Bond-modified oligomeric compounds and uses thereof

Abstract

Oligomeric compounds (including oligomeric compounds that are antisense agents or portions thereof) are provided that comprise modified oligonucleotides having at least one modified internucleoside linkage group. [Solution] The oligomeric compound comprises a modified oligonucleotide consisting of 12 to 70 linked nucleosides linked via internucleoside linking groups, wherein at least one nucleoside contains a modified sugar moiety and at least one internucleoside linking group is a phosphodiester or phosphorothioate internucleoside linking group.

Description

[Technical Field]

[0001] Sequence Listing This application has been filed in electronic format along with a Sequence Listing, which is provided as a file entitled CHEM0101WOSEQ_ST25.txt, 593 kb in size, created on August 14, 2020. The information in the electronic format of this 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 modified oligonucleotides having at least one modified internucleoside linkage group. [Background technology]

[0003] The principle behind antisense technology is that antisense compounds hybridize to target nucleic acids and regulate the amount, activity, and / or function of target nucleic acids.For example, in certain cases, antisense compounds cause changes in the transcription or translation of targets.Such regulation of expression can be achieved, for example, by target RNA degradation or inhibition based on occupancy.One example of the regulation of RNA target function by degradation is the RNase H-based degradation of target RNA when hybridized with DNA-like antisense compounds.

[0004] Another example of gene expression regulation by targeted degradation is RNA interference (RNAi). RNAi refers to antisense-mediated gene silencing via a mechanism that utilizes the RNA-induced silencing complex (RISC). A further example of RNA target function regulation is through occupancy-based mechanisms, such as those naturally used by microRNAs. MicroRNAs are small, non-coding RNAs that regulate the expression of protein-coding RNAs. Binding of antisense compounds to microRNAs prevents the microRNA from binding to its messenger RNA target, thus interfering with microRNA function. MicroRNA mimics can enhance native microRNA function. Certain antisense compounds alter pre-mRNA splicing. Another example of gene expression regulation is the use of antisense compounds in CRISPR systems. Regardless of the specific mechanism, sequence specificity makes antisense compounds attractive as tools for target validation and gene functioning, as well as therapeutic agents for selectively modulating the expression of genes involved in disease pathogenesis.

[0005] Antisense technology is an effective means for regulating the expression of one or more specific gene products and may therefore prove 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 of the target nucleic acid. Summary of the Invention

[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 via internucleoside linking groups, at least one of the internucleoside linking groups having the formula VIII:

[0007] [ka]

[0008] wherein, independently for each internucleoside linking group of said modified oligonucleotide having Formula VIII: R1 is selected from H, C1-C6 alkyl, and substituted C1-C6 alkyl; T is selected from SO2R2, C(=O)R3, and P(=O)R4R5, wherein: R2 is selected from aryl, substituted aryl, heterocycle, substituted heterocycle, aromatic heterocycle, substituted aromatic heterocycle, diazole, substituted diazole, C1-C6 alkoxy, C1-C6 alkyl, and substituted C1-C6 alkyl; R3 is selected from aryl, substituted aryl, CH3, N(CH3)2, and OCH3; R4 is selected from OCH3, OH, C1-C6 alkyl, and substituted C1-C6 alkyl; R5 is selected from OCH3, OH, C1-C6 alkyl, and substituted C1-C6 alkyl.

[0009] The present disclosure provides oligomeric compounds (including oligomeric compounds that are antisense agents or portions thereof) comprising modified oligonucleotides consisting of linked nucleosides linked via internucleoside linking groups, at least one of the internucleoside linking groups having the formula VIII:

[0010] [ka]

[0011] wherein, independently for each internucleoside linking group of said modified oligonucleotide having Formula VIII: R1 is selected from H, C1-C6 alkyl, and substituted C1-C6 alkyl; T is selected from SO2R2, C(=O)R3, and P(=O)R4R5, wherein: R2 is selected from aryl, substituted aryl, heterocycle, substituted heterocycle, aromatic heterocycle, substituted aromatic heterocycle, diazole, substituted diazole, C1-C6 alkoxy, C1-C6 alkyl, and substituted C1-C6 alkyl; R3 is selected from aryl, substituted aryl, CH3, N(CH3)2, and OCH3; R4 is selected from OCH3, OH, C1-C6 alkyl, and substituted C1-C6 alkyl; R5 is selected from OCH3, OH, C1-C6 alkyl, and substituted C1-C6 alkyl However, However, when R1 is H, T is

[0012] [ka]

[0013] The condition is that it is not.

[0014] The present disclosure provides oligomeric compounds (including oligomeric compounds that are antisense agents or portions thereof) comprising modified oligonucleotides consisting of linked nucleosides joined via internucleoside linking groups, at least one of the internucleoside linking groups having the formula XVII:

[0015] [ka]

[0016] wherein, independently for each internucleoside linking group of said modified oligonucleotide having Formula XVII: X is selected from O or S; R1 is selected from H, C1-C6 alkyl, and substituted C1-C6 alkyl; T is selected from SO2R2, C(=O)R3, and P(=O)R4R5, wherein: R2 is selected from aryl, substituted aryl, heterocycle, substituted heterocycle, aromatic heterocycle, substituted aromatic heterocycle, diazole, substituted diazole, 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; R3 is selected from aryl, substituted aryl, CH3, N(CH3)2, OCH3, and a conjugate group; R4 is selected from OCH3, OH, C1-C6 alkyl, substituted C1-C6 alkyl, and a conjugate group; R5 is selected from OCH3, OH, C1-C6 alkyl, and substituted C1-C6 alkyl.

[0017] 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.

[0018] In certain embodiments, at least one nucleoside of Formula VIII or Formula XVII is Modified oligonucleotides having an internucleoside linking group have an increased therapeutic index compared to an otherwise identical oligomeric compound, except that the otherwise identical oligomeric compound lacks at least one internucleoside linking group of Formula VIII or Formula XVII. [Brief explanation of the drawings]

[0019] [Figure 1] Illustrated are isomers of 2'-deoxyfuranosyl sugar moieties having formulas I-VII. [Figure 2] Illustrated are isomers of the 2'-O-methylfuranosyl sugar moiety having formulas I-VII. [Figure 3] Illustrated are isomers of the 2'-fluorofuranosyl sugar moiety having formulas I-VII. DETAILED DESCRIPTION OF THE INVENTION

[0020] 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. As used herein, the use of the singular includes the plural unless expressly 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.

[0021] The section headings used herein are for organizational purposes only and should not 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, papers, and GenBank and NCBI reference sequence records, are expressly incorporated herein by reference in their entirety, as well as with respect to the portions of the documents discussed herein.

[0022] It is understood that the sequence defined by each SEQ ID NO contained herein is independent of any modification to the sugar moiety, internucleoside linkage, or nucleobase. Thus, a compound defined by a SEQ ID NO may independently contain one or more modifications to the sugar moiety, internucleoside linkage, or nucleobase. While the sequence listing accompanying this application identifies each sequence as either "RNA" or "DNA" as appropriate, in practice, the sequences may be modified with any combination of chemical modifications. Those skilled in the art will readily understand that designations such as "RNA" or "DNA" to describe modified oligonucleotides are arbitrary in certain instances. For example, an oligonucleotide containing a nucleoside containing a 2'-OH (H) sugar moiety and a thymine base may be described as a DNA with a modified sugar (2'-OH instead of one 2'-H in DNA) or as an RNA with a modified base (thymine (methylated uracil) instead of uracil in RNA). Thus, the 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 with modified nucleobases. By way of further example and without limitation, a modified oligonucleotide having the nucleobase sequence "ATCGATCG" encompasses any modified oligonucleotide having such a nucleobase sequence, whether modified or unmodified, including such compounds containing RNA bases, e.g., compounds having the sequence "AUCGAUCG," as well as compounds having any DNA base and any RNA base, e.g., "AUCGATCG," as well as other modified nucleobases, e.g., "AT m CGAUCG” (in the formula, m C represents a cytosine base containing a methyl group at the 5-position).

[0023] As used herein, "2'-substituted," with reference to a furanosyl sugar moiety or a nucleoside containing a furanosyl sugar moiety, means that the furanosyl sugar moiety or a nucleoside containing a furanosyl sugar moiety contains a substituent other than H or OH at the 2'-position and is a non-bicyclic furanosyl sugar moiety. A 2'-substituted furanosyl sugar moiety, when in the context of an oligonucleotide, does not contain additional substituents at other positions on the furanosyl sugar moiety, other than the nucleobase and / or internucleoside linkage(s).

[0024] As used herein, "4'-substituted," with reference to a furanosyl sugar moiety or a nucleoside containing a furanosyl sugar moiety, means that the furanosyl sugar moiety or a nucleoside containing a furanosyl sugar moiety contains a substituent other than H at the 4' position and is a non-bicyclic furanosyl sugar moiety. A 4'-substituted furanosyl sugar moiety, when in the context of an oligonucleotide, does not contain additional substituents at other positions on the furanosyl sugar moiety, other than the nucleobase and / or internucleoside linkage(s).

[0025] As used herein, "5'-substituted," with reference to a furanosyl sugar moiety or a nucleoside containing a furanosyl sugar moiety, means that the furanosyl sugar moiety or a nucleoside containing a furanosyl sugar moiety contains a substituent other than H at the 5' position and is a non-bicyclic furanosyl sugar moiety. A 5'-substituted furanosyl sugar moiety, when in the context of an oligonucleotide, does not contain additional substituents at other positions on the furanosyl sugar moiety, other than the nucleobase and / or internucleoside linkage(s).

[0026] As used herein, "administration" or "administering" refers to the route of introducing a compound or composition provided herein into a subject to perform its intended function. Examples of administration routes that may be used include, but are not limited to, inhalation, subcutaneous injection, intrathecal injection, and oral administration.

[0027] As used herein, "antisense activity" refers to any detectable and / or measurable change attributable to 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 a protein encoded by such a target nucleic acid compared to the target nucleic acid level or target protein level in the absence of the antisense oligonucleotide.

[0028] As used herein, "antisense agent" means an antisense oligonucleotide or an oligonucleotide duplex that includes an antisense oligonucleotide.

[0029] As used herein, "antisense compound" means an antisense oligonucleotide or an oligonucleotide duplex comprising an antisense oligonucleotide.

[0030] As used herein, "antisense oligonucleotide" refers to an oligonucleotide that is complementary to a target nucleic acid and can achieve 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, antisense oligonucleotides are paired with sense oligonucleotides to form oligonucleotide duplexes.In certain embodiments, antisense oligonucleotides are unpaired and are single-stranded antisense oligonucleotides.In certain embodiments, antisense oligonucleotides comprise a conjugate group.

[0031] As used herein, an "artificial mRNA compound" is a modified oligonucleotide, or a portion thereof, having a nucleobase sequence comprising one or more codons.

[0032] As used herein, "bicyclic nucleoside" or "BNA" refers to a nucleoside containing a bicyclic sugar moiety. As used herein, "bicyclic sugar" or "bicyclic sugar moiety" refers to a modified sugar moiety containing two rings, where 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 contain a furanosyl moiety.

[0033] 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 and the second ring of the bicyclic sugar is formed via a bridge connecting the 4' and 2' carbons, the bridge having the formula 4'-CH(CH3)-O-2', and the methyl group of the bridge is in the S configuration. The cEt bicyclic sugar moiety is in the β-D configuration.

[0034] As used herein, "complementary" with reference to an oligonucleotide means that at least 70% of the nucleobases of such oligonucleotide, or one or more regions thereof, and another nucleic acid, or one or more regions thereof, are capable of hydrogen bonding with each other when the nucleobase sequences of the oligonucleotide and the other nucleic acid are aligned in opposite directions. Complementary nucleobases are nucleobase pairs that can form hydrogen bonds with each other. Complementary nucleobase pairs include adenine (A) and thymine (T), adenine (A) and uracil (U), cytosine (C) and guanine (G), 5-methylcytosine ( ... mComplementary oligonucleotides and / or nucleic acids need not have nucleobase complementarity at every nucleoside. Rather, some mismatches are permitted. As used herein, "fully complementary" or "100% complementary" with reference to an oligonucleotide means that such oligonucleotide is complementary to another oligonucleotide or nucleic acid at every nucleoside of the oligonucleotide.

