Embodiment 768. The modified oligonucleotide of embodiment 767, wherein R₄ is OCH₃.
• [1212] Embodiment 769. The modified oligonucleotide of embodiment 767, wherein R₄ is OH.
• [1213] Embodiment 770. The modified oligonucleotide of embodiment 767, wherein R₄ is C₁-C₆ alkyl.
• [1214] Embodiment 771. The modified oligonucleotide of embodiment 767, wherein R₄ is substituted C₁-C₆ alkyl.
• [1215] Embodiment 772. The modified oligonucleotide of embodiment 767, wherein R₄ is C₁-C₂₀, C₁-C₆, C₂-C₂₀, C₂-C₆, or C₁₀-C₂₀ alkyl.
• [1216] Embodiment 773. The modified oligonucleotide of embodiment 767, wherein R₄ is substituted C₁-C₂₀, C₁-C₆, C₂-C₂₀, C₂-C₆, or C₁₀-C₂₀ alkyl.
• [1217] Embodiment 774. The modified oligonucleotide of embodiment 767, wherein R₄ comprises a carbohydrate or carbohydrate cluster.
• [1218] Embodiment 775. The modified oligonucleotide of embodiment 767, wherein R₄ comprises at least one GalNAc.
• [1219] Embodiment 776. The modified oligonucleotide of any of embodiments 767-775, wherein R₅ is OCH₃.
• [1220] Embodiment 777. The modified oligonucleotide of any of embodiments 767-775, wherein R₅ is OH.
• [1221] Embodiment 778. The modified oligonucleotide of any of embodiments 767-775, wherein R₅ is C₁-C₆ alkyl.
• [1222] Embodiment 779. The modified oligonucleotide of any of embodiments 767-775, wherein R₅ is substituted C₁-C₆ alkyl.
• [1223] Embodiment 780. The modified oligonucleotide of embodiment 767, wherein T is:

[1224]

• [1225] Embodiment 781. The modified oligonucleotide of embodiment 767, wherein T is:

[1226]

• [1227] Embodiment 782. The modified oligonucleotide of embodiment 767, wherein T is:

[1228]
wherein n is from 2 to 20.

• [1229] Embodiment 783. The modified oligonucleotide of embodiment 782, wherein n is 15.
• [1230] Embodiment 784. The modified oligonucleotide of any of embodiments 705-783, wherein at least one internucleoside linking group of the modified oligonucleotide is not a linking group of Formula XVII.
• [1231] Embodiment 785. The modified oligonucleotide of any of embodiments 705-784, wherein exactly one internucleoside linking group of the modified oligonucleotide is an internucleoside linking group of Formula XVII.
• [1232] Embodiment 786. The modified oligonucleotide of any of embodiments 705-784, wherein exactly two internucleoside linking groups of the modified oligonucleotide are internucleoside linking groups of Formula XVII.
• [1233] Embodiment 787. The modified oligonucleotide of any of embodiments 705-784, wherein exactly three internucleoside linking groups of the modified oligonucleotide are internucleoside linking groups of Formula XVII.
• [1234] Embodiment 788. The modified oligonucleotide of any of embodiments 705-784, wherein exactly four internucleoside linking groups of the modified oligonucleotide are internucleoside linking groups of Formula XVII.
• [1235] Embodiment 789. The modified oligonucleotide of any of embodiments 705-784, wherein exactly five internucleoside linking groups of the modified oligonucleotide are internucleoside linking groups of Formula XVII.
• [1236] Embodiment 790. The modified oligonucleotide of any of embodiments 705-784, wherein at least six internucleoside linking groups of the modified oligonucleotide are internucleoside linking groups of Formula XVII.
• [1237] Embodiment 791. The modified oligonucleotide of any of embodiment 705-783 or 785-787 having at least two linking groups of Formula XVII, wherein at least two of the linking groups of Formula XVII are the same as one another.
• [1238] Embodiment 792. The modified oligonucleotide of any of embodiments 705-791, wherein each internucleoside linking group of the modified oligonucleotide that is not an internucleoside linking group of Formula XVII is either a phosphodiester internucleoside linking group or a phosphorothioate internucleoside linking group.
• [1239] Embodiment 793. The modified oligonucleotide of any of embodiments 705-784 or 790, wherein each internucleoside linking group of the modified oligonucleotide is an internucleoside linking group of Formula XVII.
• [1240] Embodiment 794. An antisense agent comprising a modified oligonucleotide, wherein at least one region of the modified oligonucleotide has Structure A:

[1241]

• • [1242] wherein:
  • [1243] each Bx is a heterocyclic base moiety;
  • [1244] X is selected from O or S;
  • [1245] each of Y₁ and Y₂ is independently selected from OH or SH;
  • [1246] each of Z¹, Z², and Z³ are independently selected from —(CH₂)_p—X^Z—(CH₂)_q—, wherein p is 0 or 1, q is 0 or
  • [1247] 1, and X^Z is O, S, or N(E₁);
  • [1248] R₁ is selected from H, C₁-C₆ alkyl, and substituted C₁—C alkyl; and
  • [1249] T is selected from SO₂R₂, C(═O)R₃, and P(═O)R₄R₅, wherein:
  • [1250] R₂ is selected from an aryl, a substituted aryl, a heterocycle, a substituted heterocycle, an aromatic heterocycle, a substituted aromatic heterocycle, a diazole, a substituted diazole, a C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ alkenyl, C₁-C₆ alkynyl, substituted C₁-C₆ alkyl, substituted C₁-C₆ alkenyl substituted C₁-C₆ alkynyl, and a conjugate group;
  • [1251] R₃ is selected from an aryl, a substituted aryl, CH₃, N(CH₃)₂, OCH₃ and a conjugate group;
  • [1252] R₄ is selected from OCH₃, OH, C₁-C₆ alkyl, substituted C₁-C₆ alkyl and a conjugate group;
  • [1253] R₅ is selected from OCH₃, OH, C₁-C₆ alkyl, and substituted C₁-C₆ alkyl;
  • [1254] either J^R1 and G¹ form a J^R1 to G¹ bridge, or J^R1 is H and G¹ is selected from H, OH, halogen or O—[C(R₆)(R₇)]_n—[(C═O)_m—X^G]_j—R₈;
  • [1255] either J^R2 and G² form a J^R2 and G² bridge, or J^R2 is H and G² is selected from H, OH, halogen or O—[C(R₆)(R₇)]_n—[(C═O)_m—X^G]_j—R₈;
  • [1256] either J^R3 and G³ form a J^R3 and G³ bridge, or J^R3 is H and G³ is selected from H, OH, halogen or O—[C(R₆)(R₇)]_n—[(C═O)_m—X^G]_j—R₈;
  • [1257] wherein each J^R to G bridge has a formula independently selected from —CH(CH₃)—O— or —(CH₂)_k—O—, wherein k is from 1 to 3;
  • [1258] each R₆ and R₇ is, independently, H, halogen, C₁-C₆ alkyl or substituted C₁-C₆ alkyl;
  • [1259] each X^G is O, S or N(E₁);
  • [1260] R₈ is H, halogen, C₁-C₆ alkyl, substituted C₁-C₆ alkyl, C₂-C₆ alkenyl, substituted C₂-C₆ alkenyl, C₂-C₆ alkynyl, substituted C₂-C₆ alkynyl or N(E₂)(E₃);
  • [1261] E₁, E₂ and E₃ are each, independently, H, C₁-C₆ alkyl or substituted C₁-C₆ alkyl;
  • [1262] n is from 1 to 6;
  • [1263] m is 0 or 1;
  • [1264] j is 0 or 1;
  • [1265] each substituted group comprises one or more optionally protected substituent groups independently selected from halogen, OJ₁, N(J₁)(J₂), ═NJ₁, SJ₁, N₃, CN, OC(═X₂)J₁, OC(═X₂)N(J₁)(J₂) and C(=Q₂)N(J₁)(J₂);
  • [1266] Q₂ is O, S or NJ₃; and
  • [1267] each J₁, J₂ and J₃ is, independently, H or C₁-C₆ alkyl.
• [1268] Embodiment 795. An antisense agent comprising a modified oligonucleotide, wherein at least one region of the modified oligonucleotide has Structure B:

[1269]

• • [1270] wherein:
    • [1271] each Bx is a heterocyclic base moiety;
  • [1272] X is selected from O or S;
  • [1273] each of Y₁ and Y₂ is independently selected from OH or SH;
  • [1274] each of Z₁ and Z² are independently selected from —(CH₂)_p—X^Z—(CH₂)_q—, wherein p is 0 or 1, q is 0 or 1, and X^Z is O, S, or N(E₁);
  • [1275] R₁ is selected from H, C₁-C₆ alkyl, and substituted C₁-C₆ alkyl; and
  • [1276] T is selected from SO₂R₂, C(═O)R₃, and P(═O)R₄R₅, wherein:

[1277] R₂ is selected from an aryl, a substituted aryl, a heterocycle, a substituted heterocycle, an aromatic heterocycle, a substituted aromatic heterocycle, a diazole, a substituted diazole, a C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ alkenyl, C₁-C₆ alkynyl, substituted C₁-C₆ alkyl, substituted C₁-C₆ alkenyl substituted C₁-C₆ alkynyl, and a conjugate group;

• • [1278] R₃ is selected from an aryl, a substituted aryl, CH₃, N(CH₃)₂, OCH₃ and a conjugate group;
  • [1279] R₄ is selected from OCH₃, OH, C₁-C₆ alkyl, substituted C₁-C₆ alkyl and a conjugate group;
  • [1280] R₅ is selected from OCH₃, OH, C₁-C₆ alkyl, and substituted C₁-C₆ alkyl;
  • [1281] either J^R1 and G¹ form a J^R1 to G¹ bridge, or J^R1 is H and G¹ is selected from H, OH, halogen or O—[C(R₆)(R₇)]_n—[(C═O)_m—X^G]_j—R₈;
  • [1282] either J^R2 and G² form a J^R2 and G² bridge, or J^R2 is H and G² is selected from H, OH, halogen or O—[C(R₆)(R₇)]_n—[(C═O)_m—X^G]_j—R₈;
  • [1283] wherein each J^R to G bridge has a formula independently selected from —CH(CH₃)—O— or —(CH₂)_k—O—, wherein k is from 1 to 3;
  • [1284] each R₆ and R₇ is, independently, H, halogen, C₁-C₆ alkyl or substituted C₁-C₆ alkyl;
  • [1285] each X^G is O, S or N(E₁);
  • [1286] R₈ is H, halogen, C₁-C₆ alkyl, substituted C₁-C₆ alkyl, C₂-C₆ alkenyl, substituted C₂-C₆ alkenyl, C₂-C₆ alkynyl, substituted C₂-C₆ alkynyl or N(E₂)(E₃);
  • [1287] E₁, E₂ and E₃ are each, independently, H, C₁-C₆ alkyl or substituted C₁-C₆ alkyl;
  • [1288] n is from 1 to 6;
  • [1289] m is 0 or 1;
  • [1290] j is 0 or 1;
  • [1291] each substituted group comprises one or more optionally protected substituent groups independently selected from halogen, OJ₁, N(J₁)(J₂), ═NJ₁, SJ₁, N₃, CN, OC(═X₂)J₁, OC(═X₂)N(J₁)(J₂) and C(=Q₂)N(J₁)(J₂);
  • [1292] Q₂ is O, S or NJ₃;
  • [1293] each J₁, J₂ and J₃ is, independently, H or C₁-C₆ alkyl.
• [1294] Embodiment 796. An antisense agent comprising a modified oligonucleotide, wherein at least one region of the modified oligonucleotide has Structure C:

[1295]

• • [1296] wherein:
  • [1297] each Bx is a heterocyclic base moiety;
  • [1298] X is selected from O or S;
  • [1299] each of Y₁ and Y₂ is independently selected from OH or SH;
  • [1300] each of Z² and Z³ are independently selected from —(CH₂)_p—X^Z—(CH₂)_q—, wherein p is 0 or 1, q is 0 or 1, and X^Z is O, S, or N(E₁);
  • [1301] R₁ is selected from H, C₁-C₆ alkyl, and substituted C₁-C₆ alkyl; and
  • [1302] T is selected from SO₂R₂, C(═O)R₃, and P(═O)R₄R₅, wherein:

[1303] R₂ is selected from an aryl, a substituted aryl, a heterocycle, a substituted heterocycle, an aromatic heterocycle, a substituted aromatic heterocycle, a diazole, a substituted diazole, a C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ alkenyl, C₁-C₆ alkynyl, substituted C₁-C₆ alkyl, substituted C₁-C₆ alkenyl substituted C₁-C₆ alkynyl, and a conjugate group;