[0035] As used herein, "conjugate group" means the group of atoms consisting of a conjugate moiety and a conjugate linker.

[0036] As used herein, "conjugate moiety" means a group of atoms that modify one or more properties of a molecule, including but not limited to, pharmacodynamics, pharmacokinetics, stability, binding, absorption, tissue distribution, cellular distribution, cellular uptake, charge, and clearance, compared to the same molecule lacking the conjugate moiety.

[0037] As used herein, "conjugate linker" means a group of atoms that includes at least one bond.

[0038] As used herein, "CRISPR compound" refers to a modified oligonucleotide comprising a DNA recognition portion and a tracrRNA recognition portion. As used herein, a "DNA recognition portion" is a nucleobase sequence that is complementary to a DNA target. As used herein, a "tracrRNA recognition portion" is a nucleobase sequence that is bound to or capable of binding to a tracrRNA. The tracrRNA recognition portion of a crRNA can bind to the tracrRNA via hybridization or covalent binding.

[0039] As used herein, "cytotoxic" or "cytotoxicity" in the context of the effects of an oligomeric compound or parent oligomeric compound on cultured cells means at least a two-fold increase in caspase activation following application of 10 μM or less of the oligomeric compound or parent oligomeric compound to cultured cells, compared to cells cultured under the same conditions but not receiving the oligomeric compound or parent oligomeric compound. In certain embodiments, cytotoxicity is measured using a standard in vitro cytotoxicity assay.

[0040] As used herein, a "deoxy region" refers to a region of 5 to 12 contiguous nucleotides in which 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 containing a β-D-2'-deoxyribosyl sugar moiety), a stereo-non-standard nucleoside of Formulas I-VII, a bicyclic nucleoside, and a substituted stereostandard nucleoside. In certain embodiments, the deoxy region supports RNase H activity. In certain embodiments, the deoxy region is the gap of a gapmer.

[0041] 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, wherein one of the two oligomeric compounds comprises an antisense oligonucleotide.

[0042] As used herein, "expression" includes all functions by which a gene's coded information is converted into structures present and operating within a cell. Such structures include, but are not limited to, transcription products and translation products. As used herein, "modulation of expression" refers to any change in the amount or activity of a transcription or translation product of a gene. Such a change can be any amount of increase or decrease compared to expression levels prior to modulation.

[0043] As used herein, a "gapmer" refers to an oligonucleotide having a central region containing multiple nucleosides that support RNase H cleavage, located between a 5' region and a 3' region. Herein, the nucleosides in the 5' and 3' regions each contain a 2'-substituted furanosyl sugar moiety or a bicyclic sugar moiety, and the 3'- and 5'-most nucleosides in the central region each contain a sugar moiety independently selected from a 2'-deoxyfuranosyl sugar moiety or a sugar surrogate. The position of the central region refers to the order of the nucleosides in the central region, counted starting from the 5' end of the central region. Thus, the 5'-most nucleoside in the central region is at position 1 of the central region. The "central region" may also be referred to as the "gap," and the "5' region" and "3' region" may also be referred to as the "wings." The gap in a gapmer is a deoxy region.

[0044] As used herein, "hepatotoxicity" in the context of mice means plasma ALT levels greater than 300 units / liter. Hepatotoxicity of an oligomeric compound or parent oligomeric compound administered to mice is determined by measuring plasma ALT levels in the mice 24 hours to 2 weeks after at least one dose of the compound at 1 to 150 mg / kg.

[0045] As used herein, "hepatotoxicity" in the human context means plasma ALT levels greater than 150 units / liter. Hepatotoxicity of an oligomeric compound or parent oligomeric compound administered to a human is determined by measuring the plasma ALT levels in the human 24 hours to 2 weeks after at least one dose of the compound of 10 to 300 mg / kg.

[0046] As used herein, "hybridization" refers to the pairing or annealing of complementary oligonucleotides and / or nucleic acids. While not limited to a particular mechanism, the most common hybridization mechanism involves hydrogen bonding, which can be Watson-Crick, Hoogsteen, or reversed Hoogsteen hydrogen bonding between complementary nucleobases.

[0047] As used herein, "inhibiting expression or activity" refers to a reduction or blocking of expression or activity compared to expression or activity in an untreated or control sample, and does not necessarily indicate a complete elimination of expression or activity.

[0048] As used herein, "internucleoside linkage" or "internucleoside linking group" refers to a group or bond that forms a covalent bond between adjacent nucleosides in an oligonucleotide. As used herein, "modified internucleoside linkage" refers to any internucleoside linkage other than a naturally occurring phosphodiester internucleoside linkage. "Phosphorothioate linkage" refers to a modified internucleoside linkage in which one of the non-bridging oxygen atoms of the phosphodiester is replaced with a sulfur atom. The modified internucleoside linkage may or may not contain a phosphorus atom. "Neutral internucleoside linkage" refers to a modified internucleoside linkage that does not have a negatively charged phosphate in an aqueous buffer at pH=7.0. The modified internucleoside linkage may optionally contain a conjugate group.

[0049] As used herein, "linked nucleosides" are nucleosides that are joined in contiguous sequence (ie, there are no additional nucleosides between the linked nucleosides).

[0050] As used herein, " maximum tolerated dose " refers to 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 modified oligonucleotide that does not cause ALT elevation of 3 times the upper limit of normal as measured by standard assay.

[0051] As used herein, "mismatch" or "non-complementary" means a nucleobase of a first oligonucleotide that is not complementary to the corresponding nucleobase of a second oligonucleotide or target nucleic acid when the first and second oligomeric compounds are aligned.

[0052] As used herein, "modulating" refers to changing or adjusting a characteristic in a cell, tissue, organ, or organism.

[0053] As used herein, "MOE" refers to O-methoxyethyl. "2'-MOE" or "2'-O-methoxyethyl" refers to a 2'-OCH2CHOCH3 group at the 2'-position of a furanosyl ring. In certain embodiments, the 2'-OCH2CHOCH3 group replaces the 2'-OH group of a ribosyl ring or replaces the 2'-H in a 2'-deoxyribosyl ring. A "2'-MOE sugar moiety" is a sugar moiety having a 2'-OCH2CHOCH3 group in place of the 2'-OH group of a furanosyl sugar moiety. Unless otherwise indicated, the 2'-MOE sugar moiety is in the β-D ribosyl configuration.

[0054] As used herein, a "2'-OMe sugar moiety" is a sugar moiety having a 2'-CH group in place of the 2'-OH group of a furanosyl sugar moiety. Unless otherwise indicated, the 2'-OMe sugar moiety is in the β-D ribosyl configuration and is a "stereostandard 2'OMe sugar moiety."

[0055] As used herein, a "2'-F sugar moiety" is a sugar moiety having a 2'-F group in place of the 2'-OH group of a furanosyl sugar moiety. Unless otherwise indicated, the 2'-F sugar moiety is in the β-D ribosyl configuration and is a "stereostandard 2'-F sugar moiety."

[0056] As used herein, "motif" means a pattern of unmodified and / or modified sugar moieties, nucleobases, and / or internucleoside linkages in an oligonucleotide.

[0057] As used herein, "naturally occurring" means found in nature.

[0058] As used herein, "nucleobase" refers to 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 an atomic group that can pair with at least one unmodified nucleobase. A universal base is a nucleobase that can pair with any one of these five unmodified nucleobases. 5-methylcytosine ( m C) is an example of a modified nucleobase.

[0059] As used herein, "nucleobase sequence" means the order of consecutive nucleobases in a nucleic acid or oligonucleotide, independent of any sugar moiety or internucleoside linkage modification.

[0060] As used herein, "nucleoside" refers to 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" refers to a nucleoside comprising a modified nucleobase and / or a modified sugar moiety. The modified nucleoside may comprise a conjugate group.

[0061] As used herein, "oligomeric compound" means a compound consisting of (1) an oligonucleotide (single-stranded oligomeric compound) or two oligonucleotides hybridized to one another (double-stranded oligomeric compound), and (2) optionally one or more additional features, such as a conjugate group or terminal group, that may be attached to one or both of the oligonucleotides in a single-stranded oligomeric compound or the double-stranded oligomeric compound.

[0062] As used herein, "oligonucleotide" refers to a chain of linked nucleosides joined via internucleoside linkages, where each nucleoside and internucleoside linkage may be modified or unmodified. Unless otherwise indicated, an oligonucleotide consists of 12 to 3,000 linked nucleosides and, optionally, a conjugate group or terminal group. As used herein, "modified oligonucleotide" refers to an oligonucleotide in which at least one nucleoside or internucleoside linkage is modified. As used herein, "unmodified oligonucleotide" refers to an oligonucleotide that does not contain any nucleoside or internucleoside modifications.

[0063] 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.

[0064] 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.

[0065] As used herein, "pharmaceutically acceptable carrier or diluent" means any substance suitable for use in administration to an animal. Certain such carriers allow the pharmaceutical composition to be formulated, for example, as a liquid, powder, or suspension that can be aerosolized or otherwise dispersed for inhalation by a subject. In certain embodiments, the pharmaceutically acceptable carrier or diluent is sterile water, sterile saline, or a sterile buffer solution.

[0066] 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.

[0067] As used herein, a "pharmaceutical composition" refers to a mixture of substances suitable for administration to a subject. For example, a pharmaceutical composition may include an antisense compound and an aqueous solution.

[0068] As used herein, "RNAi agent" refers to an antisense agent that acts, at least in part, through RISC or Ago2 to regulate a target nucleic acid and / or a protein encoded by the 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 include conjugate groups and / or terminal groups. In certain embodiments, RNAi agents regulate the amount, activity, and / or splicing of a target nucleic acid. The term RNAi agent excludes antisense agents that act through RNase H.

[0069] As used herein, "RNAi oligonucleotide" means an RNAi antisense modified oligonucleotide or an RNAi sense modified oligonucleotide.

[0070] As used herein, "RNAi antisense modified oligonucleotide" means an oligonucleotide that is complementary to a target sequence and includes a region containing at least one chemical modification suitable for RNAi.

[0071] As used herein, "RNAi antisense oligomeric compound" means a single-stranded oligomeric compound that is complementary to a target sequence and includes a region that contains at least one chemical modification suitable for RNAi.

[0072] As used herein, "RNAi sense modified oligonucleotide" means an oligonucleotide that contains a region complementary to a region of an RNAi antisense modified oligonucleotide and is capable of forming a duplex with such an RNAi antisense modified oligonucleotide.

[0073] As used herein, "RNAi sense oligomeric compound" refers to an RNAi antisense modified oligonucleotide and / or an RNAi antisense oligomeric compound. It refers to a single-stranded oligomeric compound that contains a region complementary to a region and is capable of forming a duplex with such an RNAi antisense modified oligonucleotide and / or RNAi antisense oligomeric compound.

[0074] The duplex formed by an RNAi sense modified oligonucleotide and / or RNAi sense oligomeric compound and an RNAi sense modified oligonucleotide and / or RNAi sense oligomeric compound is referred to as a double-stranded RNAi compound (dsRNAi) or short interfering RNA (siRNA).

[0075] As used herein, "RNase H agent" refers to an antisense agent that acts to regulate a target nucleic acid and / or a protein encoded by a target nucleic acid at least in part through RNase H. In certain embodiments, RNase H The RNase H agent is single-stranded. In certain embodiments, the RNase H agent is double-stranded. The RNase H compound may include a conjugate group and / or a terminal group. In certain embodiments, the RNase H agent modulates the amount or activity of a target nucleic acid. The term RNase H agent excludes antisense agents that act primarily through RISC / Ago2.

[0076] As used herein, "RNase H antisense modified oligonucleotide" means an oligonucleotide that is complementary to a target sequence and includes a region containing at least one chemical modification suitable for RNase H-mediated nucleic acid degradation.

[0077] As used herein, "RNAi compound" refers to an antisense compound that acts to regulate a target nucleic acid and / or a protein encoded by the target nucleic acid, at least in part, through RISC or Ago2. 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 regulates the amount, activity, and / or splicing of a target nucleic acid. The term RNAi compound excludes antisense oligonucleotides that act through RNase H.

[0078] As used herein, the term "single-stranded" in reference to antisense compounds refers to a compound that consists of one oligomeric compound, and does not pair with a second oligomeric compound to form a duplex.The term "self-complementary" in reference to oligonucleotides refers to an oligonucleotide that at least partially hybridizes with itself.A compound that consists of one oligomeric compound, and the oligonucleotide of the oligomeric compound is self-complementary, is a single-stranded compound.Single-stranded antisense or oligomeric compounds can be bound to complementary oligomeric compounds to form a duplex, and then the compound is no longer single-stranded.

[0079] As used herein, a "stabilizing phosphate group" refers to a 5' chemical moiety that stabilizes the 5' phosphate moiety of the 5'-terminal nucleoside of an oligonucleotide under biological conditions relative to the stability of the unmodified 5' phosphate of the unmodified nucleoside. Such stabilization of the 5' phosphate group includes, but is not limited to, resistance to removal by phosphatases. Stabilizing phosphate groups include, but are not limited to, 5'-vinyl phosphonate and 5'-cyclopropyl phosphonate.

[0080] As used herein, "stereostandard nucleoside" means a nucleoside containing a non-bicyclic furanosyl sugar moiety having the naturally occurring DNA and RNA configuration as shown below. "Stereostandard DNA nucleoside" means a β-D-2'-deoxyribonucleic acid nucleoside. A "stereostandard RNA nucleoside" is a nucleoside containing a β-D-ribosyl sugar moiety. A "substituted stereostandard nucleoside" is a stereostandard nucleoside other than a stereostandard DNA or stereostandard 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, OCH2CHOCH3, 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-methylcytosine, adenine, or guanine. In certain embodiments, the heterocyclic base moiety Bx is other than uracil, thymine, cytosine, 5-methylcytosine, adenine, or guanine.

[0081] [ka]

[0082] As used herein, "stereononstandard nucleosides" refer to nucleosides that include a non-bicyclic furanosyl sugar moiety having a configuration other than that of a stereostandard sugar moiety. In certain embodiments, "stereononstandard nucleosides" are represented by Formulas I-VII below. In certain embodiments, J1-J 14 are independently selected from H, OH, F, OCH3, OCH2CH2OCH3, O-C1-C6 alkoxy, and SCH3. A "stereo-nonstandard RNA nucleoside" has one of the following formulas I to VII, wherein J1, J3, J5, J7, J9, J 11 , and J 13 Each of J2, J4, J6, J8, J10 , J 12 , and J 14 Each of J is OH. A "stereotypical DNA nucleoside" has one of the following formulae I to VII, wherein each J is H. A "2'-substituted stereotypical nucleoside" has one of the following formulae I to VII, wherein J1, J3, J5, J7, J9, J 11 , and J 13 is other than H and / or or J2, J4, J6, J8, J 10 , J 12 , and J 14 is either other than H or OH. In certain embodiments, the heterocyclic base moiety Bx is selected from uracil, thymine, cytosine, 5-methylcytosine, adenine, or guanine. In certain embodiments, the heterocyclic base moiety Bx is other than uracil, thymine, cytosine, 5-methylcytosine, adenine, or guanine.

[0083] [ka]

[0084] [ka]

[0085] [ka]

[0086] As used herein, "stereostandard sugar moiety" means the sugar moiety of a stereostandard nucleoside.

[0087] As used herein, "stereotypical sugar moiety" means the sugar moiety of a stereotypical nucleoside.

[0088] As used herein, "substituted stereononstandard nucleosides" refers to stereononstandard nucleosides that contain substituents other than those corresponding to natural RNA or DNA. Substituted stereononstandard nucleosides include, but are not limited to, nucleosides of Formulas I-VII, except that the J groups are (1) both H, or (2) one H and the other OH.

[0089] As used herein, "subject" means a human or non-human animal selected for treatment or therapy.

[0090] As used herein, "sugar moiety" refers to an unmodified sugar moiety or a modified sugar moiety. As used herein, "unmodified sugar moiety" refers to 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" refers to a sugar surrogate or furanosyl sugar moiety other than β-D-ribosyl or β-D-2'-deoxyribosyl. Modified furanosyl sugar moieties may or may not be modified or substituted at certain position(s) on the sugar moiety, and they may or may not be stereo-nonstandard sugar moieties. Modified furanosyl sugar moieties include bicyclic and non-bicyclic sugars. As used herein, "sugar "Surrogate" means a modified sugar moiety that does not contain a furanosyl or tetrahydrofuranyl ring (not a "furanosyl sugar moiety") and that can link a nucleobase to another group, such as an internucleoside linkage, a conjugate group, or a terminal group, in an oligonucleotide. Modified nucleosides containing sugar surrogates can be incorporated at one or more positions within an oligonucleotide, and such oligonucleotides can hybridize to complementary oligomeric compounds or nucleic acids.

[0091] As used herein, "target nucleic acid," "target RNA," "target RNA transcript," and "nucleic acid target" refer to 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, and only one of these RNAs is the target RNA of the oligomeric compound. In certain embodiments, the target RNA is an RNA present in the species to which the oligomeric compound is administered.

[0092] As used herein, "therapeutic index" refers to the amount of a compound that causes a therapeutic effect compared to the amount that causes toxicity. A compound with a high therapeutic index has 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.

[0093] As used herein, "treating" refers to administering a compound or pharmaceutical composition to an animal to effect an alteration or amelioration of a disease, disorder, or condition in the animal.

[0094] As used herein, "translation repression element" refers to 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, the translation repression element comprises a uORF. In certain embodiments, the translation repression element does not comprise a uORF. In certain embodiments, the translation repression element comprises one or more stem-loops. In certain embodiments, the translation repression element comprises a GC content of greater than 60%, greater than 70%, or greater than 80%. In certain embodiments, the translation repression element is a uORF. In certain embodiments, the translation repression element is a stem-loop.

[0095] Certain embodiments The present disclosure provides the following non-limiting embodiments. Embodiment 1. An oligomeric compound comprising a modified oligonucleotide consisting of linked nucleosides linked via internucleoside linking groups, wherein at least one of said internucleoside linking groups has the formula VIII:

[0096] [ka]

[0097] wherein, independently for each internucleoside linking group of said modified oligonucleotide having Formula VIII: R1 is selected from H, C1-C6 alkyl, and substituted C1-C6 alkyl; T is selected from SO2R2, C(=O)R3, and P(=O)R4R5, wherein: R2 is selected from aryl, substituted aryl, heterocycle, substituted heterocycle, aromatic heterocycle, substituted aromatic heterocycle, diazole, substituted diazole, amine, substituted amine, C1-C6 alkoxy, C1-C6 alkyl, and substituted C1-C6 alkyl; R3 is selected from aryl, substituted aryl, CH3, N(CH3)2, and OCH3; R4 is selected from OCH3, OH, C1-C6 alkyl, and substituted C1-C6 alkyl; R5 is selected from OCH3, OH, C1-C6 alkyl, and substituted C1-C6 alkyl; The oligomeric compound.

[0098] Embodiment 2. An oligomeric compound comprising a modified oligonucleotide consisting of linked nucleosides linked via internucleoside linking groups, wherein at least one of said internucleoside linking groups has the formula VIII:

[0099] [ka]

[0100] wherein, independently for each internucleoside linking group of said modified oligonucleotide having Formula VIII: R1 is selected from H, C1-C6 alkyl, and substituted C1-C6 alkyl; T is selected from SO2R2, C(=O)R3, and P(=O)R4R5, wherein: R2 is selected from aryl, substituted aryl, heterocycle, substituted heterocycle, aromatic heterocycle, substituted aromatic heterocycle, diazole, substituted diazole, C1-C6 alkoxy, C1-C6 alkyl, and substituted C1-C6 alkyl; R3 is selected from aryl, substituted aryl, CH3, N(CH3)2, and OCH3; R4 is selected from OCH3, OH, C1-C6 alkyl, and substituted C1-C6 alkyl; R5 is selected from OCH3, OH, C1-C6 alkyl, and substituted C1-C6 alkyl; However, when R1 is H, T is

[0101] [ka]

[0102] provided that it is not The oligomeric compound.

[0103] Embodiment 3. The oligomeric compound of embodiment 1 or 2, wherein R1 is H.

[0104] Embodiment 4. The oligomeric compound of embodiment 1 or 2, wherein R1 is C1-C6 alkyl.

[0105] Embodiment 5. The oligomeric compound of embodiment 4, wherein R1 is methyl.

[0106] Embodiment 6. The oligomeric compound of embodiment 1 or 2, wherein R1 is substituted C1-C6 alkyl.

[0107] Embodiment 7. The oligomeric compound of any one of embodiments 1-6, wherein T is SO2R2.

[0108] Embodiment 8. The oligomeric compound of embodiment 7, wherein R2 is aryl.

[0109] Embodiment 9. The oligomeric compound of embodiment 7, wherein R2 is substituted aryl.

[0110] Embodiment 10. The oligomeric compound of embodiment 7, wherein R2 is a heterocycle.

[0111] Embodiment 11. The oligomeric compound of embodiment 7, wherein R2 is a substituted heterocycle.

[0112] Embodiment 12. The oligomeric compound of embodiment 7, wherein R2 is an aromatic heterocycle.

[0113] Embodiment 13. The oligomeric compound of embodiment 7, wherein R2 is a substituted aromatic heterocycle.

[0114] Embodiment 14. The oligomeric compound of embodiment 7, wherein R2 is diazole.

[0115] Embodiment 15. The oligomeric compound of embodiment 7, wherein R2 is a substituted diazole.

[0116] Embodiment 16. The oligomeric compound of embodiment 7, wherein R2 is an amine.

[0117] Embodiment 17. The oligomeric compound of embodiment 7, wherein R2 is a substituted amine.

[0118] Embodiment 18. The oligomeric compound of embodiment 7, wherein R2 is C1-C6 alkoxy.

[0119] Embodiment 19. The oligomeric compound of embodiment 7, wherein R2 is C1-C6 alkyl.

[0120] Embodiment 20. The oligomeric compound of embodiment 7, wherein R2 is substituted C1-C6 alkyl.

[0121] Embodiment 21. The oligomeric compound of embodiment 7, wherein T is:

[0122] [ka]

[0123] Embodiment 22. The oligomeric compound of embodiment 7, wherein T is:

[0124] [ka]

[0125] Embodiment 23. The oligomeric compound of embodiment 7, wherein T is:

[0126] [ka]

[0127] Embodiment 24. The oligomeric compound of embodiment 7, wherein T is:

[0128] [ka]

[0129] Embodiment 25. The oligomeric compound of embodiment 7, wherein T is:

[0130] [ka]

[0131] Embodiment 26. The oligomeric compound of embodiment 7, wherein T is:

[0132] [ka]

[0133] Embodiment 27. The oligomeric compound of embodiment 7, wherein T is:

[0134] [ka]

[0135] Embodiment 28. The oligomeric compound of embodiment 7, wherein T is:

[0136] [ka]

[0137] Embodiment 29. The oligomeric compound of embodiment 7, wherein T is:

[0138] [ka]

[0139] Embodiment 30. The oligomeric compound of any one of embodiments 1 to 6, wherein T is C(=O)R3.

[0140] Embodiment 31. The oligomeric compound of embodiment 30, wherein R3 is aryl.

[0141] Embodiment 32. The oligomeric compound of embodiment 30, wherein R3 is substituted aryl.

[0142] Embodiment 33. The oligomeric compound of embodiment 30, wherein R3 is CH3.

[0143] Embodiment 34. The oligomeric compound of embodiment 30, wherein R3 is N(CH3)2.

[0144] Embodiment 35. The oligomeric compound of embodiment 30, wherein R3 is OCH3.

[0145] Embodiment 36. The oligomeric compound of embodiment 30, wherein T is:

[0146] [ka]

[0147] Embodiment 37. The oligomeric compound of embodiment 30, wherein T is:

[0148] [ka]

[0149] Embodiment 38. The oligomeric compound of embodiment 30, wherein T is:

[0150] [ka]

[0151] Embodiment 39. The oligomeric compound of embodiment 30, wherein T is:

[0152] [ka]

[0153] Embodiment 40. The oligomeric compound according to any one of embodiments 1 to 6, wherein T is P(=O)R4R5.

[0154] Embodiment 41. The oligomeric compound of embodiment 40, wherein R4 is OCH3.

[0155] Embodiment 42. The oligomeric compound of embodiment 40, wherein R4 is OH.