• • [1304] R₃ is selected from an aryl, a substituted aryl, CH₃, N(CH₃)₂, OCH₃ and a conjugate group;
  • [1305] R₄ is selected from OCH₃, OH, C₁-C₆ alkyl, substituted C₁-C₆ alkyl and a conjugate group;
  • [1306] R₅ is selected from OCH₃, OH, C₁-C₆ alkyl, and substituted C₁-C₆ alkyl;
    • [1307] either J^R2 and G² form a J^R2 and G² bridge, or J^R2 is H and G² is selected from H, OH, halogen or O—[C(R₆)(R₇)]_n—[(C═O)_m—X^G]_j—R₈;
  • [1308] either J^R3 and G³ form a J^R3 and G³ bridge, or J^R3 is H and G³ is selected from H, OH, halogen or O—[C(R₆)(R₇)]_n—[(C═O)_m—X^G]_j—R₈;
  • [1309] wherein each J^R to G bridge has a formula independently selected from —CH(CH₃)—O— or —(CH₂)_k—O—, wherein k is from 1 to 3;
  • [1310] each R₆ and R₇ is, independently, H, halogen, C₁-C₆ alkyl or substituted C₁-C₆ alkyl;
  • [1311] each X^G is O, S or N(E₁);
  • [1312] R₈ is H, halogen, C₁-C₆ alkyl, substituted C₁-C₆ alkyl, C₂-C₆ alkenyl, substituted C₂-C₆ alkenyl, C₂-C₆ alkynyl, substituted C₂-C₆ alkynyl or N(E₂)(E₃);
  • [1313] E₁, E₂ and E₃ are each, independently, H, C₁-C₆ alkyl or substituted C₁-C₆ alkyl;
  • [1314] n is from 1 to 6;
  • [1315] m is 0 or 1;
  • [1316] j is 0 or 1;
  • [1317] each substituted group comprises one or more optionally protected substituent groups independently selected from halogen, OJ₁, N(J₁)(J₂), =NJ₁, SJ₁, N₃, CN, OC(═X₂)J₁, OC(═X₂)N(J₁)(J₂) and C(=Q₂)N(J₁)(J₂);
  • [1318] Q₂ is O, S or NJ₃;
  • [1319] each J₁, J₂ and J₃ is, independently, H or C₁-C₆ alkyl.
• [1320] Embodiment 797. An antisense agent comprising a modified oligonucleotide, wherein at least one region of the modified oligonucleotide has Structure D:

[1321]

• • [1322] wherein:
  • [1323] each Bx is a heterocyclic base moiety;
  • [1324] X is selected from O or S;
  • [1325] each of Y₁ and Y₂ is independently selected from OH or SH;
  • [1326] each of Z² and Z³ are independently selected from —(CH₂)_p—X^Z—(CH₂)_q—, wherein p is 0 or 1, q is 0 or 1, and X^Z is O, S, or N(E₁);
  • [1327] R₁ is selected from H, C₁-C₆ alkyl, and substituted C₁-C₆ alkyl; and
  • [1328] T is selected from SO₂R₂, C(═O)R₃, and P(═O)R₄R₅, wherein:

[1329] R₂ is selected from an aryl, a substituted aryl, a heterocycle, a substituted heterocycle, an aromatic heterocycle, a substituted aromatic heterocycle, a diazole, a substituted diazole, a C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ alkenyl, C₁-C₆ alkynyl, substituted C₁-C₆ alkyl, substituted C₁-C₆ alkenyl substituted C₁-C₆ alkynyl, and a conjugate group;

• • [1330] R₃ is selected from an aryl, a substituted aryl, CH₃, N(CH₃)₂, OCH₃ and a conjugate group;
  • [1331] R₄ is selected from OCH₃, OH, C₁-C₆ alkyl, substituted C₁-C₆ alkyl and a conjugate group;
  • [1332] R₅ is selected from OCH₃, OH, C₁-C₆ alkyl, and substituted C₁-C₆ alkyl;
  • [1333] either J^R1 and G¹ form a J^R1 to G¹ bridge, or J^R1 is H and G¹ is selected from H, OH, halogen or O—[C(R₆)(R₇)]_n—[(C═O)_m—X^G]_j—R₈;
  • [1334] either J^R2 and G² form a J^R2 and G² bridge, or J^R2 is H and G² is selected from H, OH, halogen or O—[C(R₆)(R₇)]_n—[(C═O)_m—X^G]_j—R₈;
  • [1335] either J^R3 and G³ form a J^R3 and G³ bridge, or J^R3 is H and G³ is selected from H, OH, halogen or O—[C(R₆)(R₇)]_n—[(C═O)_m—X^G]_j—R₈;
  • [1336] wherein each J^R to G bridge has a formula independently selected from —CH(CH₃)—O— or —(CH₂)_k—O—, wherein k is from 1 to 3;
  • [1337] each R₆ and R₇ is, independently, H, halogen, C₁-C₆ alkyl or substituted C₁-C₆ alkyl;
  • [1338] each X^G is O, S or N(E₁);
  • [1339] R₈ is H, halogen, C₁-C₆ alkyl, substituted C₁-C₆ alkyl, C₂-C₆ alkenyl, substituted C₂-C₆ alkenyl, C₂-C₆ alkynyl, substituted C₂-C₆ alkynyl or N(E₂)(E₃);
  • [1340] E₁, E₂ and E₃ are each, independently, H, C₁-C₆ alkyl or substituted C₁-C₆ alkyl;
  • [1341] n is from 1 to 6;
  • [1342] m is 0 or 1;
  • [1343] j is 0 or 1;
  • [1344] each substituted group comprises one or more optionally protected substituent groups independently selected from halogen, OJ₁, N(J₁)(J₂), ═NJ₁, SJ₁, N₃, CN, OC(═X₂)J₁, OC(═X₂)N(J₁)(J₂) and C(=Q₂)N(J₁)(J₂);
  • [1345] Q₂ is O, S or NJ₃;
  • [1346] each J₁, J₂ and J₃ is, independently, H or C₁-C₆ alkyl.
• [1347] Embodiment 798. An antisense agent comprising a modified oligonucleotide, wherein at least one region of the modified oligonucleotide has Structure E:

[1348]

• • [1349] wherein:
  • [1350] each Bx is a heterocyclic base moiety;
  • [1351] X is selected from O or S;
  • [1352] each of Y₁ and Y₂ is independently selected from OH or SH;
  • [1353] each of Z² and Z³ are independently selected from —(CH₂)_p—X^Z—(CH₂)_q—, wherein p is 0 or 1, q is 0 or 1, and X^Z is O, S, or N(E₁);
  • [1354] R₁ is selected from H, C₁-C₆ alkyl, and substituted C₁-C₆ alkyl; and
  • [1355] T is selected from SO₂R₂, C(═O)R₃, and P(═O)R₄R₅, wherein:

[1356] R₂ is selected from an aryl, a substituted aryl, a heterocycle, a substituted heterocycle, an aromatic heterocycle, a substituted aromatic heterocycle, a diazole, a substituted diazole, a C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ alkenyl, C₁-C₆ alkynyl, substituted C₁-C₆ alkyl, substituted C₁-C₆ alkenyl substituted C₁-C₆ alkynyl, and a conjugate group;

• • [1357] R₃ is selected from an aryl, a substituted aryl, CH₃, N(CH₃)₂, OCH₃ and a conjugate group;
  • [1358] R₄ is selected from OCH₃, OH, C₁-C₆ alkyl, substituted C₁-C₆ alkyl and a conjugate group;
  • [1359] R₅ is selected from OCH₃, OH, C₁-C₆ alkyl, and substituted C₁-C₆ alkyl;
  • [1360] either J^R1 and G¹ form a J^R1 to G¹ bridge, or J^R1 is H and G¹ is selected from H, OH, halogen or O—[C(R₆)(R₇)]_n—[(C═O)_m—X^G]_j—R₈;
  • [1361] either J^R2 and G² form a J^R2 and G² bridge, or J^R2 is H and G² is selected from H, OH, halogen or O—[C(R₆)(R₇)]_n—[(C═O)_m—X^G]_j—R₈;
  • [1362] either J^R3 and G³ form a J^R3 and G³ bridge, or J^R3 is H and G³ is selected from H, OH, halogen or O—[C(R₆)(R₇)]_n—[(C═O)_m—X^G]_j—R₈;
  • [1363] wherein each J^R to G bridge has a formula independently selected from —CH(CH₃)—O— or —(CH₂)_k—O—, wherein k is from 1 to 3;
  • [1364] each R₆ and R₇ is, independently, H, halogen, C₁-C₆ alkyl or substituted C₁-C₆ alkyl;
  • [1365] each X^G is O, S or N(E₁);
  • [1366] R₈ is H, halogen, C₁-C₆ alkyl, substituted C₁-C₆ alkyl, C₂-C₆ alkenyl, substituted C₂-C₆ alkenyl, C₂-C₆ alkynyl, substituted C₂-C₆ alkynyl or N(E₂)(E₃);
  • [1367] E₁, E₂ and E₃ are each, independently, H, C₁-C₆ alkyl or substituted C₁-C₆ alkyl;
  • [1368] n is from 1 to 6;
  • [1369] m is 0 or 1;
  • [1370] j is 0 or 1;
  • [1371] each substituted group comprises one or more optionally protected substituent groups independently selected from halogen, OJ₁, N(J₁)(J₂), =NJ₁, SJ₁, N₃, CN, OC(═X₂)J₁, OC(═X₂)N(J₁)(J₂) and C(=Q₂)N(J₁)(J₂);
  • [1372] Q₂ is O, S or NJ₃;
  • [1373] each J₁, J₂ and J₃ is, independently, H or C₁-C₆ alkyl.
• [1374] Embodiment 799. The modified oligonucleotide of any of embodiments 794-798, wherein each Z is O.
• [1375] Embodiment 800. The modified oligonucleotide of any of embodiments 794-799, wherein at least one G is selected from H, OH, halogen, C₁-C₆ alkoxy, —O(CH₂)₂OCH₃, or —OCH₂(C═O)NHCH₃.
• [1376] Embodiment 801. The modified oligonucleotide of any of embodiments 794-799, wherein each G is selected from H, OH, halogen, C₁-C₆ alkoxy, —O(CH₂)₂OCH₃, or —OCH₂(C═O)NHCH₃.
• [1377] Embodiment 802. The modified oligonucleotide of any of embodiments 794-801, wherein at least one J^R forms a bridge with at least one G, wherein said J^R to G bridge has a formula selected from —CH(CH₃)—O— or —(CH₂)_k—O′, wherein k is from 1 to 3.
• [1378] Embodiment 803. The modified oligonucleotide of any of embodiments 794-802, wherein each J^R and G form a bridge, wherein said J^R to G bridge has a formula selected from —CH(CH₃)—O— or —(CH₂)_k—O—, wherein k is from 1 to 3.
• [1379] Embodiment 804. The modified oligonucleotide of any of embodiments 802 or 803, wherein at least one Z is O and the corresponding J^R to G bridge has a formula (CH₂)_k—O—, wherein k is 1.
• [1380] Embodiment 805. The modified oligonucleotide of any of embodiments 794-804 wherein each nucleoside of structure A, B, C, D, or E is a stereo standard nucleoside.
• [1381] Embodiment 806. The modified oligonucleotide of any of embodiments 794-804, wherein at least one nucleoside of structure A, B, C, D, or E is a stereo-non-standard nucleoside.
• [1382] Embodiment 807. The modified oligonucleotide of any of embodiments 802-804 or 806, wherein at least one nucleoside having a J^R to G bridge is in the α-L-ribosyl configuration.
• [1383] Embodiment 808. The modified oligonucleotide of any of embodiments 794-807, wherein the modified oligonucleotide comprises at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 regions having structures A, B, C, D, or E.
• [1384] Embodiment 809. The modified oligonucleotide of any of embodiments 794-807, wherein at least one region having structure A, B, C, D, or E is at the 5′ end of the modified oligonucleotide.
• [1385] Embodiment 810. The modified oligonucleotide of any of embodiments 794-807, wherein at least one region having structure A, B, C, D, or E is at the 3′ end of the modified oligonucleotide.
• [1386] Embodiment 811. The modified oligonucleotide of any of embodiments 794-807, wherein at least one region having structure A, B, C, D, or E is internal to the modified oligonucleotide.
• [1387] Embodiment 812. An antisense agent comprising a modified oligonucleotide consisting of 10-30 linked nucleosides, wherein a region of the modified oligonucleotide has the formula (N_g1)_L1(N_g2)_L2(N_g3)_L3, wherein each N_g is a nucleoside and each L is an internucleoside linking group; wherein each of L₁, and L₂ is a phosphodiester internucleoside linking group, a phosphorothioate internucleoside linking group, or an internucleoside linking group of Formula XVII:

[1388]

[1389] wherein L₃ is absent or is a phosphodiester internucleoside linking group, a phosphorothioate internucleoside linking group, or an internucleoside linking group of Formula XVII;

[1390] wherein at least one of L₁, L₂, and L₃ is an internucleoside linking group of Formula XVII; and at least one of L₁, L₂, and L₃ is a phosphorothioate or a phosphodiester internucleoside linking group,

[1391] wherein independently for each internucleoside linking group of the modified oligonucleotide having Formula XVII:

• • [1392] X is selected from O or S;
  • [1393] R₁ is selected from H, C₁-C₆ alkyl, and substituted C₁-C₆ alkyl; and
  • [1394] T is selected from SO₂R₂, C(═O)R₃, and P(═O)R₄R₅, wherein:

[1395] R₂ is selected from an aryl, a substituted aryl, a heterocycle, a substituted heterocycle, an aromatic heterocycle, a substituted aromatic heterocycle, a diazole, a substituted diazole, a C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ alkenyl, C₁-C₆ alkynyl, substituted C₁-C₆ alkyl, substituted C₁-C₆ alkenyl substituted C₁-C₆ alkynyl, and a conjugate group;

[1396] R₃ is selected from an aryl, a substituted aryl, CH₃, N(CH₃)₂, OCH₃ and a conjugate;

[1397] R₄ is selected from OCH₃, OH, C₁-C₆ alkyl, substituted C₁-C₆ alkyl and a conjugate; and

[1398] R₅ is selected from OCH₃, OH, C₁-C₆ alkyl, and substituted C₁-C₆ alkyl.