[0156] Embodiment 43. The oligomeric compound according to embodiment 40, wherein R4 is C1-C6 alkyl.

[0157] Embodiment 44. The oligomeric compound of embodiment 40, wherein R4 is substituted C1-C6 alkyl.

[0158] Embodiment 45. The oligomeric compound of any of embodiments 40-42, wherein R5 is OCH3.

[0159] Embodiment 46. The oligomeric compound of any of embodiments 40-42, wherein R5 is OH.

[0160] Embodiment 47. The oligomeric compound of any of embodiments 40-42, wherein R5 is C1-C6 alkyl.

[0161] Embodiment 48. The oligomeric compound of any of embodiments 40-42, wherein R5 is substituted C1-C6 alkyl.

[0162] Embodiment 49. The oligomeric compound of embodiment 40, wherein T is:

[0163] [ka]

[0164] Embodiment 50. The oligomeric compound of embodiment 40, wherein T is:

[0165] [ka]

[0166] Embodiment 51. The oligomeric compound of any one of Embodiments 1 to 50, wherein at least one internucleoside linkage group of said modified oligonucleotide is not a linkage group of Formula VIII.

[0167] Embodiment 52. The oligomeric compound of any one of embodiments 1 to 50, wherein exactly one internucleoside linking group of said modified oligonucleotide is an internucleoside linking group of any one of embodiments 1 to 50.

[0168] Embodiment 53. The oligomeric compound of any one of Embodiments 1 to 50, wherein exactly two internucleoside linking groups of said modified oligonucleotide are internucleoside linking groups of any one of Embodiments 1 to 50.

[0169] Embodiment 54. The oligomeric compound of any one of Embodiments 1 to 50, wherein exactly three internucleoside linkage groups of said modified oligonucleotide are internucleoside linkage groups as defined in any one of Embodiments 1 to 50.

[0170] Embodiment 55. The oligomeric compound of any one of Embodiments 1 to 50, wherein exactly four internucleoside linkage groups of said modified oligonucleotide are internucleoside linkage groups described in any one of Embodiments 1 to 50.

[0171] Embodiment 56. The oligomeric compound of any one of embodiments 1 to 50, wherein exactly five internucleoside linkage groups of said modified oligonucleotide are internucleoside linkage groups described in any one of embodiments 1 to 50.

[0172] Embodiment 57. The oligomeric compound of any one of embodiments 1 to 50, wherein at least six internucleoside linkage groups of said modified oligonucleotide are an internucleoside linkage group of any one of embodiments 1 to 50.

[0173] Embodiment 58. The oligomeric compound of any of embodiments 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 each other.

[0174] Embodiment 59. The oligomeric compound of any one of embodiments 1 to 58, wherein each internucleoside linkage group of the modified oligonucleotide that is not an internucleoside linkage group of any one of embodiments 1 to 50 is either a phosphodiester internucleoside linkage group or a phosphorothioate internucleoside linkage group.

[0175] Embodiment 60. The oligomeric compound of any one of Embodiments 1-58, wherein each internucleoside linking group of said modified oligonucleotide is an internucleoside linking group described in any one of Embodiments 1-50.

[0176] Embodiment 61. The oligomeric compound of any one of embodiments 1 to 60, wherein at least one nucleoside of the modified oligonucleotide is a modified nucleoside.

[0177] Embodiment 62. The oligomeric compound of embodiment 61, wherein at least one nucleoside of said modified oligonucleotide is a modified nucleoside selected from a bicyclic nucleoside and a non-bicyclic substituted nucleoside.

[0178] Embodiment 63. The oligomeric compound of any one of embodiments 1 to 62, wherein at least one nucleoside of the modified oligonucleotide is selected from β-D-LNA nucleosides, α-L-LNA nucleosides, ENA nucleosides, cEt nucleosides, 2'-MOE nucleosides, 2'-OMe nucleosides, 2'-F nucleosides, 2'-NMA nucleosides, 5'-Me nucleosides, DNA nucleosides, and RNA nucleosides.

[0179] Embodiment 64. The oligomeric compound of any one of embodiments 1 to 62, wherein each nucleoside of the modified oligonucleotide is selected from β-D-LNA nucleosides, α-L-LNA nucleosides, ENA nucleosides, cEt nucleosides, 2'-MOE nucleosides, 2'-OMe nucleosides, 2'-F nucleosides, 2'-NMA nucleosides, 5'-Me nucleosides, DNA nucleosides, and RNA nucleosides.

[0180] Embodiment 65. The oligomeric compound of any of embodiments 1 to 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.

[0181] Embodiment 66. The oligomeric compound of any one of embodiments 1 to 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.

[0182] Embodiment 67. The oligomer of any one of embodiments 61 to 66, wherein the modified oligonucleotide has a region of alternating nucleoside types having the motif ABABA, where each A is a stereostandard nucleoside of a first type and each B is a stereostandard nucleoside of a second type, and the first type and the second type are different from each other. compound.

[0183] Embodiment 68. The oligomeric compound of embodiment 67, wherein A and B are selected from 2'-F substituted nucleosides, 2'-OMe substituted nucleosides, and stereostandard RNA nucleosides.

[0184] Embodiment 69. The oligomeric compound of any one of embodiments 1 to 68, wherein the 5' end of the modified oligonucleotide comprises a stabilizing phosphate group.

[0185] Embodiment 70. The oligomeric compound of any one of embodiments 1 to 69, wherein the modified oligonucleotide consists of 12 to 30 linked nucleosides.

[0186] Embodiment 71. The oligomeric compound of any one of embodiments 1 to 69, wherein the modified oligonucleotide consists of 16 to 24 linked nucleosides.

[0187] Embodiment 72. The oligomeric compound of any one of embodiments 1 to 69, wherein the modified oligonucleotide consists of 18 to 22 linked nucleosides.

[0188] Embodiment 73. The oligomeric compound of any one of embodiments 1 to 69, wherein the modified oligonucleotide consists of 16 linked nucleosides.

[0189] Embodiment 74. The oligomeric compound of any one of embodiments 1 to 69, wherein the modified oligonucleotide consists of 17 linked nucleosides.

[0190] Embodiment 75. The oligomeric compound of any one of embodiments 1 to 69, wherein the modified oligonucleotide consists of 18 linked nucleosides.

[0191] Embodiment 76. The oligomeric compound of any one of embodiments 1 to 69, wherein the modified oligonucleotide consists of 19 linked nucleosides.

[0192] Embodiment 77. The oligomeric compound of any one of embodiments 1 to 69, wherein the modified oligonucleotide consists of 20 linked nucleosides.

[0193] Embodiment 78. The oligomeric compound of any one of embodiments 1 to 69, wherein the modified oligonucleotide consists of 21 linked nucleosides.

[0194] Embodiment 79. The oligomeric compound of any one of embodiments 1 to 69, wherein the modified oligonucleotide consists of 22 linked nucleosides.

[0195] Embodiment 80. The oligomeric compound of any one of embodiments 1 to 69, wherein the modified oligonucleotide consists of 23 linked nucleosides.

[0196] Embodiment 81. The oligomeric compound of any one of embodiments 1 to 80, wherein the oligomeric compound is an RNAi compound.

[0197] Embodiment 82. The oligomeric compound of embodiment 81, wherein the RNAi compound is a single-stranded RNAi compound comprising an RNAi antisense modified oligonucleotide, and the RNAi antisense modified compound is a modified oligonucleotide described in any of embodiments 1 to 78.

[0198] 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, and the RNAi antisense modified oligonucleotide and / or the RNAi sense modified oligonucleotide is a modified oligonucleotide described in any of embodiments 1 to 78.

[0199] Embodiment 84. The oligomeric compound of embodiment 82 or 83, wherein at least one internucleoside linkage group of said RNAi antisense modified oligonucleotide is an internucleoside linkage group described in any of embodiments 1 to 50.

[0200] Embodiment 85. The oligomeric compound of embodiment 82 or 83, wherein at least two internucleoside linkage groups of said RNAi antisense modified oligonucleotide are independently selected internucleoside linkage groups described in any of embodiments 1 to 50.

[0201] Embodiment 86. The oligomeric compound of any of Embodiments 82-85, wherein at least one of the five 3'-most internucleoside linkage groups of said RNAi antisense modified oligonucleotide is an internucleoside linkage group described in any of Embodiments 1-50.

[0202] Embodiment 87. The oligomeric compound of any of embodiments 82-86, wherein at least two of the five 3'-most internucleoside linkage groups of the RNAi antisense modified oligonucleotide are internucleoside linkage groups described in any of embodiments 1-50.

[0203] Embodiment 88. The oligomeric compound of any of embodiments 82-87, wherein at least one internucleoside linkage group in the seed region of said RNAi antisense modified oligonucleotide is an internucleoside linkage group described in any of embodiments 1-50.

[0204] Embodiment 89. The oligomeric compound of any one of embodiments 83-88, wherein at least one internucleoside linkage group of said RNAi sense modified oligonucleotide is an internucleoside linkage group described in any one of embodiments 1-50.

[0205] Embodiment 90. The oligomeric compound of embodiment 89, wherein at least one of the first five internucleoside linkage groups from the 5' end of said RNAi sense modified oligonucleotide is an internucleoside linkage group described in any of embodiments 1 to 50.

[0206] Embodiment 91. The oligomeric compound of any of embodiments 89-90, wherein at least one of the five 3'-most internucleoside linkage groups of said RNAi sense modified oligonucleotide is an internucleoside linkage group of any of embodiments 1-50.

[0207] Embodiment 92. The oligomeric compound of any of Embodiments 89-91, wherein at least one of the first five internucleoside linkage groups from the 5' end of the RNAi sense modified oligonucleotide and at least one of the five 3'-most linkage groups of the RNAi sense modified oligonucleotide is an internucleoside linkage group described in any of Embodiments 1-50.

[0208] Embodiment 93. The oligomeric compound of any one of embodiments 1 to 92, wherein at least one nucleoside of the modified oligonucleotide is a stereo-nonstandard nucleoside.

[0209] Embodiment 94. The internucleoside linking group connecting at least one stereo-nonstandard nucleoside to an adjacent nucleoside is a nucleoside of any one of embodiments 1 to 50. The oligomeric compound of embodiment 93, wherein the intercidal linking group is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29,

[0210] Embodiment 95 The oligomeric compound of embodiment 93 or 94, wherein at least two nucleosides of said modified oligonucleotide are stereo-nonstandard nucleosides.

[0211] Embodiment 96 The oligomeric compound of embodiment 95, wherein at least two stereononstandard nucleosides of said modified oligonucleotide are adjacent to each other.

[0212] Embodiment 97. The oligomeric compound of embodiment 96, wherein at least two stereononstandard nucleosides of said modified oligonucleotide are linked to each other by an internucleoside linking group as described in any of embodiments 1 to 50.

[0213] Embodiment 98. The oligomeric compound of any of embodiments 95 to 97, wherein at least one stereotypical nucleoside of the modified oligonucleotide is a stereotypical DNA nucleoside.

[0214] Embodiment 99. The oligomeric compound of any of embodiments 95 to 97, wherein at least one stereotypical nucleoside of the modified oligonucleotide is a substituted stereotypical nucleoside or a stereotypical RNA nucleoside.

[0215] Embodiment 100. The oligomeric compound of embodiment 99, wherein the 2' substituent of said at least one substituted stereononstandard nucleoside of said modified oligonucleotide is selected from 2'-MOE, 2'-OMe, 2'-F, or 2'-OH.

[0216] Embodiment 101. The oligomeric compound of any of embodiments 1 to 100, wherein the modified oligonucleotide comprises a deoxy region consisting of 6 to 11 linked nucleosides, each nucleoside of the deoxy region being either a modified nucleoside or a stereostandard DNA nucleoside, at least three consecutive nucleosides of the deoxy region being stereostandard DNA nucleosides, and no more than three nucleosides of the deoxy region being modified nucleosides.

[0217] Embodiment 102. The oligomeric compound of embodiment 101, wherein at least four consecutive nucleosides of said deoxy region are stereostandard DNA nucleosides.

[0218] Embodiment 103. The oligomeric compound of embodiment 101, wherein at least 5 consecutive nucleosides of said deoxy region are stereostandard DNA nucleosides.

[0219] Embodiment 104. The oligomeric compound of embodiment 101, wherein at least 6 consecutive nucleosides of said deoxy region are stereostandard DNA nucleosides.

[0220] Embodiment 105. The oligomeric compound of embodiment 101, wherein at least 7 consecutive nucleosides of said deoxy region are stereostandard DNA nucleosides.

[0221] Embodiment 106 The oligomeric compound of embodiment 101, wherein at least 8 consecutive nucleosides of said deoxy region are stereostandard DNA nucleosides.

[0222] Embodiment 107. The oligomeric compound of any of embodiments 101 to 106, wherein the deoxy region consists of 8 to 10 linked nucleosides.

[0223] Embodiment 108. The method of embodiment 1, wherein the deoxy region consists of 9 linked nucleosides. The oligomeric compound according to any one of

[01] to

[106] .

[0224] Embodiment 109. The oligomeric compound of any of Embodiments 101-106, wherein the deoxy region consists of 10 linked nucleosides.

[0225] Embodiment 110. The oligomeric compound of any of embodiments 101-106, wherein the deoxy region consists of 11 linked nucleosides.

[0226] Embodiment 111. The oligomeric compound of any of embodiments 101 to 110, wherein at least six nucleosides of said deoxy region are stereostandard DNA nucleosides.

[0227] Embodiment 112. The oligomeric compound of any of embodiments 101 to 110, wherein at least 7 nucleosides of said deoxy region are stereostandard DNA nucleosides.

[0228] Embodiment 113. The oligomeric compound of any of embodiments 101 to 110, wherein at least 8 nucleosides of said deoxy region are stereostandard DNA nucleosides.

[0229] Embodiment 114. The oligomeric compound of any of embodiments 101 to 110, wherein at least 9 nucleosides of said deoxy region are stereostandard DNA nucleosides.

[0230] Embodiment 115. The oligomeric compound of any of Embodiments 101-114, wherein two nucleosides of said deoxy region are modified nucleosides.

[0231] Embodiment 116. The oligomeric compound of any of embodiments 101-114, wherein one nucleoside of the deoxy region is a modified nucleoside.

[0232] Embodiment 117. The oligomeric compound of any of embodiments 101 to 116, wherein at least one modified nucleoside in the deoxy region is a stereostandard modified nucleoside or bicyclic nucleoside selected from β-D-LNA nucleosides, α-L-LNA nucleosides, ENA nucleosides, cEt nucleosides, 2'-MOE nucleosides, 2'-OMe nucleosides, 2'-F nucleosides, and 5'-alkyl nucleosides.

[0233] Embodiment 118. The oligomeric compound of any of embodiments 101 to 117, wherein at least one modified nucleoside in the deoxy region is a stereononstandard nucleoside.

[0234] Embodiment 119. The oligomeric compound of embodiment 118, wherein said at least one stereononstandard isomeric nucleoside of said deoxy region is a stereononstandard DNA nucleoside.

[0235] Embodiment 120. The oligomeric compound of embodiment 119, wherein said stereo-nonstandard DNA nucleoside is selected from stereo-nonstandard DNA nucleosides having Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, and Formula VII.

[0236] Embodiment 121. The stereo-nonstandard DNA nucleoside has the structure of Formula V and Formula II. 121. The oligomeric compound according to embodiment 120, wherein said nucleoside is selected from non-canonical DNA nucleosides.

[0237] Embodiment 122. The oligomeric compound of any of Embodiments 118-121, wherein at least one stereononstandard nucleoside in the deoxy region is a substituted stereononstandard nucleoside.

[0238] Embodiment 123. The oligomeric compound of embodiment 122, wherein at least one substituted stereononstandard nucleoside has a 2' substituent selected from 2'-MOE, 2'-OMe, 2'-F, or 2'-OH.

[0239] Embodiment 124. The oligomeric compound of any of Embodiments 101-123, wherein the second nucleoside from the 5' end of the deoxy region is a modified nucleoside.

[0240] Embodiment 125. The oligomeric compound of any of Embodiments 101-124, wherein the third nucleoside from the 5' end of the deoxy region is a modified nucleoside.

[0241] Embodiment 126. The oligomeric compound of any of Embodiments 101-125, wherein the fourth nucleoside from the 5' end of the deoxy region is a modified nucleoside.

[0242] Embodiment 127. The oligomeric compound of any of embodiments 101 to 126, wherein each nucleoside of the deoxy region is a stereostandard DNA nucleoside.

[0243] Embodiment 128. The oligomeric compound of any of embodiments 101-127, wherein at least one internucleoside linking group in said deoxy region is an internucleoside linking group described in any of embodiments 1-50.

[0244] Embodiment 129. The oligomeric compound of any of Embodiments 101-128, wherein the internucleoside linking group connecting the first and second nucleosides of the deoxy region, counting from the 5' end of the deoxy region, is an internucleoside linking group as defined in any of Embodiments 1-50.

[0245] Embodiment 130. The oligomeric compound of any of Embodiments 101-129, wherein the internucleoside linking group connecting the second and third nucleosides of the deoxy region, counting from the 5' end of the deoxy region, is an internucleoside linking group described in any of Embodiments 1-50.

[0246] Embodiment 131. The oligomeric compound of any of Embodiments 101-130, wherein the internucleoside linking group connecting the third and fourth nucleosides of the deoxy region, counting from the 5' end of the deoxy region, is an internucleoside linking group of any of Embodiments 1-50.

[0247] Embodiment 132. The oligomeric compound of any of Embodiments 101-131, wherein the internucleoside linking group connecting the fourth and fifth nucleosides of the deoxy region, counting from the 5' end of the deoxy region, is an internucleoside linking group described in any of Embodiments 1-50.

[0248] Embodiment 133. One internucleoside linking group in the deoxy region is a linking group described in any one of embodiments 1 to 50, and the other internucleoside linking groups in the deoxy region are each phosphodiester or phosphorothioate internucleoside linking groups. 133. The oligomeric compound according to any one of embodiments 101 to 132.

[0249] Embodiment 134. The oligomeric compound of any of embodiments 101-133, wherein two internucleoside linking groups in the deoxy region are linking groups described in any of embodiments 1-50, and each remaining internucleoside linking group in the deoxy region is a phosphodiester or phosphorothioate internucleoside linking group.

[0250] Embodiment 135. The oligomeric compound of any of embodiments 101-134, wherein three internucleoside linking groups in the deoxy region are linking groups described in any of embodiments 1-50, and each remaining internucleoside linking group in the deoxy region is a phosphodiester or phosphorothioate internucleoside linking group.

[0251] Embodiment 136. The deoxy region is flanked on the 5' side by a 5' region consisting of 1 to 6 linked 5' region nucleosides and on the 3' side by a 3' region consisting of 1 to 6 linked 3' region nucleosides; the 3'-most nucleoside of the 5' region is a modified nucleoside; The oligomeric compound according to any of embodiments 101 to 135, wherein the 5'-most nucleoside of said 3' region is a modified nucleoside.

[0252] Embodiment 137. The oligomeric compound of embodiment 136, wherein at least one 5' region nucleoside is a stereostandard DNA nucleoside.

[0253] Embodiment 138 The oligomeric compound of embodiment 136, wherein each 5' region nucleoside is a modified nucleoside.

[0254] Embodiment 139. The oligomeric compound of any of embodiments 136, wherein at least one 5' region nucleoside is a 2' substituted nucleoside.

[0255] Embodiment 140. The oligomeric compound of any of embodiments 136 or 138-139, wherein each 5' region nucleoside is a 2' substituted nucleoside.

[0256] Embodiment 141. The oligomeric compound of any one of embodiments 139-140, wherein the 2' substituent is selected from among 2'-F, 2'-OCH3, and 2'-MOE.

[0257] Embodiment 142. The oligomeric compound of any of embodiments 136-139 or 141, wherein at least one 5' region nucleoside is a bicyclic nucleoside.

[0258] Embodiment 143 The oligomeric compound of embodiment 142, wherein each 5' region nucleoside is a bicyclic nucleoside.

[0259] Embodiment 144. The oligomeric compound according to any one of embodiments 142 to 143, wherein the bicyclic 5' region nucleoside is selected from among β-D-LNA nucleosides, α-L-LNA nucleosides, ENA nucleosides, and cEt nucleosides.

[0260] Embodiment 145. The oligomeric compound according to any of embodiments 136 to 144, wherein at least one 3' region nucleoside is a stereostandard DNA nucleoside.

[0261] Embodiment 146. The oligomeric compound of any of embodiments 136 to 144, wherein each 3' region nucleoside is a modified nucleoside.

[0262] Embodiment 147. The oligomeric compound of any of embodiments 136-146, wherein at least one 3' region nucleoside is a 2' substituted nucleoside.

[0263] Embodiment 148. The oligomeric compound of any of embodiments 136-144 or 146-147, wherein each 3' region nucleoside is a 2' substituted nucleoside.

[0264] 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.

[0265] Embodiment 150. The oligomeric compound of any of embodiments 136-147 or 149, wherein at least one 3' region nucleoside is a bicyclic nucleoside.

[0266] Embodiment 151 The oligomeric compound of embodiment 150, wherein each 3' region nucleoside is a bicyclic nucleoside.

[0267] Embodiment 152. The oligomeric compound of any of embodiments 150-151, wherein the bicyclic 3' region nucleoside is selected from among β-D-LNA nucleosides, α-L-LNA nucleosides, ENA nucleosides, and cEt nucleosides.

[0268] Embodiment 153. The oligomeric compound of any of embodiments 101 to 152, wherein the modified oligonucleotide is a gapmer.

[0269] 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.

[0270] Embodiment 155. The oligomeric compound of any of embodiments 1 to 153, wherein the nucleobase sequence of the modified oligonucleotide is complementary to a target nucleic acid.

[0271] 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.

[0272] 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.

[0273] 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.

[0274] 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.

[0275] Embodiment 160. The oligomeric compound of embodiment 155, wherein the nucleobase sequence of the modified oligonucleotide is 100% complementary to the target nucleic acid.

[0276] Embodiment 161. The oligomeric compound of any of embodiments 155 to 160, wherein the target nucleic acid is a target RNA.

[0277] Embodiment 162. The oligomeric compound according to embodiment 161, wherein the target RNA is selected from mRNA, pre-mRNA, microRNA, and non-coding RNA.

[0278] Embodiment 163. The oligomeric compound of embodiment 161, wherein the target RNA is not a microRNA.

[0279] Embodiment 164. The oligomeric compound of any of embodiments 1 to 162, wherein said modified oligonucleotide is not complementary to miR-21.

[0280] Embodiment 165. An oligomeric compound according to any one of embodiments 1 to 163, comprising a conjugate group.

[0281] Embodiment 166. The oligomeric compound of embodiment 164, wherein the conjugate group comprises at least one GalNAc.

[0282] Embodiment 167. The oligomeric compound of embodiment 164 or 165, wherein the conjugate group comprises 1 to 5 linker nucleosides.

[0283] Embodiment 168. The oligomeric compound of any one of embodiments 1 to 80, wherein the oligomeric compound is a CRISPR compound.

[0284] Embodiment 169. The oligomeric compound of embodiment 168, wherein the CRISPR compound consists of 20 to 50 linked nucleosides.

[0285] Embodiment 170. The oligomeric compound of embodiment 168, wherein the CRISPR compound consists of 29 to 32 linked nucleosides.

[0286] Embodiment 171. A pharmaceutical composition comprising a CRISPR compound according to embodiments 169-170 and a pharmaceutically acceptable carrier or diluent.

[0287] Embodiment 172. A method comprising contacting a cell with a CRISPR compound or composition described in any of embodiments 169-170.

[0288] Embodiment 173. The method of embodiment 172, comprising contacting the cell with a plasmid encoding Cas9 or Cpf1.

[0289] Embodiment 174. The method of embodiments 172-173, wherein the plasmid encodes tracrRNA.

[0290] Embodiment 175. The method of embodiment 174, comprising contacting the cell with mRNA encoding Cas9 or Cpf1.

[0291] Embodiment 176. The method of any one of embodiments 172 to 175, comprising contacting the cell with a plasmid encoding tracrRNA.

[0292] Embodiment 177. The method of any one of embodiments 172 to 176, wherein the target gene is edited.