• [1399] Embodiment 813. The modified oligonucleotide of embodiment 812, wherein the modified oligonucleotide comprises at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 regions having the formula (N_g1)_L1(N_g2)_L2(N_g3)_L3.
• [1400] Embodiment 814. The modified oligonucleotide of embodiment 812 or 813, wherein at least one region having the formula (N_g1)_L1(N_g2)_L2(N_g3)_L3 is at the 5′ end of the oligonucleotide
• [1401] Embodiment 815. The modified oligonucleotide of embodiment 812 or 813, wherein at least one region having the formula (N_g1)_L1(N_g2)_L2(N_g3)_L3 is internal to the oligonucleotide.
• [1402] Embodiment 816. The modified oligonucleotide of embodiment 812 or 813, wherein at least one region having the formula (N_g1)_L1(N_g2)_L2(N_g3)_L3 is at the 3′ end of the oligonucleotide.
• [1403] Embodiment 817. The modified oligonucleotide of any of embodiments 705-816, wherein at least one nucleoside of the modified oligonucleotide is a modified nucleoside selected from a bicyclic nucleoside and a non-bicyclic substituted nucleoside.
• [1404] Embodiment 818. The modified oligonucleotide of any of embodiments 705-817, wherein at least one nucleoside of the modified oligonucleotide is selected from: a β-D-LNA nucleoside, an α-L-LNA nucleoside, an ENA nucleoside, a cEt nucleoside, a 2′-MOE nucleoside, a 2′-OMe nucleoside, a 2′-F nucleoside, a 2′-NMA nucleoside, a 5′-Me nucleoside, a DNA nucleoside, and an RNA nucleoside.
• [1405] Embodiment 819. The modified oligonucleotide of any of embodiments 705-818, wherein each nucleoside of the modified oligonucleotide is selected from: a β-D-LNA nucleoside, an α-L-LNA nucleoside, an ENA nucleoside, a cEt nucleoside, a 2′-MOE nucleoside, a 2′-OMe nucleoside, a 2′-F nucleoside, a 2′-NMA nucleoside, a 5′-Me nucleoside, a DNA nucleoside, and an RNA nucleoside.
• [1406] Embodiment 820. The modified oligonucleotide of any of embodiments 705-819, wherein at least one nucleoside of the modified oligonucleotide is a stereo-non-standard nucleoside.
• [1407] Embodiment 821. The modified oligonucleotide of embodiment 820, wherein the internucleoside linking group linking at least one stereo-non-standard nucleoside to an adjacent nucleoside is an internucleoside linking group of Formula XVII.
• [1408] Embodiment 822. The modified oligonucleotide of embodiment 820 or 821, wherein at least two nucleosides of the modified oligonucleotide are stereo-non-standard nucleosides.
• [1409] Embodiment 823. The modified oligonucleotide of embodiment 822, wherein at least two stereo-non-standard nucleosides of the modified oligonucleotide are adjacent to one another.
• [1410] Embodiment 824. The modified oligonucleotide of embodiment 823, wherein at least two stereo-non-standard nucleosides of the modified oligonucleotide are linked to one another with an internucleoside linking group of Formula XVII.
• [1411] Embodiment 825. The modified oligonucleotide of any of embodiments 820-824, wherein at least one stereo-non-standard nucleoside of the modified oligonucleotide is a stereo-non-standard DNA nucleoside.
• [1412] Embodiment 826. The modified oligonucleotide of embodiment 825 wherein the stereo-non-standard DNA nucleoside is selected from a stereo-non-standard DNA nucleoside having: Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, and Formula VII.
• [1413] Embodiment 827. The modified oligonucleotide of embodiment 826 wherein the stereo-non-standard DNA nucleoside is selected from a stereo-non-standard DNA nucleoside having: Formula V and Formula II.
• [1414] Embodiment 828. The modified oligonucleotide of any of embodiments 820-827, wherein at least one stereo-non-standard nucleoside of the modified oligonucleotide is a substituted stereo-non-standard nucleoside or a stereo-non-standard RNA nucleoside.
• [1415] Embodiment 829. The modified oligonucleotide of embodiment 828, wherein the 2′-substituent of the at least one substituted stereo-non-standard nucleoside of the modified oligonucleotide is selected from: 2′-MOE, 2′-OMe, 2′-F, or 2′-OH.
• [1416] Embodiment 830. The modified oligonucleotide of any of embodiments 705-819, wherein each nucleoside is a stereo-standard nucleoside.
• [1417] Embodiment 831. The modified oligonucleotide of any of embodiments 705-829, wherein the modified oligonucleotide consists of 12-30 linked nucleosides.
• [1418] Embodiment 832. The modified oligonucleotide of any of embodiments 705-829, wherein the modified oligonucleotide consists of 16-24 linked nucleosides.
• [1419] Embodiment 833. The modified oligonucleotide of any of embodiments 705-829, wherein the modified oligonucleotide consists of 18-22 linked nucleosides.
• [1420] Embodiment 834. The modified oligonucleotide of any of embodiments 705-832, wherein the modified oligonucleotide consists of 16 linked nucleosides.
• [1421] Embodiment 835. The modified oligonucleotide of any of embodiments 705-832, wherein the modified oligonucleotide consists of 17 linked nucleosides.
• [1422] Embodiment 836. The modified oligonucleotide of any of embodiments 705-833, wherein the modified oligonucleotide consists of 18 linked nucleosides.
• [1423] Embodiment 837. The modified oligonucleotide of any of embodiments 705-833, wherein the modified oligonucleotide consists of 19 linked nucleosides.
• [1424] Embodiment 838. The modified oligonucleotide of any of embodiments 705-833, wherein the modified oligonucleotide consists of 20 linked nucleosides.
• [1425] Embodiment 839. The modified oligonucleotide of any of embodiments 705-833, wherein the modified oligonucleotide consists of 21 linked nucleosides.
• [1426] Embodiment 840. The modified oligonucleotide of any of embodiments 705-833, wherein the modified oligonucleotide consists of 22 linked nucleosides.
• [1427] Embodiment 841. The modified oligonucleotide of any of embodiments 705-832, wherein the modified oligonucleotide consists of 23 linked nucleosides.
• [1428] Embodiment 842. The modified oligonucleotide of any of embodiments 705-841, wherein at least one nucleoside of the modified oligonucleotide is selected from: a 2′-OMe nucleoside, a 2′-F nucleoside, and an RNA nucleoside.
• [1429] Embodiment 843. The modified oligonucleotide of any of embodiments 705-842, wherein at least one nucleoside of the modified oligonucleotide is a 2′-OMe nucleoside, and at least one nucleoside of the modified oligonucleotide is a 2′-F nucleoside.
• [1430] Embodiment 844. The modified oligonucleotide of embodiment 843, wherein each nucleoside of the modified oligonucleotide is selected from a 2′-OMe nucleoside or a 2′-F nucleoside.
• [1431] Embodiment 845. The modified oligonucleotide of any of embodiments 705-743, wherein at least one nucleoside of the modified oligonucleotide is a 2′-OMe nucleoside, at least one nucleoside of the modified oligonucleotide is a 2′-F nucleoside, and at least one nucleoside of the modified oligonucleotide comprises a sugar surrogate.
• [1432] Embodiment 846. The modified oligonucleotide of embodiment 845, wherein each nucleoside of the modified oligonucleotide is selected from a 2′-OMe nucleoside, a 2′-F nucleoside, and a nucleoside comprising a sugar surrogate.
• [1433] Embodiment 847. The modified oligonucleotide of any of embodiments 845-846, wherein the nucleoside comprising a sugar surrogate is selected from:

[1434]
wherein Bx is a heterocyclic base moiety.

• [1435] Embodiment 848. The modified oligonucleotide of embodiment 847, wherein the nucleoside comprising a sugar surrogate is GNA.
• [1436] Embodiment 849. The modified oligonucleotide of any of embodiments 842-848, wherein the modified oligonucleotide has a region of alternating nucleoside types having the motif ABABA, wherein each A is a stereo-standard nucleoside of a first type and each B is a stereo-standard nucleoside of a second type, wherein the first type and the second type are different from one another.
• [1437] Embodiment 850. The modified oligonucleotide of embodiment 849, wherein A and B are selected from 2′-F substituted nucleosides, 2′-OMe substituted nucleosides, and stereo-standard RNA nucleosides.
• [1438] Embodiment 851. The modified oligonucleotide of any of embodiments 705-850, wherein the 5′-end of the modified oligonucleotide comprises a terminal group.
• [1439] Embodiment 852. The modified oligonucleotide of embodiment 851, wherein the terminal group is a stabilized phosphate group.
• [1440] Embodiment 853. The modified oligonucleotide of embodiment 852, wherein the stabilized phosphate group is a 5′-vinyl phosphonate or a 5′-cyclopropyl phosphonate.
• [1441] Embodiment 854. The modified oligonucleotide of embodiment 851, wherein the terminal group is selected from

[1442]

[1443] wherein R^A is OH, OP(═O)OH, OP(═O)SH, or a stabilized phosphate group;

[1444] G^A is H, OH, OMe, MOE, or a halogen;

[1445] X is OH, SH, or NSO₂R₂;

[1446] R₂ is selected from an aryl, a substituted aryl, a heterocycle, a substituted heterocycle, an aromatic heterocycle, a substituted aromatic heterocycle, a diazole, a substituted diazole, a C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ alkenyl, C₁-C₆ alkynyl, substituted C₁-C₆ alkyl, substituted C₁-C₆ alkenyl substituted C₁-C₆ alkynyl, and a conjugate group.

• [1447] Embodiment 855. The modified oligonucleotide of embodiment 854, wherein G^A is selected from H or OH and X is SH.
• [1448] Embodiment 856. The antisense agent of any of embodiments 705-855, wherein the antisense agent is an RNAi agent.
• [1449] Embodiment 857. The RNAi agent of embodiment 856, wherein the RNAi agent is a single-stranded RNAi agent comprising an RNAi antisense modified oligonucleotide, wherein the RNAi antisense modified oligonucleotide is a modified oligonucleotide of any of embodiments 705-855.
• [1450] Embodiment 858. The RNAi agent of embodiment 856, wherein the RNAi agent is an oligonucleotide duplex comprising an RNAi antisense modified oligonucleotide and an RNAi sense modified oligonucleotide, wherein the RNAi antisense modified oligonucleotide and/or the RNAi sense modified oligonucleotide is a modified oligonucleotide of any of embodiments 705-855.
• [1451] Embodiment 859. The RNAi agent of embodiment 857 or 858, wherein at least one internucleoside linking group of the RNAi antisense modified oligonucleotide is an internucleoside linking group of Formula XVII.
• [1452] Embodiment 860. The RNAi agent of embodiment 857 or 858, wherein at least two internucleoside linking groups of the RNAi antisense modified oligonucleotide are independently selected internucleoside linking groups of Formula XVII.
• [1453] Embodiment 861. The RNAi agent of any of embodiments 857-860, wherein at least one of the five 3′-most internucleoside linking groups of the RNAi antisense modified oligonucleotide is an internucleoside linking group of Formula XVII.
• [1454] Embodiment 862. The RNAi agent of any of embodiments 857-861, wherein at least two of the five 3′-most internucleoside linking groups of RNAi antisense modified oligonucleotide is an internucleoside linking group of Formula XVII.
• [1455] Embodiment 863. The RNAi agent of any of embodiments 857-862, wherein 1-3 of the three 3′-most internucleoside linking groups are internucleoside linking groups of Formula XVII, and each of these three internucleoside linking groups that is not an internucleoside linking group of Formula XVII is a phosphodiester or phosphorothioate internucleoside linking group.
• [1456] Embodiment 864. The RNAi agent of embodiment 863, wherein the two 3′-most internucleoside linking groups are internucleoside linking groups of Formula XVII.
• [1457] Embodiment 865. The RNAi agent of any of embodiments 857-864, wherein exactly one of the 5′-most and penultimate 5′-most internucleoside linking groups is an internucleoside linking group of Formula XVII.
• [1458] Embodiment 866. The RNAi agent of any of embodiments 857-865, wherein exactly one of the 5′-most and penultimate 5′-most internucleoside linking groups of the RNAi antisense oligonucleotide is an internucleoside linking groups of Formula XVII, the other of the 5′-most and penultimate 5′-most internucleoside linking groups of the RNAi antisense oligonucleotide is selected from a phosphodiester and a phosphorothioate internucleoside linkage, the two 3′-most internucleoside linking groups of the RNAi antisense oligonucleotide are internucleoside linking groups of Formula XVII, and the remaining internucleoside linking groups of the RNAi antisense oligonucleotide are phosphodiester internucleoside linkages.
• [1459] Embodiment 867. The RNAi agent of any of embodiments 857-866, wherein the antisense modified oligonucleotide comprises a 3′-overhang.
• [1460] Embodiment 868. The RNAi agent of embodiment 867, wherein the 3′-overhang consists of two nucleosides.
• [1461] Embodiment 869. The RNAi agent of any of embodiments 857-865 or 867-868, wherein at least one internucleoside linking group within the seed region of the RNAi antisense modified oligonucleotide is an internucleoside linking group of Formula XVII.
• [1462] Embodiment 870. The RNAi agent of any of embodiments 857-869, wherein for each internucleoside linking group of Formula XVII, R₁ is H and T is SO₂Me.
• [1463] Embodiment 871. The RNAi agent of any of embodiments 857-870, wherein the RNAi antisense modified oligonucleotide consists of 23 linked nucleosides, and the internucleoside linkage motif is selected from: ooooooooooooooooooooaa, aaoooooooooooooooooooo, aaooooooooooooooooooaa, asooooooooooooooooooss, saoooooooooooooooooooo, oooooooooooooooooooaaa, ooooooooooooooooaaaoss, oooooooooooooaaaooooss, ooooooooooaaaoooooooss, oooooooaaaooooooooooss, ooooaaaoooooooooooooss, saoooaoooooooaoaooooss, ssoooaoooooooaoaooooss, or ssooooooooooooooooooaa, wherein each “a” represents an internucleoside linkage of Formula XVII, each “s” represents a phosphorothioate internucleoside linkage, and each “o” represents a phosphodiester internucleoside linkage.
• [1464] Embodiment 872. The RNAi agent of embodiment 871, wherein the internucleoside linkage motif of the RNAi antisense modified oligonucleotide is selected from oooooooooooooooooooaa, asooooooooooooooooooss, or saoooooooooooooooooooo.
• [1465] Embodiment 873. The RNAi agent of embodiment 871 or 872, wherein the sugar motif of the RNAi antisense modified oligonucleotide from 5′ to 3′ is yfyfyfyfyfyfyfyfyfyfyfy or yfyyyfyyyyyyyfyfyyyyyyy, wherein “y” represents a 2′-OMe sugar moiety and “f” represents a 2′-F sugar moiety.
• [1466] Embodiment 874. The RNAi agent of any of embodiments 857-870, wherein the RNAi antisense modified oligonucleotide consists of 21 linked nucleosides, and the internucleoside linkage motif is selected from: aaososososososssssss, ssaaosososososssssss, ssosaaososososssssss, ssososaaosososssssss, ssosososaaososssssss, ssososososaaosssssss, ssosososososaassssss, ssososososososaassss, ssososososososssaass, ssososososososssssaa wherein each “a” represents an internucleoside linkage of Formula XVII, each “s” represents a phosphorothioate internucleoside linkage, and each “o” represents a phosphodiester internucleoside linkage.
• [1467] Embodiment 875. The RNAi agent of embodiment 874, wherein the internucleoside linkage motif of the RNAi antisense modified oligonucleotide is selected from aaososososososssssss, ssaaosososososssssss, ssososaaosososssssss, ssosososaaososssssss, ssososososososssaass, or ssososososososssssaa, wherein each “a” represents an internucleoside linkage of Formula XVII, each “s” represents a phosphorothioate internucleoside linkage, and each “o” represents a phosphodiester internucleoside linkage.
• [1468] Embodiment 876. The RNAi agent of embodiment 874 or 875, wherein the sugar motif of the RNAi antisense modified oligonucleotide from 5′ to 3′ is yfyfyfyfyfyfyfyfyfyfyfy, wherein “y” represents a 2′-OMe sugar moiety and “f” represents a 2′-F sugar moiety.
• [1469] Embodiment 877. The RNAi agent of any of embodiments 873-876 wherein each “a” is a mesyl phosphoramidate linkage.
• [1470] Embodiment 878. The RNAi agent of any of embodiments 857-878, wherein at least one region of the RNAi antisense modified oligonucleotide has structure A, B, C, D, or E.
• [1471] Embodiment 879. The RNAi agent of embodiment 878, wherein at least one region having structure A, B, C, D, or E is within the seed region of the RNAi antisense modified oligonucleotide.
• [1472] Embodiment 880. The RNAi agent of embodiment 878, wherein at least one region having structure A, B, C, D, or E is at the 3′ end of the RNAi antisense modified oligonucleotide.
• [1473] Embodiment 881. The RNAi agent of any of embodiments 857-880, wherein at least one region of the RNAi antisense modified oligonucleotide has the formula (N_g1)_L1(N_g2)_L2(N_g3)_L3, wherein each N_g is a nucleoside and each L is an internucleoside linking group; wherein each of L₁, and L₂ is a phosphodiester internucleoside linking group, a phosphorothioate internucleoside linking group, or an internucleoside linking group of Formula XVII:

[1474]

[1475] wherein L₃ is absent or is a phosphodiester internucleoside linking group, a phosphorothioate internucleoside linking group, or an internucleoside linking group of Formula XVII;

[1476] wherein at least one of L₁, L₂, and L₃ an internucleoside linking group of Formula XVII; and at least one of L₁, L₂, and L₃ is a phosphorothioate or a phosphodiester internucleoside linking group,

[1477] wherein independently for each internucleoside linking group of the modified oligonucleotide having Formula XVII:

• • [1478] X is selected from O or S;
  • [1479] R₁ is selected from H, C₁-C₆ alkyl, and substituted C₁-C₆ alkyl; and
  • [1480] T is selected from SO₂R₂, C(═O)R₃, and P(═O)R₄R₅, wherein:

[1481] R₂ is selected from an aryl, a substituted aryl, a heterocycle, a substituted heterocycle, an aromatic heterocycle, a substituted aromatic heterocycle, a diazole, a substituted diazole, a C₁-C₆ alkoxy, C₁-C₆ alkyl, substituted C₁-C₆ alkyl, and a conjugate;

• • [1482] R₃ is selected from an aryl, a substituted aryl, CH₃, N(CH₃)₂, OCH₃ and a conjugate;
  • [1483] R₄ is selected from OCH₃, OH, C₁-C₆ alkyl, substituted C₁-C₆ alkyl and a conjugate; and
  • [1484] R₅ is selected from OCH₃, OH, C₁-C₆ alkyl, and substituted C₁-C₆ alkyl.
• [1485] Embodiment 882. The RNAi agent of embodiment 881, wherein the region having the formula (N_g1)_L1(N_g2)_L2(N_g3)_L3 includes one or two 3′-overhang nucleosides.
• [1486] Embodiment 883. The RNAi agent of embodiment 881, wherein at least one region having the formula (N_g1)_L1(N_g2)_L2(N_g3)_L3 is at the 3′ end of the RNAi antisense modified oligonucleotide.
• [1487] Embodiment 884. The RNAi agent of embodiment 883, wherein L₁ and L₂ are each internucleoside linkages of Formula XVII wherein R₁ is H and T is SO₂Me, and L₃ is a phosphodiester internucleoside linkage.
• [1488] Embodiment 885. The RNAi agent of embodiment 881, wherein at least one region having the formula (N_g1)_L1(N_g2)_L2(N_g3)_L3 is at the 5′ end of the RNAi antisense modified oligonucleotide.
• [1489] Embodiment 886. The RNAi agent of embodiment 885, wherein one of L₁ or L₂ is an internucleoside linkages of Formula XVII wherein R₁ is H and T is SO₂Me, the other of L₁ or L₂ is a phosphorothioate internucleoside linkage, and L₃ is a phosphodiester internucleoside linkage.
• [1490] Embodiment 887. The RNAi agent of embodiment 881, wherein at least one region having the formula (N_g1)_L1(N_g2)_L2(N_g3)_L3 is within the seed region of the RNAi antisense modified oligonucleotide.
• [1491] Embodiment 888. The RNAi agent of any of embodiments 857-887, wherein the region of the RNAi antisense oligonucleotide that is complementary to a target is at least 15 nucleobases.
• [1492] Embodiment 889. The RNAi agent of any of embodiments 857-888, wherein the region of the RNAi antisense oligonucleotide that is complementary to a target is at least 17 nucleobases.
• [1493] Embodiment 890. The RNAi agent of any of embodiments 857-889, wherein the region of the RNAi antisense oligonucleotide that is complementary to a target is at least 19 nucleobases.
• [1494] Embodiment 891. The RNAi agent of any of embodiments 857-890, wherein the region of the RNAi antisense oligonucleotide that is complementary to a target is at least 21 nucleobases.
• [1495] Embodiment 892. The RNAi agent of any of embodiments 857-890, wherein the region of the RNAi antisense oligonucleotide that is complementary to a target is exactly 19 nucleobases.
• [1496] Embodiment 893. The RNAi agent of any of embodiments 857-891, wherein the region of the RNAi antisense oligonucleotide that is complementary to a target is exactly 21 nucleobases.
• [1497] Embodiment 894. The RNAi agent of any of embodiments 857-893, wherein at least one nucleoside of the RNAi antisense modified oligonucleotide is selected from: a 2′-OMe nucleoside, a 2′-F nucleoside, and an RNA nucleoside.
• [1498] Embodiment 895. The RNAi agent of any of embodiments 857-894, wherein at least one nucleoside of the modified oligonucleotide is a 2′-OMe nucleoside, and at least one nucleoside of the modified oligonucleotide is an RNA nucleoside.
• [1499] Embodiment 896. The RNAi agent of any of embodiments 857-894, wherein at least one nucleoside of the RNAi antisense modified oligonucleotide is a 2′-OMe nucleoside, and at least one nucleoside of the RNAi antisense modified oligonucleotide is a 2′-F nucleoside.
• [1500] Embodiment 897. The RNAi agent of embodiment 896, wherein each nucleoside of the RNAi antisense modified oligonucleotide is selected from a 2′-OMe nucleoside or a 2′-F nucleoside.
• [1501] Embodiment 898. The RNAi agent of any of embodiments 887-894, wherein at least one nucleoside of the RNAi antisense modified oligonucleotide is a 2′-OMe nucleoside, at least one nucleoside of the RNAi antisense modified oligonucleotide is a 2′-F nucleoside, and at least one nucleoside of the modified oligonucleotide comprises a sugar surrogate.
• [1502] Embodiment 899. The RNAi agent of embodiment 898, wherein each nucleoside of the RNAi antisense modified oligonucleotide is selected from a 2′-OMe nucleoside, a 2′-F nucleoside, and a nucleoside comprising a sugar surrogate.
• [1503] Embodiment 900. The RNAi agent of any of embodiments 898-899, wherein the nucleoside comprising a sugar surrogate is selected from:

[1504]
wherein Bx is a heterocyclic base moiety.

• [1505] Embodiment 901. The RNAi agent of embodiment 900, wherein the nucleoside comprising a sugar surrogate is GNA.
• [1506] Embodiment 902. The RNAi agent of embodiment 900 or 901, wherein at least one nucleoside comprising a sugar surrogate is one of the nine 5′-most nucleosides of the RNAi antisense modified oligonucleotide.
• [1507] Embodiment 903. The RNAi agent of any of embodiments 857-902, wherein the modified oligonucleotide has a region of alternating nucleoside types having the motif ABABA, wherein each A is a stereo-standard nucleoside of a first type and each B is a stereo-standard nucleoside of a second type, wherein the first type and the second type are different from one another.
• [1508] Embodiment 904. The RNAi agent of embodiment 903, wherein A and B are selected from 2′-F substituted nucleosides, 2′-OMe substituted nucleosides, and stereo-standard RNA nucleosides.
• [1509] Embodiment 905. The RNAi agent of any of embodiments 857-904, wherein the 5′-end of the RNAi antisense modified oligonucleotide comprises a terminal group.
• [1510] Embodiment 906. The RNAi agent of embodiment 905, wherein the terminal group is a stabilized phosphate group.
• [1511] Embodiment 907. The RNAi agent of embodiment 906, wherein the stabilized phosphate group is a 5′-vinyl phosphonate or a 5′-cyclopropyl phosphonate.
• [1512] Embodiment 908. The RNAi agent of embodiment 905, wherein the terminal group is selected from

[1513]

[1514] Wherein R^A is OH, OP(═O)OH, OP(═O)SH or a stabilized phosphate group;

[1515] G^A is H, OH, OMe, MOE, or a halogen;

[1516] X is OH, SH, or NSO₂R₂;

[1517] R₂ is selected from an aryl, a substituted aryl, a heterocycle, a substituted heterocycle, an aromatic heterocycle, a substituted aromatic heterocycle, a diazole, a substituted diazole, a C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ alkenyl, C₁-C₅ alkynyl, substituted C₁-C₆ alkyl, substituted C₁-C₅ alkenyl substituted C₁-C₆ alkynyl, and a conjugate group.

• [1518] Embodiment 909. The RNAi agent of embodiment 908, wherein G^A is selected from H or OH and X is SH.
• [1519] Embodiment 910. The RNAi agent of any of embodiments 858-909, wherein at least one internucleoside linking group of the RNAi sense modified oligonucleotide is an internucleoside linking group of Formula XVII.
• [1520] Embodiment 911. The RNAi agent of embodiment 910, wherein at least one of the five 5′-most internucleoside linking groups of the RNAi sense modified oligonucleotide is an internucleoside linking group of Formula XVII.
• [1521] Embodiment 912. The RNAi agent of embodiment 910, wherein at least two of the five 5′-most internucleoside linking groups of the RNAi sense modified oligonucleotide are internucleoside linking groups of Formula XVII.
• [1522] Embodiment 913. The RNAi agent of embodiment 910, wherein the two 5′-most internucleoside linking groups of the RNAi sense modified oligonucleotide are internucleoside linking groups of Formula XVII.
• [1523] Embodiment 914. The RNAi agent of any of embodiments 910-913, wherein at least one of the five 3′-most internucleoside linking groups of the RNAi sense modified oligonucleotide is an internucleoside linking group of Formula XVII.
• [1524] Embodiment 915. The RNAi agent of any of embodiments 910-913, wherein at least two of the five 3′-most internucleoside linking groups of RNAi sense modified oligonucleotide is an internucleoside linking group of Formula XVII.
• [1525] Embodiment 916. The RNAi agent of any of embodiments 910-913, wherein the two 3′-most internucleoside linking groups are internucleoside linking groups of Formula XVII.
• [1526] Embodiment 917. The RNAi agent of embodiment 910, wherein the two 3′-most and the two 5′-most internucleoside linking groups of the RNAi sense oligonucleotide are internucleoside linking groups of Formula XVII, and the remaining internucleoside linking groups of the RNAi sense oligonucleotide are phosphodiester internucleoside linkages.
• [1527] Embodiment 918. The RNAi agent of any of embodiments 910-917, wherein for each internucleoside linking group of Formula XVII, R₁ is H and T is SO₂Me.
• [1528] Embodiment 919. The RNAi agent of any of embodiments 910-918, wherein the RNAi sense modified oligonucleotide consists of 21 linked nucleosides, and the internucleoside linkage motif is selected from: ooooooooooooooooooaa, aaooooooooooooooooaa, ooooooooooooooooooaa, or ssooooaoaaaooooooooo, wherein each “a” represents an internucleoside linkage of Formula XVII, each “s” represents a phosphorothioate internucleoside linkage, and each “o” represents a phosphodiester internucleoside linkage.
• [1529] Embodiment 920. The RNAi agent of embodiment 919, wherein the internucleoside linkage motif of the RNAi sense modified oligonucleotide is selected from ooooooooooooooooooaa, aaooooooooooooooooaa, or ooooooooooooooooooaa, wherein each “a” represents an internucleoside linkage of Formula XVII, each “s” represents a phosphorothioate internucleoside linkage, and each “o” represents a phosphodiester internucleoside linkage.
• [1530] Embodiment 921. The RNAi agent of embodiment 919 or 920, wherein the sugar motif of the RNAi sense modified oligonucleotide is selected from: yyyyyyfyfffyyyyyyyyyy or fyfyfyfyfyfyfyfyfyfyf, wherein “y” represents a 2′-OMe sugar moiety and “f” represents a 2′-F sugar moiety.
• [1531] Embodiment 922. The RNAi agent of embodiment 921, wherein the RNAi sense modified oligonucleotide has an internucleoside linkage motif of aaooooooooooooooooaa wherein each “a” represents an internucleoside linkage of Formula XVII, each “s” represents a phosphorothioate internucleoside linkage, and each “o” represents a phosphodiester internucleoside linkage, and a sugar motif of yyyyyyfyfffyyyyyyyyyy, wherein “y” represents a 2′-OMe sugar moiety and “f” represents a 2′-F sugar moiety.
• [1532] Embodiment 923. The RNAi agent of any of embodiments 919-922 wherein each “a” is a mesyl phosphoramidate linkage.
• [1533] Embodiment 924. The RNAi agent of any of embodiments 910-923, wherein at least one region of the RNAi sense modified oligonucleotide has structure A, B, C, D, or E.
• [1534] Embodiment 925. The RNAi agent of embodiment 924, wherein at least one region having structure A, B, C, D, or E is at the 3′ end of the RNAi sense modified oligonucleotide.
• [1535] Embodiment 926. The RNAi agent of embodiment 924, wherein at least one region having structure A, B, C, D, or E is at the 5′ end of the RNAi sense modified oligonucleotide.
• [1536] Embodiment 927. The RNAi agent of any of embodiments 910-926, wherein at least one region of the RNAi sense modified oligonucleotide has the formula (N_g1)_L1(N_g2)_L2(N_g3)_L3, wherein each N_g is a nucleoside and each L is an internucleoside linking group; wherein each of L₁, and L₂ is a phosphodiester internucleoside linking group, a phosphorothioate internucleoside linking group, or an internucleoside linking group of Formula XVII:

[1537]

[1538] wherein L₃ is absent or is a phosphodiester internucleoside linking group, a phosphorothioate internucleoside linking group, or an internucleoside linking group of Formula XVII;

[1539] wherein at least one of L₁, L₂, and L₃ an internucleoside linking group of Formula XVII; and at least one of L₁, L₂, and L₃ is a phosphorothioate or a phosphodiester internucleoside linking group,

• • [1540] wherein independently for each internucleoside linking group of the modified oligonucleotide having Formula XVII:
  • [1541] X is selected from O or S;
  • [1542] R₁ is selected from H, C₁-C₆ alkyl, and substituted C₁-C₆ alkyl; and
  • [1543] T is selected from SO₂R₂, C(═O)R₃, and P(═O)R₄R₅, wherein:

[1544] R₂ is selected from an aryl, a substituted aryl, a heterocycle, a substituted heterocycle, an aromatic heterocycle, a substituted aromatic heterocycle, a diazole, a substituted diazole, a C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ alkenyl, C₁-C₆ alkynyl, substituted C₁-C₆ alkyl, substituted C₁-C₆ alkenyl substituted C₁-C₆ alkynyl, and a conjugate group;

• • [1545] R₃ is selected from an aryl, a substituted aryl, CH₃, N(CH₃)₂, OCH₃ and a conjugate;
  • [1546] R₄ is selected from OCH₃, OH, C₁-C₆ alkyl, substituted C₁-C₆ alkyl and a conjugate; and
  • [1547] R₅ is selected from OCH₃, OH, C₁-C₆ alkyl, and substituted C₁-C₆ alkyl.
• [1548] Embodiment 928. The RNAi agent of embodiment 927, wherein at least one region having the formula (N_g1)_L1(N_g2)_L2(N_g3)_L3 is at the 3′ end of the RNAi sense modified oligonucleotide.
• [1549] Embodiment 929. The RNAi agent of embodiment 928, wherein L₁ and L₂ are internucleoside linking groups of Formula XVII, wherein R₁ is H and T is SO₂Me, and L₃ is a phosphodiester internucleoside linkage.
• [1550] Embodiment 930. The RNAi agent of embodiment 927, wherein at least one region having the formula (N_g1)_L1(N_g2)_L2(N_g3)_L3 is at the 5′ end of the RNAi sense modified oligonucleotide.
• [1551] Embodiment 931. The RNAi agent of embodiment 930, wherein L₁ is a phosphodiester internucleoside linking group and L₂ and L₃ are each internucleoside linking groups of Formula XVII, wherein R₁ is H and T is SO₂Me.
• [1552] Embodiment 932. The RNAi agent of any of embodiments 858-931, wherein the RNAi sense modified oligonucleotide comprises a 3′ terminal group and/or a 5′ terminal group.
• [1553] Embodiment 933. The RNAi agent of any of embodiments 858-932, wherein the RNAi sense strand comprises a conjugate group.
• [1554] Embodiment 934. The RNAi agent of embodiment 933, wherein the conjugate group comprises a cell-targeting moiety.
• [1555] Embodiment 935. The RNAi agent of embodiment 933, wherein the conjugate group comprises a carbohydrate or carbohydrate cluster.
• [1556] Embodiment 936. The RNAi agent of embodiment 933, wherein the conjugate group comprises at least one GalNAc.
• [1557] Embodiment 937. The RNAi agent of embodiment 933, wherein the conjugate group comprises a C₁₀-C₂₀ alkyl chain.
• [1558] Embodiment 938. The RNAi agent of embodiment 933, wherein the conjugate group comprises C₁₆ alkyl.
• [1559] Embodiment 939. The RNAi agent of any of embodiments 858-938, wherein the double-stranded region of the oligonucleotide duplex is at least 15 nucleosides.
• [1560] Embodiment 940. The RNAi agent of any of embodiments 858-938, wherein the double-stranded region of the oligonucleotide duplex is at least 17 nucleosides.
• [1561] Embodiment 941. The RNAi agent of any of embodiments 858-938, wherein the double-stranded region of the oligonucleotide duplex is at least 19 nucleosides.
• [1562] Embodiment 942. The RNAi agent of any of embodiments 858-938, wherein the double-stranded region of the oligonucleotide duplex is exactly 19 nucleosides.
• [1563] Embodiment 943. The modified oligonucleotide of any of embodiments 705-841, wherein each nucleoside of the modified oligonucleotide is a modified nucleoside comprising a modified sugar moiety.
• [1564] Embodiment 944. The modified oligonucleotide of embodiment 943, wherein each modified sugar moiety is independently selected from a bicyclic sugar moiety and a 2′-substituted furanosyl sugar moiety.
• [1565] Embodiment 945. The modified oligonucleotide of embodiment 943 or 944, wherein each modified sugar moiety comprises the same modification.
• [1566] Embodiment 946. The modified oligonucleotide of any of embodiments 943-945, wherein each modified sugar moiety is selected from a 2′-OMe sugar moiety, a 2′-MOE sugar moiety, and a 2′-NMA sugar moiety.
• [1567] Embodiment 947. The modified oligonucleotide of embodiment 943 or 944, wherein the three 3′-most nucleosides comprise a bicyclic sugar moiety, and the remaining nucleosides comprise a 2′-substituted furanosyl sugar moiety.
• [1568] Embodiment 948. The modified oligonucleotide of embodiment 943 or 944, wherein the four 3′-most nucleosides comprise a bicyclic sugar moiety, and the remaining nucleosides comprise a 2′-substituted furanosyl sugar moiety.
• [1569] Embodiment 949. The modified oligonucleotide of embodiment 943 or 944, wherein the five 3′-most nucleosides comprise a bicyclic sugar moiety, and the remaining nucleosides comprise a 2′-substituted furanosyl sugar moiety.
• [1570] Embodiment 950. The modified oligonucleotide of embodiment 943 or 944, wherein the six 3′-most nucleosides comprise a bicyclic sugar moiety, and the remaining nucleosides comprise a 2′-substituted furanosyl sugar moiety.
• [1571] Embodiment 951. The modified oligonucleotide of any of embodiments 947-950, wherein each bicyclic sugar moiety is selected from among cEt, LNA, and ENA.
• [1572] Embodiment 952. The modified oligonucleotide of embodiment 951, wherein the bicyclic sugar moiety is cEt.
• [1573] Embodiment 953. The modified oligonucleotide of any of embodiments 947-952, wherein the 2′-substituted furanosyl sugar moiety is selected from 2′-OMe, 2′-MOE, and 2′-F.
• [1574] Embodiment 954. The modified oligonucleotide of any of embodiments 943-953, wherein at least one of the ten 5′-most linking groups of the modified oligonucleotide is an internucleoside linking group of Formula XVII.
• [1575] Embodiment 955. The modified oligonucleotide of embodiment 954, wherein at least 2 of the ten 5′-most linking groups of the modified oligonucleotide are internucleoside linking groups of Formula XVII.
• [1576] Embodiment 956. The modified oligonucleotide of embodiment 954, wherein at least 3 of the ten 5′-most linking groups of the modified oligonucleotide are internucleoside linking groups of Formula XVII.
• [1577] Embodiment 957. The modified oligonucleotide of embodiment 954, wherein at least 4 of the ten 5′-most linking groups of the modified oligonucleotide are internucleoside linking groups of Formula XVII.
• [1578] Embodiment 958. The modified oligonucleotide of embodiment 954, wherein at least 5 of the ten 5′-most linking groups of the modified oligonucleotide are internucleoside linking groups of Formula XVII.
• [1579] Embodiment 959. The modified oligonucleotide of embodiment 954, wherein at least 6 of the ten 5′-most linking groups of the modified oligonucleotide are internucleoside linking groups of Formula XVII.
• [1580] Embodiment 960. The modified oligonucleotide of embodiment 954, wherein the two 5′-most internucleoside linking groups are internucleoside linking groups of Formula XVII.
• [1581] Embodiment 961. The modified oligonucleotide of any of embodiments 943-960, wherein at least one of the ten 3′-most internucleoside linking groups of the modified oligonucleotide is an internucleoside linking group of Formula XVII.
• [1582] Embodiment 962. The modified oligonucleotide of embodiment 961, wherein at least 2 of the ten 3′-most internucleoside linking groups of the modified oligonucleotide are internucleoside linking groups of Formula XVII.
• [1583] Embodiment 963. The modified oligonucleotide of embodiment 961, wherein at least 3 of the ten 3′-most internucleoside linking groups are internucleoside linking groups of Formula XVII.
• [1584] Embodiment 964. The modified oligonucleotide of embodiment 961, wherein at least 4 of the ten 3′-most internucleoside linking groups are internucleoside linking groups of Formula XVII.
• [1585] Embodiment 965. The modified oligonucleotide of embodiment 961, wherein at least 5 of the ten 3′-most internucleoside linking groups are internucleoside linking 961 of Formula XVII.
• [1586] Embodiment 966. The modified oligonucleotide of embodiment 961, wherein at least 6 of the ten 3′-most internucleoside linking groups are internucleoside linking groups of Formula XVII.
• [1587] Embodiment 967. The modified oligonucleotide of embodiment 961, wherein the two 3′-most internucleoside linking groups of the modified oligonucleotide are internucleoside linking groups of Formula XVII.
• [1588] Embodiment 968. The modified oligonucleotide of any of embodiments 943-953, wherein the modified oligonucleotide comprises at least one block of at least 3 consecutive internucleoside linking groups of Formula XVII.
• [1589] Embodiment 969. The modified oligonucleotide of any of embodiments 943-953, wherein the modified oligonucleotide comprises at least one block of at least 4 consecutive internucleoside linking groups of Formula XVII.
• [1590] Embodiment 970. The modified oligonucleotide of any of embodiments 943-953, wherein the modified oligonucleotide comprises at least one block of at least 5 consecutive internucleoside linking groups of Formula XVII.
• [1591] Embodiment 971. The modified oligonucleotide of any of embodiments 943-953, wherein the modified oligonucleotide comprises at least one block of at least 6 consecutive internucleoside linking groups of Formula XVII.
• [1592] Embodiment 972. The modified oligonucleotide of any of embodiments 968-971, wherein at least one block of consecutive internucleoside linking groups of Formula XVII is at the 5′ end of the modified oligonucleotide.
• [1593] Embodiment 973. The modified oligonucleotide of any of embodiments 968-971, wherein at least one block of consecutive internucleoside linking groups of Formula XVII is at the 3′ end of the modified oligonucleotide.
• [1594] Embodiment 974. The modified oligonucleotide of any of embodiments 943-973, wherein for each internucleoside linking group of Formula XVII, R₁ is H and T is SO₂Me.
• [1595] Embodiment 975. The modified oligonucleotide of any of embodiments 943-953, wherein the internucleoside linkage motif is selected from: aaaaaasssssssss, sssssaaaaaassss, or sssssssssaaaaaa, wherein each “a” represents an internucleoside linkage of Formula XVII, each “s” represents a phosphorothioate internucleoside linkage, and each “o” represents a phosphodiester internucleoside linkage.
• [1596] Embodiment 976. The modified oligonucleotide of embodiment 975, wherein each “a” represents a mesyl phosphoramidate internucleoside linkage.
• [1597] Embodiment 977. The modified oligonucleotide of any of embodiments 705-841, wherein the modified oligonucleotide comprises a deoxy region consisting of 6-11 linked nucleosides wherein each nucleoside of the deoxy region is either a modified nucleoside or a stereo-standard DNA nucleoside and wherein at least 3 contiguous nucleosides of the deoxy region are stereo-standard DNA nucleosides and not more than three nucleosides of the deoxy region are modified nucleosides.
• [1598] Embodiment 978. The modified oligonucleotide of embodiment 977, wherein at least 5 contiguous nucleosides of the deoxy region are stereo-standard DNA nucleosides.
• [1599] Embodiment 979. The modified oligonucleotide of embodiment 977, wherein at least 6 contiguous nucleosides of the deoxy region are stereo-standard DNA nucleosides.
• [1600] Embodiment 980. The modified oligonucleotide of embodiment 977, wherein at least 7 contiguous nucleosides of the deoxy region are stereo-standard DNA nucleosides.
• [1601] Embodiment 981. The modified oligonucleotide of embodiment 977, wherein at least 8 contiguous nucleosides of the deoxy region are stereo-standard DNA nucleosides.
• [1602] Embodiment 982. The modified oligonucleotide of any of embodiments 977-981, wherein the deoxy region consists of 8-10 linked nucleosides.
• [1603] Embodiment 983. The modified oligonucleotide of any of embodiments 977-981, wherein the deoxy region consists of 9 linked nucleosides.
• [1604] Embodiment 984. The modified oligonucleotide of any of embodiments 977-981, wherein the deoxy region consists of 10 linked nucleosides.
• [1605] Embodiment 985. The modified oligonucleotide of any of embodiments 977-981, wherein the deoxy region consists of 11 linked nucleosides.
• [1606] Embodiment 986. The modified oligonucleotide of any of embodiments 977-981, wherein at least 6 nucleosides of the deoxy region are stereo-standard DNA nucleosides.
• [1607] Embodiment 987. The modified oligonucleotide of any of embodiments 977-981, wherein at least 7 nucleosides of the deoxy region are stereo-standard DNA nucleosides.
• [1608] Embodiment 988. The modified oligonucleotide of any of embodiments 977-981, wherein at least 8 nucleosides of the deoxy region are stereo-standard DNA nucleosides.
• [1609] Embodiment 989. The modified oligonucleotide of any of embodiments 977-981, wherein at least 9 nucleosides of the deoxy region are stereo-standard DNA nucleosides.
• [1610] Embodiment 990. The modified oligonucleotide of any of embodiments 977-989 wherein exactly two nucleosides of the deoxy region are modified nucleosides.
• [1611] Embodiment 991. The modified oligonucleotide of any of embodiments 977-989 wherein exactly one nucleoside of the deoxy region is a modified nucleoside.
• [1612] Embodiment 992. The modified oligonucleotide of any of embodiments 977-991 wherein at least one modified nucleoside of the deoxy region is a stereo-standard modified nucleoside or bicyclic nucleoside selected from a β-D-LNA nucleoside, an α-L-LNA nucleoside, an ENA nucleoside, a cEt nucleoside, a 2′-MOE nucleoside, a 2′-OMe nucleoside, a 2′-F nucleoside, and a 5′-alkyl nucleoside.
• [1613] Embodiment 993. The modified oligonucleotide of any of embodiments 977-991, wherein at least one modified nucleoside of the deoxy region is stereo-non-standard nucleoside.
• [1614] Embodiment 994. The modified oligonucleotide of embodiment 993, wherein the at least one is stereo-non-standard nucleoside of the deoxy region is a stereo-non-standard DNA nucleoside.
• [1615] Embodiment 995. The modified oligonucleotide of embodiment 994, wherein the stereo-non-standard DNA nucleoside is selected from a stereo-non-standard DNA nucleoside having: Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, and Formula VII.
• [1616] Embodiment 996. The modified oligonucleotide of embodiment 995, wherein the stereo-non-standard DNA nucleoside is selected from a stereo-non-standard DNA nucleoside having: Formula V and Formula II.
• [1617] Embodiment 997. The modified oligonucleotide of embodiment 996, wherein at least one stereo-non-standard nucleoside of the deoxy region is a substituted stereo-non-standard nucleoside.
• [1618] Embodiment 998. The modified oligonucleotide of embodiment 997, wherein at least one substituted stereo-non-standard nucleoside has a 2′-substituent selected from: 2′-MOE, 2′-OMe, 2′-F, or 2′-OH.
• [1619] Embodiment 999. The modified oligonucleotide of any of embodiments 977-998, wherein the 2^nd nucleoside from the 5′-end of the deoxy region is a modified nucleoside.
• [1620] Embodiment 1000. The modified oligonucleotide of any of embodiments 977-998, wherein the 3^rd nucleoside from the 5′-end of the deoxy region is a modified nucleoside.
• [1621] Embodiment 1001. The modified oligonucleotide of any of embodiments 977-998 wherein the 4^th nucleoside from the 5′-end of the deoxy region is a modified nucleoside.
• [1622] Embodiment 1002. The modified oligonucleotide of any of embodiments 999-1001, wherein the modified nucleoside in the deoxy region is a 2′-OMe nucleoside.
• [1623] Embodiment 1003. The modified oligonucleotide of any of embodiments 977-989, wherein each nucleoside of the deoxy region is a stereo-standard DNA nucleoside.
• [1624] Embodiment 1004. The modified oligonucleotide of any of embodiments 977-1003 wherein at least one internucleoside linking group within the deoxy region is an internucleoside linking group of Formula XVII.
• [1625] Embodiment 1005. The modified oligonucleotide of any of embodiments 977-1004, wherein the internucleoside linking group linking the 1^st and 2^nd nucleosides of the deoxy region as counted from the 5′-end of the deoxy region is an internucleoside linking group of Formula XVII.
• [1626] Embodiment 1006. The modified oligonucleotide of any of embodiments 977-1005, wherein the internucleoside linking group linking the 2^nd and 3^rd nucleosides of the deoxy region as counted from the 5′-end of the deoxy region is an internucleoside linking group of Formula XVII.
• [1627] Embodiment 1007. The modified oligonucleotide of any of embodiments 977-1006, wherein the internucleoside linking group linking the 3^rd and 4^th nucleosides of the deoxy region as counted from the 5′-end of the deoxy region is an internucleoside linking group of Formula XVII.
• [1628] Embodiment 1008. The modified oligonucleotide of any of embodiments 977-1007, wherein the internucleoside linking group linking the 4^th and 5^th nucleosides of the deoxy region as counted from the 5′-end of the deoxy region is an internucleoside linking group of Formula XVII.
• [1629] Embodiment 1009. The modified oligonucleotide of any of embodiments 977-1008, wherein one internucleoside linking group in the deoxy region is a linking group of Formula XVII and the other internucleoside linking groups of the deoxy region are independently selected from phosphodiester and phosphorothioate internucleoside linking groups.
• [1630] Embodiment 1010. The modified oligonucleotide of any of embodiments 977-1008, wherein two internucleoside linking groups in the deoxy region are linking groups of Formula XVII and the other internucleoside linking groups of the deoxy region are independently selected from phosphodiester and phosphorothioate internucleoside linking groups.
• [1631] Embodiment 1011. The modified oligonucleotide of any of embodiments 977-1008, wherein three internucleoside linking groups in the deoxy region are linking groups linking groups of Formula XVII and the other internucleoside linking groups of the deoxy region are independently selected from phosphodiester and phosphorothioate internucleoside linking groups.
• [1632] Embodiment 1012. The modified oligonucleotide of any of embodiments 977-1008, wherein four internucleoside linking groups in the deoxy region are linking groups linking groups of Formula XVII and the other internucleoside linking groups of the deoxy region are each phosphodiester or phosphorothioate internucleoside linking groups.
• [1633] Embodiment 1013. The modified oligonucleotide of any of embodiments 1009-1012, wherein the internucleoside linking groups of Formula XVII are linking the 1^st and 2^nd, 2^nd and 3^rd, 3^rd and 4^th, and/or the 4^th and 5^th nucleosides of the deoxy region, as counted from the 5′-end of the deoxy region.
• [1634] Embodiment 1014. The modified oligonucleotide of any of embodiments 877-1013, wherein the deoxy region comprises at least one region having structure A, B, C, D, or E.
• [1635] Embodiment 1015. The modified oligonucleotide of embodiment 1014, wherein the region having structure A, B, C, D, or E is at the 3′ end of the deoxy region.
• [1636] Embodiment 1016. The modified oligonucleotide of embodiment 1014, wherein the region having structure A, B, C, D, or E is at the 5′ end of the deoxy region.
• [1637] Embodiment 1017. The modified oligonucleotide of any of embodiments 877-1016, wherein the deoxy region comprises at least one region having the formula (N_g1)_L1(N_g2)_L2(N_g3)_L3, wherein each N_g is a nucleoside and each L is an internucleoside linking group; wherein each of L₁, and L₂ is a phosphodiester internucleoside linking group, a phosphorothioate internucleoside linking group, or an internucleoside linking group of Formula XVII:

[1638]

[1639] wherein L₃ is absent or is a phosphodiester internucleoside linking group, a phosphorothioate internucleoside linking group, or an internucleoside linking group of Formula XVII;

[1640] wherein at least one of L₁, L₂, and L₃ an internucleoside linking group of Formula XVII; and at least one of L₁, L₂, and L₃ is a phosphorothioate or a phosphodiester internucleoside linking group,

• • [1641] wherein independently for each internucleoside linking group of the modified oligonucleotide having Formula XVII:
  • [1642] X is selected from O or S;
  • [1643] R₁ is selected from H, C₁-C₆ alkyl, and substituted C₁-C₆ alkyl; and
  • [1644] T is selected from SO₂R₂, C(═O)R₃, and P(═O)R₄R₅, wherein:

[1645] R₂ is selected from an aryl, a substituted aryl, a heterocycle, a substituted heterocycle, an aromatic heterocycle, a substituted aromatic heterocycle, a diazole, a substituted diazole, a C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ alkenyl, C₁-C₆ alkynyl, substituted C₁-C₆ alkyl, substituted C₁-C₆ alkenyl substituted C₁-C₆ alkynyl, and a conjugate group;

• • [1646] R₃ is selected from an aryl, a substituted aryl, CH₃, N(CH₃)₂, OCH₃ and a conjugate;
  • [1647] R₄ is selected from OCH₃, OH, C₁-C₆ alkyl, substituted C₁-C₆ alkyl and a conjugate; and
  • [1648] R₅ is selected from OCH₃, OH, C₁-C₆ alkyl, and substituted C₁-C₆ alkyl.
• [1649] Embodiment 1018. The modified oligonucleotide of embodiment 1017, wherein the region having the formula (N_g1)_L1(N_g2)_L2(N_g3)_L3 is at the 3′ end of the deoxy region.
• [1650] Embodiment 1019. The modified oligonucleotide of embodiment 1017, wherein the region having the formula (N_g1)_L1(N_g2)_L2(N_g3)_L3 is at the 5′ end of the deoxy region.
• [1651] Embodiment 1020. The modified oligonucleotide of any of embodiments 1004-1019, wherein for each internucleoside linkage of Formula XVII, R₁ is H and T is SO₂Me.
• [1652] Embodiment 1021. The modified oligonucleotide of any of embodiments 877-1020 wherein the deoxy region is flanked on the 5′ side by a 5′-region consisting of 1-6 linked 5′-region nucleosides and on the 3′ side by a 3′-region consisting of 1-6 linked 3′-region nucleosides; wherein

[1653] the 3′-most nucleoside of the 5′-region comprises a modified sugar moiety; and

[1654] the 5′-most nucleoside of the 3′-region comprises a modified sugar moiety.

• [1655] Embodiment 1022. The modified oligonucleotide of embodiment 1021, wherein the deoxy region consists of 7-11 linked nucleosides, and has the formula:
  (N_d1)_L1(N_d2)_L2(N_d3)_L3(N_d4)_L4[N_d)_L5]_q;

[1656] wherein N_d1, N_d2, N_d3, N_d4 are independently selected from among

[1657] a stereo-standard DNA nucleoside, a stereo-non-standard DNA nucleoside, or a 2′-substituted nucleoside;

[1658] with the proviso that no more than one of N_d1, N_d2, N₃, or N_d4 is a 2′-substituted nucleoside;

[1659] each N_d is independently selected from among a stereo-standard DNA nucleoside and a stereo-non-standard DNA nucleoside;

[1660] q is from 3-8;

[1661] wherein each of L₁, L₂, L₃, L₄, and each L₅ is an internucleoside linkage;

[1662] wherein at least two of L₁, L₂, L₃, L₄ are internucleoside linkages of Formula XVII.