[0293] Embodiment 178. The oligomeric compound of any one of embodiments 1 to 80, wherein the oligomeric compound is an artificial mRNA compound.

[0294] Embodiment 179. The artificial mRNA compound of embodiment 178, wherein the artificial mRNA oligonucleotide consists of 17 to 3000 linked nucleosides.

[0295] Embodiment 180. The artificial mRNA compound of embodiment 178 or 179, wherein the artificial mRNA oligonucleotide encodes a protein.

[0296] Embodiment 181. A pharmaceutical composition comprising an artificial mRNA compound according to any one of embodiments 178 to 180 and a pharmaceutically acceptable carrier or diluent.

[0297] Embodiment 182. A method comprising contacting a cell with an artificial mRNA compound or composition according to any one of embodiments 178 to 181.

[0298] Embodiment 183. A pharmaceutical composition comprising an oligomeric compound according to any one of embodiments 1 to 182 and a pharmaceutically acceptable carrier or diluent.

[0299] Embodiment 184. A method comprising contacting a cell with an oligomeric compound or pharmaceutical composition according to any one of embodiments 1 to 167 or 183.

[0300] Embodiment 185. A method for modulating the amount or activity of a target nucleic acid in a cell, comprising contacting the cell with an oligomeric compound or pharmaceutical composition of any of embodiments 1 to 167 or 183, thereby modulating the amount or activity of the target nucleic acid.

[0301] Embodiment 186. A method for modulating the amount or activity of a target nucleic acid in a cell, comprising contacting the cell with an oligomeric compound or pharmaceutical composition of any of embodiments 1 to 167 or 183.

[0302] Embodiment 187. The method of embodiment 186, wherein the amount or activity of the target nucleic acid is reduced.

[0303] Embodiment 188. Use of an oligomeric compound or composition according to any of embodiments 1 to 171, 178 to 181, or 183 for the treatment of a disease or condition.

[0304] Embodiment 189. Use of an oligomeric compound or composition according to any of embodiments 1 to 171, 178 to 181, or 183 for the preparation of a medicament for the treatment of a disease or condition.

[0305] Embodiment 190. An oligomeric compound comprising a modified oligonucleotide consisting of 12 to 23 linked nucleosides, wherein the modified oligonucleotide comprises a 5' region, a central region, and a 3' region; the 5' region consists of 1 to 5 linked nucleosides, wherein at least one 5' region nucleoside is modified; the 3' region consists of 1 to 5 linked nucleosides, wherein at least one 3' region nucleoside is modified; the central region consists of 7 to 11 linked nucleosides and has the formula: (N d1 ) L1 (N d2 ) L2 (N d3 ) L3 (N d4 ) L4 [(N d ) L5 ] q , In the formula, N d1 , N d2 , N d3 , N d4 But independently, a stereostandard DNA nucleoside, a stereononstandard DNA nucleoside, or a 2'-substituted nucleoside, with the proviso that N d1 , N d2 , N d3 , or N d4 is a 2'-substituted nucleoside; each N d are independently selected from stereostandard and stereononstandard DNA nucleosides; q is 3 to 8; each of L1, L2, L3, L4, and each L5 is an internucleoside linkage; at least two of L1, L2, L3, and L4 are internucleoside linkages having formula VIII;

[0306] [ka]

[0307] wherein, independently for each internucleoside linking group of said modified oligonucleotide having Formula VIII: R1 is selected from H, C1-C6 alkyl, and substituted C1-C6 alkyl; T is selected from SO2R2, C(=O)R3, and P(=O)R4R5, wherein: R2 is selected from aryl, substituted aryl, heterocycle, substituted heterocycle, aromatic heterocycle, substituted aromatic heterocycle, diazole, substituted diazole, amine, substituted amine, C1-C6 alkoxy, C1-C6 alkyl, and substituted C1-C6 alkyl; R3 is selected from aryl, substituted aryl, CH3, N(CH3)2, and OCH3; R4 is selected from OCH3, OH, C1-C6 alkyl, and substituted C1-C6 alkyl; R5 is selected from OCH3, OH, C1-C6 alkyl, and substituted C1-C6 alkyl; The oligomeric compound.

[0308] Embodiment 191.N d1 , N d2 , N d3 , or N d4 The oligomeric compound of embodiment 190, wherein one of: is a 2'-substituted nucleoside.

[0309] Embodiment 192. The oligomeric compound of embodiment 191, wherein the 2'-substituted nucleoside is a 2'-OMe nucleoside.

[0310] Embodiment 193. The oligomeric compound of embodiment 191, wherein said 2'-OMe nucleoside is a stereostandard 2'-OMe nucleoside.

[0311] Embodiment 194. The 2'-substituted nucleoside is N d2 194. The oligomeric compound of any of embodiments 191-193, wherein

[0312] Embodiment 195.N d1 , N d2 , N d3 , N d4 Each of the above, and each N d The oligomeric compound according to embodiment 190, wherein is a DNA nucleoside.

[0313] Embodiment 196. The oligomeric compound of embodiment 195, wherein each DNA nucleoside is a stereostandard DNA nucleoside.

[0314] Embodiment 197. The oligomeric compound according to any of embodiments 190 to 196, wherein L1 and L2 are internucleoside linkages having formula VIII.

[0315] Embodiment 198. The oligomeric compound according to any of embodiments 190 to 196, wherein L2 and L3 are internucleoside linkages having formula VIII.

[0316] Embodiment 199. The oligomeric compound according to any of embodiments 190 to 196, wherein L3 and L4 are internucleoside linkages having formula VIII.

[0317] Embodiment 200. The oligomeric compound according to any of embodiments 190-196, wherein L1, L2, and L3 are internucleoside linkages having formula VIII.

[0318] Embodiment 201. The oligomeric compound according to any of embodiments 190-196, wherein L2, L3, and L4 are internucleoside linkages having formula VIII.

[0319] Embodiment 202. The oligomeric compound according to any of embodiments 190-196, wherein L1, L2, L3, and L4 are internucleoside linkages having formula VIII.

[0320] Embodiment 203. The oligomeric compound according to any one of embodiments 190 to 202, wherein R1 is H.

[0321] Embodiment 204. The oligomeric compound according to any one of embodiments 190 to 202, wherein R1 is C1-C6 alkyl.

[0322] Embodiment 205. The oligomeric compound according to embodiment 204, wherein R1 is methyl.

[0323] Embodiment 206. The oligomeric compound according to any one of embodiments 190 to 202, wherein R1 is substituted C1-C6 alkyl.

[0324] Embodiment 207. The oligomeric compound according to any one of embodiments 190 to 206, wherein T is SO2R2.

[0325] Embodiment 208. The oligomeric compound according to embodiment 207, wherein R2 is aryl.

[0326] Embodiment 209. The oligomeric compound of embodiment 207, wherein R2 is substituted aryl.

[0327] Embodiment 210. The oligomeric compound according to embodiment 207, wherein R2 is a heterocycle.

[0328] Embodiment 211. The oligomeric compound according to embodiment 207, wherein R2 is a substituted heterocycle.

[0329] Embodiment 212. The oligomeric compound according to embodiment 207, wherein R2 is an aromatic heterocycle.

[0330] Embodiment 213. The oligomeric compound according to embodiment 207, wherein R2 is a substituted aromatic heterocycle.

[0331] Embodiment 214. The oligomeric compound according to embodiment 207, wherein R2 is a diazole.

[0332] Embodiment 215. The oligomer according to embodiment 207, wherein R2 is a substituted diazole. compound.

[0333] Embodiment 216. The oligomeric compound according to embodiment 207, wherein R2 is an amine.

[0334] Embodiment 217. The oligomeric compound according to embodiment 207, wherein R2 is a substituted amine.

[0335] Embodiment 218. The oligomeric compound according to embodiment 207, wherein R2 is C1-C6 alkoxy.

[0336] Embodiment 219. The oligomeric compound according to embodiment 207, wherein R2 is C1-C6 alkyl.

[0337] Embodiment 220. The oligomeric compound according to embodiment 207, wherein R2 is substituted C1-C6 alkyl.

[0338] Embodiment 221. The oligomeric compound of embodiment 207, wherein T is:

[0339] [ka]

[0340] Embodiment 222. The oligomeric compound of embodiment 207, wherein T is:

[0341] [ka]

[0342] Embodiment 223. The oligomeric compound of embodiment 207, wherein T is:

[0343] [ka]

[0344] Embodiment 224. The oligomeric compound of embodiment 207, wherein T is:

[0345] [ka]

[0346] Embodiment 225. The oligomeric compound of embodiment 207, wherein T is:

[0347] [ka]

[0348] Embodiment 226. The oligomeric compound of embodiment 207, wherein T is:

[0349] [ka]

[0350] Embodiment 227. The oligomeric compound of embodiment 207, wherein T is:

[0351] [ka]

[0352] Embodiment 228. The oligomeric compound of embodiment 207, wherein T is:

[0353] [ka]

[0354] Embodiment 229. The oligomeric compound of embodiment 207, wherein T is:

[0355] [ka]

[0356] Embodiment 230. The oligomeric compound according to any one of embodiments 190 to 206, wherein T is C(=O)R3.

[0357] Embodiment 231. An oligomeric compound according to embodiment 230, wherein R3 is aryl.

[0358] Embodiment 232. An oligomeric compound according to embodiment 230, wherein R3 is substituted aryl.

[0359] Embodiment 233. An oligomeric compound according to embodiment 230, wherein R3 is CH3.

[0360] Embodiment 234. An oligomeric compound according to embodiment 230, wherein R3 is N(CH3)2.

[0361] Embodiment 235. An oligomeric compound according to embodiment 230, wherein R3 is OCH3.

[0362] Embodiment 236. The oligomeric compound of embodiment 230, wherein T is:

[0363] [ka]

[0364] Embodiment 237. The oligomeric compound of embodiment 230, wherein T is:

[0365] [ka]

[0366] Embodiment 238. The oligomeric compound of embodiment 230, wherein T is:

[0367] [ka]

[0368] Embodiment 239. The oligomeric compound of embodiment 230, wherein T is:

[0369] [ka]

[0370] Embodiment 240. The oligomeric compound according to any one of embodiments 190 to 206, wherein T is P(=O)R4R5.

[0371] Embodiment 241. The oligomeric compound of embodiment 240, wherein R4 is OCH3.

[0372] Embodiment 242. An oligomeric compound according to embodiment 240, wherein R4 is OH.

[0373] Embodiment 243. The oligomeric compound according to embodiment 240, wherein R4 is C1-C6 alkyl.

[0374] Embodiment 244. The oligomeric compound according to embodiment 240, wherein R4 is substituted C1-C6 alkyl.

[0375] Embodiment 245. The oligomeric compound according to any one of embodiments 240-242, wherein R5 is OCH3.

[0376] Embodiment 246. The oligomeric compound according to any one of embodiments 240 to 242, wherein R5 is OH.

[0377] Embodiment 247. The oligomeric compound according to any one of embodiments 240 to 242, wherein R5 is C1 to C6 alkyl.

[0378] Embodiment 248. The oligomeric compound according to any one of embodiments 240 to 242, wherein R5 is substituted C1-C6 alkyl.

[0379] Embodiment 249. The oligomeric compound of embodiment 240, wherein T is:

[0380] [ka]

[0381] Embodiment 250. The oligomeric compound of embodiment 240, wherein T is:

[0382] [ka]

[0383] Embodiment 251. The oligomeric compound of any of embodiments 190-250, wherein at least one internucleoside linkage group of said modified oligonucleotide is not a linkage group of Formula VIII.

[0384] Embodiment 252. The oligomeric compound of any of embodiments 190-250, wherein exactly two internucleoside linking groups of said modified oligonucleotide are any of the internucleoside linking groups of Formula VIII.

[0385] Embodiment 253. The oligomeric compound of any of embodiments 190-250, wherein exactly three internucleoside linking groups of said modified oligonucleotide are any of the internucleoside linking groups of Formula VIII.

[0386] Embodiment 254. The oligomeric compound of any of embodiments 190-250, wherein exactly four internucleoside linking groups of said modified oligonucleotide are any of the internucleoside linking groups of Formula VIII.

[0387] Embodiment 255. The oligomeric compound of any of embodiments 190-250, having at least two linking groups of Formula VIII, wherein at least two of said linking groups of Formula VIII are the same as each other.

[0388] Embodiment 256. The oligomeric compound of any of embodiments 190-255, wherein each internucleoside linkage group of the modified oligonucleotide that is not an internucleoside linkage group of Formula VIII is either a phosphodiester internucleoside linkage group or a phosphorothioate internucleoside linkage group.

[0389] Embodiment 257. The oligomeric compound of any of embodiments 190 to 256, wherein the 5' region consists of 2 to 5 linked nucleosides.

[0390] Embodiment 258. The oligomeric compound of embodiment 257, wherein the 5' region consists of 3 linked nucleosides.

[0391] Embodiment 259. The oligomeric compound of embodiment 257, wherein the 5' region consists of 5 linked nucleosides.

[0392] Embodiment 260. The oligomeric compound of any of embodiments 190-259, wherein each nucleoside of the 5' region is a modified nucleoside.

[0393] Embodiment 261. The oligomeric compound of any of embodiments 190-259, wherein each nucleoside in the 5' region is a modified nucleoside comprising a modified sugar.

[0394] 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.

[0395] Embodiment 263. The oligomeric compound of any of embodiments 190-261, wherein at least one nucleoside of said 5' region comprises a bicyclic furanosyl sugar moiety.

[0396] Embodiment 264. The oligomeric compound of any of embodiments 190-261, wherein each nucleoside of the 5' region comprises a bicyclic furanosyl sugar moiety.

[0397] 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.

[0398] Embodiment 266. The oligomeric compound of embodiment 263, wherein each bicyclic sugar moiety in the 5' region is a cEt sugar moiety.

[0399] Embodiment 267. The oligomeric compound of embodiment 262, wherein each 2'-substituted furanosyl sugar moiety in the 5' region is a ribosyl sugar moiety and has a 2'-substituent selected from among 2'-MOE, 2'-OMe, and 2'-NMA.

[0400] Embodiment 268. Each nucleobase of the 5' region is independently selected from among thymine, uracil, guanine, cytosine, 5-methylcytosine, and adenine. 268. The oligomeric compound according to any one of claims 1 to 267.

[0401] Embodiment 269. The oligomeric compound of any of embodiments 190 to 268, wherein the 3' region consists of 2 to 5 linked nucleosides.

[0402] Embodiment 270. The oligomeric compound of embodiment 269, wherein the 3' region consists of 3 linked nucleosides.

[0403] Embodiment 271. The oligomeric compound of embodiment 269, wherein the 3' region consists of 5 linked nucleosides.

[0404] Embodiment 272. The oligomeric compound of any of embodiments 190-271, wherein each nucleoside of the 3' region is a modified nucleoside.

[0405] Embodiment 273. The oligomeric compound of any of Embodiments 190-272, wherein each nucleoside in the 3' region is a modified nucleoside comprising a modified sugar.

[0406] 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.

[0407] Embodiment 275. The oligomeric compound of any of embodiments 190 to 273, wherein at least one nucleoside of the 3' region comprises a bicyclic furanosyl sugar moiety.

[0408] Embodiment 276. The oligomeric compound of any of embodiments 190 to 273, wherein each nucleoside of the 3' region comprises a bicyclic furanosyl sugar moiety.

[0409] 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.

[0410] Embodiment 278. The oligomeric compound of embodiment 276, wherein each bicyclic sugar moiety of the 3' region is a cEt sugar moiety.

[0411] Embodiment 279. The oligomeric compound of embodiment 274, wherein each 2'-substituted furanosyl sugar moiety in the 5' region is a ribosyl sugar moiety and has a 2'-substituent selected from among 2'-MOE, 2'-OMe, and 2'-NMA.

[0412] Embodiment 280. The oligomeric compound of any of embodiments 190 to 279, wherein each nucleobase of the 5' region is independently selected from among thymine, uracil, guanine, cytosine, 5-methylcytosine, and adenine.

[0413] 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.

[0414] 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.

[0415] 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.

[0416] 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.

[0417] 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.

[0418] 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.

[0419] Embodiment 287. The oligomeric compound of any of embodiments 282 to 286, wherein each bicyclic sugar moiety is selected from among cEt, LNA, and ENA.

[0420] Embodiment 288. The oligomeric compound of embodiment 287, wherein the bicyclic sugar moiety is cEt.

[0421] Embodiment 289. The oligomeric compound of any of embodiments 282 to 289, wherein the 2'-substituted furanosyl sugar moiety is selected from 2'-OMe, 2'-MOE, and 2'-F.

[0422] Embodiment 290. The oligomeric compound of any of embodiments 281-289, wherein at least one of the first 10 internucleoside linkage groups from the 5' end of said modified oligonucleotide is an internucleoside linkage group described in any of embodiments 1-50.

[0423] Embodiment 291. The oligomeric compound of embodiment 289, wherein at least two of the first 10 internucleoside linkage groups from the 5' end of said modified oligonucleotide are an internucleoside linkage group described in any of embodiments 1 to 50.

[0424] Embodiment 292. The oligomeric compound of embodiment 289, wherein at least three of the first ten internucleoside linkage groups from the 5' end of said modified oligonucleotide are internucleoside linkage groups described in any of embodiments 1 to 50.

[0425] Embodiment 293. The oligomeric compound of embodiment 289, wherein at least four of the first ten internucleoside linkage groups from the 5' end of said modified oligonucleotide are internucleoside linkage groups described in any of embodiments 1 to 50.

[0426] Embodiment 294. The oligomeric compound of embodiment 289, wherein at least 5 of the first 10 internucleoside linkage groups from the 5' end of said modified oligonucleotide are an internucleoside linkage group described in any of embodiments 1 to 50.

[0427] Embodiment 295. The oligomeric compound of embodiment 289, wherein at least 6 of the first 10 internucleoside linkage groups from the 5' end of said modified oligonucleotide are an internucleoside linkage group described in any of embodiments 1 to 50.

[0428] Embodiment 296. The oligomeric compound of embodiment 289, wherein the first two internucleoside linking groups from the 5' end of said modified oligonucleotide are an internucleoside linking group described in any of embodiments 1-50.

[0429] Embodiment 297. The oligomeric compound of embodiment 289, wherein the first three internucleoside linkage groups from the 5' end of said modified oligonucleotide are an internucleoside linkage group described in any of embodiments 1-50.

[0430] Embodiment 298. The oligomeric compound of embodiment 289, wherein the first four internucleoside linkage groups from the 5' end of said modified oligonucleotide are an internucleoside linkage group described in any of embodiments 1-50.

[0431] Embodiment 299. The oligomeric compound of embodiment 289, wherein the first five internucleoside linkage groups from the 5' end of said modified oligonucleotide are an internucleoside linkage group described in any of embodiments 1-50.

[0432] Embodiment 300. The oligomeric compound of embodiment 289, wherein the first six internucleoside linkage groups from the 5' end of the modified oligonucleotide are an internucleoside linkage group described in any of embodiments 1-50.

[0433] Embodiment 301. A method for increasing translation of a target protein in a cell, comprising contacting said cell with an oligomeric compound according to any of embodiments 281 to 300.

[0434] Embodiment 302. The method of embodiment 301, wherein the target protein is encoded by a target nucleic acid comprising at least one translational repression element, and wherein the modified oligonucleotide is complementary to a target site within the translational repression element region of the target nucleic acid.

[0435] Embodiment 303. The method of embodiment 302, wherein the translational repression element region comprises at least one stem-loop structure.

[0436] Embodiment 304. A pharmaceutical composition comprising an oligomeric compound according to any of embodiments 190-300 and a pharmaceutically acceptable carrier or diluent.

[0437] Embodiment 305. A method comprising contacting a cell with an oligomeric compound or pharmaceutical composition according to any one of embodiments 190 to 300.

[0438] Embodiment 306. A method for modulating the amount or activity of a target nucleic acid in a cell, comprising contacting the cell with an oligomeric compound or pharmaceutical composition according to any of embodiments 190 to 300, thereby modulating the amount or activity of the target nucleic acid.

[0439] Embodiment 307. The method of embodiment 306, wherein the amount or activity of the target nucleic acid is reduced.

[0440] Embodiment 308. The method of embodiment 306, wherein the amount or activity of the target nucleic acid is increased.

[0441] Embodiment 309. Use of an oligomeric compound or composition according to any of embodiments 190 to 300 for the treatment of a disease or condition.

[0442] Embodiment 310. Use of an oligomeric compound or composition according to any of embodiments 190 to 300 for the preparation of a medicament for the treatment of a disease or pathological condition.

[0443] Embodiment 311. Consists of linked nucleosides linked via internucleoside linking groups 1. An antisense agent comprising a modified oligonucleotide, wherein at least one of the internucleoside linking groups has the formula XVII:

[0444] [ka]

[0445] wherein, independently for each internucleoside linking group of said modified oligonucleotide having Formula XVII: X is selected from O or S; R1 is selected from H, C1-C6 alkyl, and substituted C1-C6 alkyl; T is selected from SO2R2, C(=O)R3, and P(=O)R4R5, wherein: R2 is selected from aryl, substituted aryl, heterocycle, substituted heterocycle, aromatic heterocycle, substituted aromatic heterocycle, diazole, substituted diazole, 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; R3 is selected from aryl, substituted aryl, CH3, N(CH3)2, OCH3, and a conjugate group; R4 is selected from OCH3, OH, C1-C6 alkyl, substituted C1-C6 alkyl, and a conjugate group; R5 is selected from OCH3, OH, C1-C6 alkyl, and substituted C1-C6 alkyl; The antisense agent.

[0446] Embodiment 312. An antisense agent comprising a modified oligonucleotide consisting of linked nucleosides linked via internucleoside linking groups, wherein at least one of the internucleoside linking groups has the formula XVII:

[0447] [ka]

[0448] wherein, independently for each internucleoside linking group of said modified oligonucleotide having Formula XVII: X is selected from O or S; R1 is selected from H, C1-C6 alkyl, and substituted C1-C6 alkyl; T is selected from SO2R2, C(=O)R3, and P(=O)R4R5, wherein: R2 is 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, a C1 is selected from C-C alkenyl, C-C alkynyl, substituted C-C alkyl, substituted C-C alkenyl-substituted C-C alkynyl, and a conjugate group; R3 is selected from aryl, substituted aryl, CH3, N(CH3)2, OCH3, and a conjugate group; R4 is selected from OCH3, OH, C1-C6 alkyl, substituted C1-C6 alkyl, and a conjugate group; R5 is selected from OCH3, OH, C1-C6 alkyl, and substituted C1-C6 alkyl; However, when X is O and R1 is H, T is

[0449] [ka]

[0450] provided that it is not The antisense agent.

[0451] Embodiment 313. The modified oligonucleotide of embodiment 311 or 312, wherein for at least one internucleoside linking group of Formula XVII, X is O.

[0452] Embodiment 314. The modified oligonucleotide of embodiment 311 or 312, wherein for at least one internucleoside linking group of Formula XVII, X is S.

[0453] Embodiment 315. The modified oligonucleotide of embodiment 311 or 312, wherein for at least one internucleoside linking group of Formula XVII, R1 is H.

[0454] Embodiment 316. The modified oligonucleotide of embodiment 311 or 312, wherein for at least one internucleoside linking group of Formula XVII, R1 is C1-C6 alkyl, C1-C6 alkenyl, or C1-C6 alkynyl.

[0455] Embodiment 317. The modified oligonucleotide of embodiment 6, wherein R1 is methyl.

[0456] Embodiment 318. The modified oligonucleotide of embodiment 311 or 312, wherein for at least one internucleoside linking group of Formula XVII, R1 is substituted C1-C6 alkyl.

[0457] 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.

[0458] Embodiment 320. The modified oligonucleotide of embodiment 319, wherein the conjugate group comprises a carbohydrate or carbohydrate cluster.

[0459] Embodiment 321. The modified oligonucleotide of embodiment 319 or 320, wherein the conjugate group comprises at least one GalNAc.

[0460] Embodiment 322. The conjugate group is C 10 ~C 20 320. The modified oligonucleotide of embodiment 319, comprising an alkyl chain.

[0461] Embodiment 323. The conjugate group is C 16 The modified oligonucleotide of embodiment 322, comprising an alkyl.

[0462] Embodiment 324. The modified oligonucleotide of any of embodiments 311 to 318, wherein for at least one internucleoside linking group of Formula XVII, T does not comprise a conjugate group.