• [1663] Embodiment 1023. The modified oligonucleotide of embodiment 1022, wherein one of N_d1, N_d2, N_d3, or N_d4 is a 2′-substituted nucleoside.
• [1664] Embodiment 1024. The modified oligonucleotide of embodiment 1023, wherein the 2′-substituted nucleoside is a 2′-OMe nucleoside.
• [1665] Embodiment 1025. The modified oligonucleotide of embodiment 1024, wherein the 2′-OMe nucleoside is a stereo-standard 2′-OMe nucleoside.
• [1666] Embodiment 1026. The modified oligonucleotide of any of embodiments 1022-1025, wherein the 2′-substituted nucleoside is N_d2
• [1667] Embodiment 1027. The modified oligonucleotide of embodiment 1022, wherein each of N_d1, N_d2, N_d3, N_d4 and each N_d is a DNA nucleoside.
• [1668] Embodiment 1028. The modified oligonucleotide of embodiment 1027, wherein each DNA nucleoside is a stereo-standard DNA nucleoside.
• [1669] Embodiment 1029. The modified oligonucleotide of any of embodiments 1022-1028, wherein L₁ and L₂ are internucleoside linkages of Formula XVI.
• [1670] Embodiment 1030. The modified oligonucleotide of any of embodiments 1022-1028, wherein L₂ and L₃ are internucleoside linkages of Formula XVI.
• [1671] Embodiment 1031. The modified oligonucleotide of any of embodiments 1022-1028, wherein L₃ and L₄ are internucleoside linkages of Formula XVI.
• [1672] Embodiment 1032. The modified oligonucleotide of any of embodiments 1022-1028, wherein L₁, L₂, and L₃ are internucleoside linkages of Formula XVI.
• [1673] Embodiment 1033. The modified oligonucleotide of any of embodiments 1022-1028, wherein L₂, L₃, and L₄ are internucleoside linkages of Formula XVI.
• [1674] Embodiment 1034. The modified oligonucleotide of any of embodiments 1022-1028, wherein L₁, L₂, L₃, and L₄ are internucleoside linkages of Formula XVI.
• [1675] Embodiment 1035. The modified oligonucleotide of embodiments 1029-1034, wherein each internucleoside linkage that is not an internucleoside linkage of Formula XVII is a phosphorothioate internucleoside linkage.
• [1676] Embodiment 1036. The modified oligonucleotide of any of embodiments 1029-1035, wherein for each internucleoside linkage of Formula XVII, R₁ is H and T is SO₂Me
• [1677] Embodiment 1037. The modified oligonucleotide of any of embodiments 1021-1036, wherein the 5′-region consists of 2-5 linked nucleosides.
• [1678] Embodiment 1038. The modified oligonucleotide of embodiment 1037, wherein the 5′-region consists of 3 linked nucleosides.
• [1679] Embodiment 1039. The modified oligonucleotide of embodiment 1037, wherein the 5′-region consists of 5 linked nucleosides.
• [1680] Embodiment 1040. The modified oligonucleotide of any of embodiments 1021-1039 wherein each nucleoside of the 5′-region is a modified nucleoside.
• [1681] Embodiment 1041. The modified oligonucleotide of any of embodiments 1021-1040, wherein each nucleoside of the 5′-region is a modified nucleoside comprising a modified sugar.
• [1682] Embodiment 1042. The modified oligonucleotide of any of embodiments 1021-1041, wherein at least one nucleoside of the 5′-region comprises a 2′-substituted furanosyl sugar moiety.
• [1683] Embodiment 1043. The modified oligonucleotide of any of embodiments 1021-1041, wherein each nucleoside of the 5′-region comprises a 2′-substituted furanosyl sugar moiety.
• [1684] Embodiment 1044. The modified oligonucleotide of any of embodiments 1021-1043, wherein each 2′-substituted furanosyl sugar moiety of the 5′-region has a 2′-substituent selected from among 2′-MOE, 2′-OMe, and 2′-NMA.
• [1685] Embodiment 1045. The modified oligonucleotide of any of embodiments 1021-1042 or 1044, wherein at least one nucleoside of the 5′-region comprises a bicyclic furanosyl sugar moiety.
• [1686] Embodiment 1046. The modified oligonucleotide of any of embodiments 1021-1042 or 1044-1045, wherein each nucleoside of the 5′-region comprises a bicyclic furanosyl sugar moiety.
• [1687] Embodiment 1047. The modified oligonucleotide of embodiment 341 or 342, wherein each bicyclic sugar moiety of the 5′-region is selected from among cEt, LNA, and ENA.
• [1688] Embodiment 1048. The modified oligonucleotide of embodiment 1047, wherein each bicyclic sugar moiety of the 5′-region is a cEt sugar moiety.
• [1689] Embodiment 1049. The modified oligonucleotide of any of embodiments 1021-1039, 1042 or 1045, wherein at least one nucleoside of the 5′ region is a stereo-standard DNA nucleoside.
• [1690] Embodiment 1050. The modified oligonucleotide of any of embodiments 1021-1048, wherein at least one nucleoside of the 5′ region is a stereo-non-standard nucleoside.
• [1691] Embodiment 1051. The modified oligonucleotide of any of embodiments 1021-1050, wherein each nucleobase of the 5′-region is independently selected from among thymine, uracil, guanine, cytosine, 5-methylcytosine, and adenine.
• [1692] Embodiment 1052. The modified oligonucleotide of any of embodiments 1021-1051, wherein the 3′-region consists of 2-5 linked nucleosides.
• [1693] Embodiment 1053. The modified oligonucleotide of embodiment 1052, wherein the 3′-region consists of 3 linked nucleosides.
• [1694] Embodiment 1054. The modified oligonucleotide of embodiment 1052, wherein the 3′-region consists of 5 linked nucleosides.
• [1695] Embodiment 1055. The modified oligonucleotide of any of embodiments 1021-1054, wherein each nucleoside of the 3′-region is a modified nucleoside.
• [1696] Embodiment 1056. The modified oligonucleotide of any of embodiments 1021-1055, wherein each nucleoside of the 3′-region is a modified nucleoside comprising a modified sugar.
• [1697] Embodiment 1057. The modified oligonucleotide of any of embodiments 1021-1056, wherein at least one nucleoside of the 3′-region comprises a 2′-substituted furanosyl sugar moiety.
• [1698] Embodiment 1058. The modified oligonucleotide of any of embodiments 1021-1057, wherein each nucleoside of the 3′-region comprises a 2′-substituted furanosyl sugar moiety.
• [1699] Embodiment 1059. The modified oligonucleotide of any of embodiments 1021-1058, wherein each 2′-substituted furanosyl sugar moiety of the 3′-region has a 2′-substituent selected from among 2′-MOE, 2′-OMe, and 2′-NMA.
• [1700] Embodiment 1060. The modified oligonucleotide of any of embodiments 1021-1057 or 1059, wherein at least one nucleoside of the 3′-region comprises a bicyclic furanosyl sugar moiety.
• [1701] Embodiment 1061. The modified oligonucleotide of any of embodiments 1021-1057 or 1059-1060, wherein each nucleoside of the 3′-region comprises a bicyclic furanosyl sugar moiety.
• [1702] Embodiment 1062. The modified oligonucleotide of embodiment 1060 or 1061, wherein each bicyclic sugar moiety of the 3′-region is selected from among cEt, LNA, and ENA.
• [1703] Embodiment 1063. The modified oligonucleotide of embodiment 1062, wherein each bicyclic sugar moiety of the 3′-region is a cEt sugar moiety.
• [1704] Embodiment 1064. The modified oligonucleotide of any of embodiments 1021-1054, 1057 or 1060, wherein at least one nucleoside of the 3′ region is a stereo-standard DNA nucleoside.
• [1705] Embodiment 1065. The modified oligonucleotide of any of embodiments 1021-1064, wherein at least one nucleoside of the 3′ region is a stereo-non-standard nucleoside.
• [1706] Embodiment 1066. The modified oligonucleotide of any of embodiments 1021-1065, wherein each nucleobase of the 3′-region is independently selected from among thymine, uracil, guanine, cytosine, 5-methylcytosine, and adenine.
• [1707] Embodiment 1067. The modified oligonucleotide of any of embodiments 1021-1066 wherein the modified oligonucleotide is a gapmer.
• [1708] Embodiment 1068. The modified oligonucleotide of any of embodiments 1021-1066, wherein the modified oligonucleotide has a sugar motif selected from kkkddddddddddkkk and kkkdyddddddddkkk, wherein each “k” represents a cEt sugar moiety, “y” represents a 2′-OMe sugar moiety, and each “d” represents a β-D-2′-deoxyribosyl sugar moiety.
• [1709] Embodiment 1069. The modified oligonucleotide of any of embodiments 1021-1066, wherein the modified oligonucleotide has an internucleoside linkage motif selected from: ssssssssssssssa, sssssssssssssas, ssssssssssssass, sssssssssssasss, ssssssssssassss, sssssssssasssss, ssssssssassssss, sssssssasssssss, ssssssassssssss, sssssasssssssss, ssssassssssssss, sssasssssssssss, ssassssssssssss, sasssssssssssss, assssssssssssss, sssssssssssssaa, ssssssssssssaas, sssssssssssaass, ssssssssssaasss, sssssssssaassss, ssssssssaasssss, sssssssaassssss, ssssssaasssssss, sssssaassssssss, ssssaasssssssss, sssaassssssssss, ssaasssssssssss, saassssssssssss, aasssssssssssss, aaaaaaaaaaaaaaa, ssaaaaaaaaaaass, ssaaaaaaaaaasss, sssaaaaaaaaasss, aassssssssssaaa, sssaaasssssssss, ssssaaassssssss, sssaaaassssssss, ssaaassssssssss, ssaaaasssssssss, ssaaaaassssssss, ssaaaaaasssssss, ssaaaaaaassssss, ssaaaaaaaasssss, ssaaaaaaaaassss, ssssssssssaaass, sssssssssaaaass, ssssssssaaaaass, sssssssaaaaaass, ssssssaaaaaaass, sssssaaaaaaaass, ssssaaaaaaaaass, sssaaaaaaaaaass, ssasasasasasass, sssasasasasasss, ooossssssssssoo, soossssssssssos, aoosssssssssooa, aoasssssssssaoa, aoaaaassssssaoa, aoossssssssssoa, ooasssssssssaoo, aoosaasssssssoa, aossaasssssssoa, aooaaaasssssaoa, aoossssssaaaaoa, sssssaaasssssss, ssssssaaassssss, sssssssaaasssss, ssssssssaaassss, sssssssssaaasss, ssssaaaasssssss, sssssaaaassssss, ssssssaaaasssss, sssssssaaaassss, ssssssssaaaasss, sssaassssssaass, sssaasssssaasss, sssaassssaassss, sssaasssaasssss, sssaassaassssss, sssaasaasssssss, ssaasssssssaass, ssssaasssssaass, sssssaassssaass, ssssssaasssaass, sssssssaassaass, ssssssssaasaass, ssssaasssaassss, sssssaasaasssss, ssssssssssssssS, aaassssssssssss, aaassssssssssaa, aaaaaasssssssss, aoooosaasssssssooaa, aoooossssssssssooaa, sooooaassssssssooss, soooosaasssssssooss, soooossaassssssooss, soooossssssaassooss, sssaaaaasssssss, sssssaaaaaassss, or sssssssssaaaaaa wherein each “a” represents an internucleoside linkage of Formula XVII, each “s” represents a phosphorothioate internucleoside linkage, and each “o” represents a phosphodiester internucleoside linkage.
• [1710] Embodiment 1070. The modified oligonucleotide of embodiment 1069, wherein the modified oligonucleotide has an internucleoside linkage motif selected from: sssaaaassssssss, sssaaasssssssss, ssssaaassssssss, ssssaasssssaass, sssaassssssssss, ssssaasssssssss, sssssaassssssss, or sssssssssaassss, wherein each “a” represents an internucleoside linkage of Formula XVII, each “s” represents a phosphorothioate internucleoside linkage, and each “o” represents a phosphodiester internucleoside linkage.
• [1711] Embodiment 1071. The modified oligonucleotide of embodiment 1069-1070, wherein each “a” represents a mesyl phosphoramidate internucleoside linkage.
• [1712] Embodiment 1072. The modified oligonucleotide of any of embodiments 705-841, wherein the modified oligonucleotide is a CRISPR compound.
• [1713] Embodiment 1073. The modified oligonucleotide of embodiment 1072, wherein the CRISPR compound consists of 20-50 or 29-32 linked nucleosides.
• [1714] Embodiment 1074. The modified oligonucleotide of any of embodiments 794-1073, wherein each X is O.
• [1715] Embodiment 1075. The modified oligonucleotide of any of embodiments 794-1073, wherein each X is S.
• [1716] Embodiment 1076. The modified oligonucleotide of any of embodiments 794-1075, wherein at least one R₁ is H.
• [1717] Embodiment 1077. The modified oligonucleotide of any of embodiments 794-1075, wherein at least one R₁ is a C₁-C₆ alkyl.
• [1718] Embodiment 1078. The modified oligonucleotide of embodiment 1077, wherein the at least one R₁ is methyl.
• [1719] Embodiment 1079. The modified oligonucleotide of any of embodiments 794-1075, at least one R₁ is a substituted C₁-C₆ alkyl.
• [1720] Embodiment 1080. The modified oligonucleotide of any of embodiments 794-1079, wherein at least one T comprises a conjugate group.
• [1721] Embodiment 1081. The modified oligonucleotide of embodiment 1080, wherein the conjugate group comprises a cell-targeting moiety.
• [1722] Embodiment 1082. The modified oligonucleotide of embodiment 1080, wherein the conjugate group comprises a carbohydrate or carbohydrate cluster.
• [1723] Embodiment 1083. The modified oligonucleotide of any of embodiments 1080-1082, wherein the conjugate group comprises at least one GalNAc.
• [1724] Embodiment 1084. The modified oligonucleotide of embodiment 1080, wherein the conjugate group comprises a C₁-C₂₀ alkyl chain.
• [1725] Embodiment 1085. The modified oligonucleotide of embodiment 1084, wherein the conjugate group comprises C₁₆ alkyl.
• [1726] Embodiment 1086. The modified oligonucleotide of any of embodiments 794-1085, wherein at least one T does not comprise a conjugate group.
• [1727] Embodiment 1087. The modified oligonucleotide of any of embodiments 794-1079, wherein each T does not comprise a conjugate group.
• [1728] Embodiment 1088. The modified oligonucleotide of any of embodiments 794-1087, wherein at least one T is SO₂R₂.
• [1729] Embodiment 1089. The modified oligonucleotide of embodiment 1088, wherein R₂ is an aryl.
• [1730] Embodiment 1090. The modified oligonucleotide of embodiment 1088, wherein R₂ is a substituted aryl.
• [1731] Embodiment 1091. The modified oligonucleotide of embodiment 1088, wherein R₂ is a heterocycle.
• [1732] Embodiment 1092. The modified oligonucleotide of embodiment 1088, wherein R₂ is a substituted heterocycle.
• [1733] Embodiment 1093. The modified oligonucleotide of embodiment 1088, wherein R₂ is an aromatic heterocycle.
• [1734] Embodiment 1094. The modified oligonucleotide of embodiment 1088, wherein R₂ is a substituted aromatic heterocycle.
• [1735] Embodiment 1095. The modified oligonucleotide of embodiment 1088, wherein R₂ is a diazole.
• [1736] Embodiment 1096. The modified oligonucleotide of embodiment 1088, wherein R₂ is a substituted diazole.
• [1737] Embodiment 1097. The modified oligonucleotide of embodiment 1088, wherein R₂ is an amine.
• [1738] Embodiment 1098. The modified oligonucleotide of embodiment 1088, wherein R₂ is a substituted amine.
• [1739] Embodiment 1099. The modified oligonucleotide of embodiment 1088, wherein R₂ is a C₁-C₆ alkoxy, C₁-C₆ alkenyl, or C₁-C₆ alkynyl.
• [1740] Embodiment 1100. The modified oligonucleotide of embodiment 1088, wherein R₂ is C₁-C₂₀, C₁-C₆, C₂-C₂₀, C₂-C₆, or C₁₀-C₂₀ alkyl.
• [1741] Embodiment 1101. The modified oligonucleotide of embodiment 1088, wherein R₂ is substituted C₁-C₂₀, C₁-C₆, C₂-C₂₀, C₂-C₆, or C₁₀-C₂₀ alkyl.
• [1742] Embodiment 1102. The modified oligonucleotide of embodiment 1088, wherein R₂ comprises a carbohydrate or carbohydrate cluster.
• [1743] Embodiment 1103. The modified oligonucleotide of embodiment 1088, wherein R₂ comprises at least one GalNAc.
• [1744] Embodiment 1104. The modified oligonucleotide of embodiment 1088, wherein T is:

[1745]

• [1746] Embodiment 1105. The modified oligonucleotide of embodiment 1088, wherein T is:

[1747]

• [1748] Embodiment 1106. The modified oligonucleotide of embodiment 1088, wherein T is:

[1749]

• [1750] Embodiment 1107. The modified oligonucleotide of embodiment 1088, wherein T is:

[1751]

• [1752] Embodiment 1108. The modified oligonucleotide of embodiment 1088, wherein T is:

[1753]

• [1754] Embodiment 1109. The modified oligonucleotide of embodiment 1088, wherein T is:

[1755]

• [1756] Embodiment 1110. The modified oligonucleotide of embodiment 1088, wherein T is:

[1757]

• [1758] Embodiment 1111. The modified oligonucleotide of embodiment 1088, wherein T is:

[1759]

• [1760] Embodiment 1112. The modified oligonucleotide of embodiment 1088, wherein T is:

[1761]

• [1762] Embodiment 1113. The modified oligonucleotide of embodiment 1088, wherein T is:

[1763]
n wherein n is from 2 to 20.

• [1764] Embodiment 1114. The modified oligonucleotide of embodiment 1113, wherein n is 15.
• [1765] Embodiment 1115. The modified oligonucleotide of any of embodiments 794-1114, wherein at least one T is C(═O)R₃.
• [1766] Embodiment 1116. The modified oligonucleotide of embodiment 1115, wherein R₃ is an aryl.
• [1767] Embodiment 1117. The modified oligonucleotide of embodiment 1115, wherein R₃ is a substituted aryl.
• [1768] Embodiment 1118. The modified oligonucleotide of embodiment 1115, wherein R₃ is CH₃.
• [1769] Embodiment 1119. The modified oligonucleotide of embodiment 1115, wherein R₃ is N(CH₃)₂.
• [1770] Embodiment 1120. The modified oligonucleotide of embodiment 1115, wherein R₃ is OCH₃.
• [1771] Embodiment 1121. The modified oligonucleotide of embodiment 1115, wherein R₃ is a C₁-C₆ alkoxy.
• [1772] Embodiment 1122. The modified oligonucleotide of embodiment 1115, wherein R₃ is C₁-C₂₀, C₁-C₆, C₂-C₂₀, C₂-C₆, or C₁₀-C₂₀ alkyl.
• [1773] Embodiment 1123. The modified oligonucleotide of embodiment 1115, wherein R₃ is substituted C₁-C₂₀, C₁-C₆, C₂-C₂₀, C₂-C₆, or C₁₀-C₂₀ alkyl.
• [1774] Embodiment 1124. The modified oligonucleotide of embodiment 1115, wherein R₃ comprises a carbohydrate or carbohydrate cluster.
• [1775] Embodiment 1125. The modified oligonucleotide of embodiment 1115, wherein R₂₃ comprises at least one GalNAc.
• [1776] Embodiment 1126. The modified oligonucleotide of embodiment 1115, wherein T is:

[1777]

• [1778] Embodiment 1127. The modified oligonucleotide of embodiment 1115, wherein T is:

[1779]

• [1780] Embodiment 1128. The modified oligonucleotide of embodiment 1115, wherein T is:

[1781]

• [1782] Embodiment 1129. The modified oligonucleotide of embodiment 1115, wherein T is:

[1783]

• [1784] Embodiment 1130. The modified oligonucleotide of embodiment 1115, wherein T is:

[1785]
wherein n is from 2 to 20.

• [1786] Embodiment 1131. The modified oligonucleotide of embodiment 1130, wherein n is 15.
• [1787] Embodiment 1132. The modified oligonucleotide of any of embodiments 794-1131, wherein at least one T is P(═O)R₄R₅.
• [1788] Embodiment 1133. The modified oligonucleotide of embodiment 1132, wherein R₄ is OCH₃.
• [1789] Embodiment 1134. The modified oligonucleotide of embodiment 1132, wherein R₄ is OH.
• [1790] Embodiment 1135. The modified oligonucleotide of embodiment 1132, wherein R₄ is C₁-C₆ alkyl.
• [1791] Embodiment 1136. The modified oligonucleotide of embodiment 1132, wherein R₄ is substituted C₁-C₆ alkyl.
• [1792] Embodiment 1137. The modified oligonucleotide of embodiment 1132, wherein R₄ is C₁-C₂₀, C₁-C₆, C₂-C₂₀, C₂-C₆, or C₁₀-C₂₀ alkyl.
• [1793] Embodiment 1138. The modified oligonucleotide of embodiment 1132, wherein R₄ is substituted C₁-C₂₀, C₁-C₆, C₂-C₂₀, C₂-C₆, or C₁₀-C₂₀ alkyl.
• [1794] Embodiment 1139. The modified oligonucleotide of embodiment 1132, wherein R₄ comprises a carbohydrate or carbohydrate cluster.
• [1795] Embodiment 1140. The modified oligonucleotide of embodiment 1132, wherein R₄ comprises at least one GalNAc.
• [1796] Embodiment 1141. The modified oligonucleotide of any of embodiments 1132-1140, wherein R₅ is OCH₃.
• [1797] Embodiment 1142. The modified oligonucleotide of any of embodiments 1132-1140, wherein R₅ is OH.
• [1798] Embodiment 1143. The modified oligonucleotide of any of embodiments 1132-1140, wherein R₅ is C₁-C₆ alkyl.
• [1799] Embodiment 1144. The modified oligonucleotide of any of embodiments 1132-1140, wherein R₅ is substituted C₁-C₆ alkyl.
• [1800] Embodiment 1145. The modified oligonucleotide of embodiment 1132, wherein T is:

[1801]

• [1802] Embodiment 1146. The modified oligonucleotide of embodiment 1132, wherein T is:

[1803]

• [1804] Embodiment 1147. The modified oligonucleotide of embodiment 1132, wherein T is:

[1805]
wherein n is from 2 to 20.

• [1806] Embodiment 1148. The modified oligonucleotide of embodiment 1147, wherein n is 15.
• [1807] Embodiment 1149. An antisense agent comprising a modified oligonucleotide consisting of 12-50 linked nucleosides linked through internucleoside linking groups, wherein at least one internucleoside linking group is a phosphodiester or a phosphorothioate internucleoside linking group, and wherein at least one of the internucleoside linking groups has Formula XX:

[1808]

[1809] wherein independently for each internucleoside linking group of the modified oligonucleotide having Formula XX, X is selected from O or S.

• [1810] Embodiment 1150. An antisense agent comprising a modified oligonucleotide, wherein the 5′-terminus of the modified oligonucleotide has Structure F:

[1811]

[1812] wherein:

[1813] p is from 0 to 6;

[1814] q is from 0 to 6;

[1815] T is OH or a conjugate group;

[1816] each Bx is an independently selected heterocyclic base moiety;

[1817] each X is independently selected from OH or SH;

[1818] each Z is independently selected from O, S, or NSO₂Me;

[1819] For each J^R and G of the same furanosyl sugar moiety, either J^R and G form a J^R to G bridge, or J^R is H and G is selected from OH, halogen or O—[C(R₆)(R₇)]_n—[(C═O)_m—X^G]_j—R₈;

[1820] wherein each J^R to G bridge has a formula independently selected from —CH(CH₃)—O— or —(CH₂)_k—O—, wherein k is from 1 to 3;

[1821] each R₆ and R₇ is, independently, H, halogen, C₁-C₆ alkyl or substituted C₁-C₆ alkyl;

[1822] each X^G is O, S or N(E₁);

[1823] R₈ is H, halogen, C₁-C₆ alkyl, substituted C₁-C₆ alkyl, C₂-C₆ alkenyl, substituted C₂-C₆ alkenyl, C₂-C₆ alkynyl, substituted C₂-C₆ alkynyl or N(E₂)(E₃);

[1824] E₁, E₂ and E₃ are each, independently, H, C₁-C₆ alkyl or substituted C₁-C₆ alkyl;

[1825] n is from 1 to 6;

[1826] m is 0 or 1;

[1827] j is 0 or 1;

[1828] each substituted group comprises one or more optionally protected substituent groups independently selected from halogen, OJ₁, N(J₁)(J₂), =NJ₁, SJ₁, N₃, CN, OC(═X₂)J₁, OC(═X₂)N(J₁)(J₂) and C(=Q₂)N(J₁)(J₂);

• • [1829] Q₂ is O, S or NJ₃;
  • [1830] each J₁, J₂ and J₃ is, independently, H or C₁-C₆ alkyl.
• [1831] Embodiment 1151. An antisense agent comprising a modified oligonucleotide, wherein the 3′-terminus of the modified oligonucleotide has Structure G:

[1832]

[1833] wherein:

[1834] p is from 0 to 6;

[1835] q is from 1 to 6;

[1836] T is OH or a conjugate group;

[1837] each Bx is an independently selected heterocyclic base moiety;

[1838] each X is independently selected from OH or SH;

[1839] each Z is independently selected from O, S, or NSO₂Me;

[1840] for each J^R and G of the same furanosyl sugar moiety, either J^R and G form a J^R to G bridge, or J^R is H and G is selected from OH, halogen or O—[C(R₆)(R₇)]_n—[(C═O)_m—X^G]_j—R₈;

[1841] wherein each J^R to G bridge has a formula independently selected from —CH(CH₃)—O— or —(CH₂)_k—O—, wherein k is from 1 to 3;

[1842] each R₆ and R₇ is, independently, H, halogen, C₁-C₆ alkyl or substituted C₁-C₆ alkyl;

[1843] each X^G is O, S or N(E₁);

[1844] R₈ is H, halogen, C₁-C₆ alkyl, substituted C₁-C₆ alkyl, C₂-C₆ alkenyl, substituted C₂-C₆ alkenyl, C₂-C₆ alkynyl, substituted C₂-C₆ alkynyl or N(E₂)(E₃);

[1845] E₁, E₂ and E₃ are each, independently, H, C₁-C₆ alkyl or substituted C₁-C₆ alkyl;

[1846] n is from 1 to 6;

[1847] m is 0 or 1;

[1848] j is 0 or 1;

[1849] each substituted group comprises one or more optionally protected substituent groups independently selected from halogen, OJ₁, N(J₁)(J₂), =NJ₁, SJ₁, N₃, CN, OC(═X₂)J₁, OC(═X₂)N(J₁)(J₂) and C(=Q₂)N(J₁)(J₂);

[1850] Q₂ is O, S or NJ₃;

[1851] each J₁, J₂ and J₃ is, independently, H or C₁-C₆ alkyl.

• [1852] Embodiment 1152. The antisense agent of embodiment 1150 or 1151, wherein the sum of p+q is selected from 2, 3, 4, or 5.
• [1853] Embodiment 1153. An antisense agent comprising a modified oligonucleotide, wherein the 5′-terminus of the modified oligonucleotide has Structure H:

[1854]

[1855] wherein:

[1856] p is from 0 to 5;

[1857] q is from 1 to 4;

[1858] T is OH or a conjugate group;

[1859] each Bx is an independently selected heterocyclic base moiety;

[1860] each X is independently selected from OH or SH;

[1861] each Z is independently selected from O, S, or NSO₂Me;

[1862] for each J^R and G of the same furanosyl sugar moiety, either J^R and G form a J^R to G bridge, or J^R is H and G is selected from OH, halogen or O—[C(R₆)(R₇)]_n—[(C═O)_m—X^G]_j—R₈;

[1863] wherein each J^R to G bridge has a formula independently selected from —CH(CH₃)—O— or —(CH₂)_k—O—, wherein k is from 1 to 3;

[1864] each R₆ and R₇ is, independently, H, halogen, C₁-C₆ alkyl or substituted C₁-C₆ alkyl;

[1865] each X^G is O, S or N(E₁);

[1866] R₈ is H, halogen, C₁-C₆ alkyl, substituted C₁-C₆ alkyl, C₂-C₆ alkenyl, substituted C₂-C₆ alkenyl, C₂-C₆ alkynyl, substituted C₂-C₆ alkynyl or N(E₂)(E₃);