[0463] 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.

[0464] Embodiment 326. The modified oligonucleotide of embodiment 325, wherein R2 is aryl.

[0465] Embodiment 327. The modified oligonucleotide of embodiment 325, wherein R2 is substituted aryl.

[0466] Embodiment 328. The modified oligonucleotide of embodiment 325, wherein R2 is a heterocycle.

[0467] Embodiment 329. The modified oligonucleotide of embodiment 325, wherein R2 is a substituted heterocycle.

[0468] Embodiment 330. The modified oligonucleotide of embodiment 325, wherein R2 is an aromatic heterocycle.

[0469] Embodiment 331. The modified oligonucleotide of embodiment 325, wherein R2 is a substituted aromatic heterocycle.

[0470] Embodiment 332. The modified oligonucleotide of embodiment 325, wherein R2 is diazole.

[0471] Embodiment 333. The modified oligonucleotide of embodiment 325, wherein R2 is a substituted diazole.

[0472] Embodiment 334. The modified oligonucleotide of embodiment 325, wherein R2 is an amine.

[0473] Embodiment 335. The modified oligonucleotide of embodiment 325, wherein R2 is a substituted amine.

[0474] Embodiment 336. The modified oligonucleotide according to embodiment 325, wherein R2 is C1-C6 alkoxy, or C1-C6 alkenyl, C1-C6 alkynyl.

[0475] Embodiment 337.R2 is C1 to C 20 , C1~C6, C2~C 20 , C2 to C6, or C 10 ~C 20 The modified oligonucleotide of embodiment 325, which is alkyl.

[0476] In the embodiment 338.R2, substitutions C1 to C 20 , C1~C6, C2~C 20 , C2 to C6, or C 10 ~C 20 The modified oligonucleotide of embodiment 325, which is alkyl.

[0477] Embodiment 339. The modified oligonucleotide of embodiment 325, wherein R2 comprises a carbohydrate or carbohydrate cluster.

[0478] Embodiment 340. The modified oligonucleotide of embodiment 325, wherein R2 comprises at least one GalNAc.

[0479] Embodiment 341. The modified oligonucleotide of embodiment 325, wherein T is:

[0480] [ka]

[0481] Embodiment 342. The modified oligonucleotide of embodiment 325, wherein T is:

[0482] [ka]

[0483] Embodiment 343. The modified oligonucleotide of embodiment 325, wherein T is:

[0484] [ka]

[0485] Embodiment 344. The modified oligonucleotide of embodiment 325, wherein T is:

[0486] [ka]

[0487] Embodiment 345. The modified oligonucleotide of embodiment 325, wherein T is: .

[0488] [ka]

[0489] Embodiment 346. The modified oligonucleotide of embodiment 325, wherein T is:

[0490] [ka]

[0491] Embodiment 347. The modified oligonucleotide of embodiment 325, wherein T is:

[0492] [ka]

[0493] Embodiment 348. The modified oligonucleotide of embodiment 325, wherein T is:

[0494] [ka]

[0495] Embodiment 349. The modified oligonucleotide of embodiment 325, wherein T is:

[0496] [ka]

[0497] Embodiment 350.T is:

[0498] [ka]

[0499] 326. The modified oligonucleotide of embodiment 325, wherein n is 2 to 20.

[0500] Embodiment 351. The modified oligonucleotide of embodiment 350, wherein n is 15.

[0501] 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.

[0502] Embodiment 353. The modified oligonucleotide of embodiment 352, wherein R3 is aryl.

[0503] Embodiment 354. The modified oligonucleotide of embodiment 352, wherein R3 is substituted aryl.

[0504] Embodiment 355. The modified oligonucleotide of embodiment 352, wherein R3 is CH3.

[0505] Embodiment 356. The modified oligonucleotide of embodiment 352, wherein R3 is N(CH3)2.

[0506] Embodiment 357. The modified oligonucleotide of embodiment 352, wherein R3 is OCH3.

[0507] Embodiment 358. The modified oligonucleotide of embodiment 352, wherein R3 is C1-C6 alkoxy.

[0508] Embodiment 359.R3 is C1 to C 20 , C1~C6, C2~C 20 , C2 to C6, or C 10 ~C 20 The modified oligonucleotide of embodiment 352, which is alkyl.

[0509] In the embodiment 360.R3, substitutions C1 to C 20 , C1~C6, C2~C 20 , C2 to C6, or C 10 ~C 20 The modified oligonucleotide of embodiment 352, which is alkyl.

[0510] Embodiment 361. The modified oligonucleotide of embodiment 352, wherein R3 comprises a carbohydrate or carbohydrate cluster.

[0511] Embodiment 362.R 23 353. The modified oligonucleotide of embodiment 352, wherein said modified oligonucleotide comprises at least one GalNAc.

[0512] Embodiment 363. The modified oligonucleotide of embodiment 352, wherein T is:

[0513] [ka]

[0514] Embodiment 364. The modified oligonucleotide of embodiment 352, wherein T is:

[0515] [ka]

[0516] Embodiment 365. The modified oligonucleotide of embodiment 352, wherein T is:

[0517] [ka]

[0518] Embodiment 366. The modified oligonucleotide of embodiment 352, wherein T is:

[0519] [ka]

[0520] In embodiment 367.T,

[0521] [ka]

[0522] 353. The modified oligonucleotide of embodiment 352, wherein n is 2 to 20.

[0523] Embodiment 368. The modified oligonucleotide according to embodiment 367, wherein n is 15. .

[0524] 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.

[0525] Embodiment 370. The modified oligonucleotide of embodiment 369, wherein R4 is OCH3.

[0526] Embodiment 371. The modified oligonucleotide of embodiment 369, wherein R4 is OH.

[0527] Embodiment 372. The modified oligonucleotide of embodiment 369, wherein R4 is C1-C6 alkyl.

[0528] Embodiment 373. The modified oligonucleotide of embodiment 369, wherein R4 is a substituted C1-C6 alkyl.

[0529] Embodiment 374.R4 is C1 to C 20 , C1~C6, C2~C 20 , C2 to C6, or C 10 ~C 20 The modified oligonucleotide of embodiment 369, which is alkyl.

[0530] In the embodiment 375.R4 is substituted C1-C 20 , C1~C6, C2~C 20 , C2 to C6, or C 10 ~C 20 The modified oligonucleotide of embodiment 369, which is alkyl.

[0531] Embodiment 376. The modified oligonucleotide of embodiment 369, wherein R4 comprises a carbohydrate or carbohydrate cluster.

[0532] Embodiment 377. The modified oligonucleotide of embodiment 369, wherein R4 comprises at least one GalNAc.

[0533] Embodiment 378. The modified oligonucleotide of any of embodiments 369-67, wherein R5 is OCH3.

[0534] Embodiment 379. The modified oligonucleotide according to any of embodiments 369 to 67, wherein R5 is OH.

[0535] Embodiment 380. The modified oligonucleotide of any of embodiments 369-67, wherein R5 is C1-C6 alkyl.

[0536] Embodiment 381. The modified oligonucleotide of any of embodiments 369-67, wherein R5 is substituted C1-C6 alkyl.

[0537] Embodiment 382. The modified oligonucleotide of embodiment 369, wherein T is:

[0538] [ka]

[0539] Embodiment 383. The modified oligonucleotide of embodiment 369, wherein T is:

[0540] [ka]

[0541] In embodiment 384.T,

[0542] [ka]

[0543] 369. The modified oligonucleotide of embodiment 369, wherein n is 2 to 20.

[0544] Embodiment 385. The modified oligonucleotide of embodiment 384, wherein n is 15.

[0545] Embodiment 386. The modified oligonucleotide of any of Embodiments 311-385, wherein at least one internucleoside linkage group of the modified oligonucleotide is not a linkage group of Formula XVII.

[0546] Embodiment 387. The modified oligonucleotide of any of Embodiments 311-385, wherein exactly one internucleoside linking group of said modified oligonucleotide is an internucleoside linking group of Formula XVII.

[0547] Embodiment 388. The modified oligonucleotide of any of Embodiments 311-385, wherein exactly two internucleoside linking groups of said modified oligonucleotide are internucleoside linking groups of Formula XVII.

[0548] Embodiment 389. The modified oligonucleotide of any of Embodiments 311-385, wherein exactly three internucleoside linking groups of said modified oligonucleotide are internucleoside linking groups of Formula XVII.

[0549] Embodiment 390. The modified oligonucleotide of any of Embodiments 311-385, wherein exactly four internucleoside linking groups of said modified oligonucleotide are internucleoside linking groups of Formula XVII.

[0550] Embodiment 391. The modified oligonucleotide of any of Embodiments 311-385, wherein exactly five internucleoside linking groups of said modified oligonucleotide are internucleoside linking groups of Formula XVII.

[0551] 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.

[0552] Embodiment 393. The modified oligonucleotide of any of embodiments 311-386 or 388-392, having at least two linking groups of Formula XVII, wherein at least two of said linking groups of Formula XVII are the same as each other.

[0553] Embodiment 394. The modified oligonucleotide of any of embodiments 311-393, wherein each internucleoside linkage group of the modified oligonucleotide that is not an internucleoside linkage group of Formula XVII is either a phosphodiester internucleoside linkage group or a phosphorothioate internucleoside linkage group.

[0554] 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.

[0555] Embodiment 396. An antisense agent comprising a modified oligonucleotide, wherein at least one region of the modified oligonucleotide has the structure A:

[0556] [ka]

[0557] During the ceremony, each Bx is a heterocyclic base moiety; X is selected from O or S; each of Y1 and Y2 is independently selected from OH or SH; Z 1 , Z 2 , and Z 3 each independently represents -(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), R1 is selected from H, C1-C6 alkyl, and substituted C1-C6 alkyl; T is selected from SO2R2, C(=O)R3, and P(=O)R4R5, wherein: R2 is selected from aryl, substituted aryl, heterocycle, substituted heterocycle, aromatic heterocycle, substituted aromatic heterocycle, diazole, substituted diazole, 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; R3 is selected from aryl, substituted aryl, CH3, N(CH3)2, OCH3, and a conjugate group; R4 is selected from OCH3, OH, C1-C6 alkyl, substituted C1-C6 alkyl, and a conjugate group; R5 is selected from OCH3, OH, C1-C6 alkyl, and substituted C1-C6 alkyl; J R1 and G 1 But, J R1 From G 1 or J R1 is H and G 1 is H, OH, halogen, or O-[C(R6)(R7)] n -[(C=O) m -X G ] j -R8, J R2 and G 2 But, J R2 and G 2 Form a bridge with or J R2 is H and G 2 is H, OH, halogen, or O-[C(R6)(R7)] n -[(C=O) m -X G ] j -R8, J R3 and G 3 But, J R3 and G 3 Form a bridge with or J R3 is H and G 3is H, OH, halogen, or O-[C(R6)(R7)] n -[(C=O) m -X G ] j -R8, In the formula, each J R The bridge of G is -CH(CH3)-O- or -(CH2) k -O-, wherein k is 1 to 3; each R6 and R7 is independently H, halogen, C1-C6 alkyl, or substituted C1-C6 alkyl; each X G is O, S, or N(E1), 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); E1, E2, and E3 are each independently H, C1-C6 alkyl, or substituted C1-C6 alkyl; n is 1 to 6; m is 0 or 1, j is 0 or 1, each substituted group comprises one or more optionally protected substituents 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; each J1, J2, and J3 is independently H or C1-C6 alkyl; The antisense agent.

[0558] Embodiment 397. An antisense agent comprising a modified oligonucleotide, wherein at least one region of the modified oligonucleotide has the structure B:

[0559] [ka]

[0560] During the ceremony, each Bx is a heterocyclic base moiety; X is selected from O or S; each of Y1 and Y2 is independently selected from OH or SH; Z 1 and Z 2 each independently represents -(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), R1 is selected from H, C1-C6 alkyl, and substituted C1-C6 alkyl; T is selected from SO2R2, C(=O)R3, and P(=O)R4R5, wherein: R2 is selected from aryl, substituted aryl, heterocycle, substituted heterocycle, aromatic heterocycle, substituted aromatic heterocycle, diazole, substituted diazole, 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; R3 is selected from aryl, substituted aryl, CH3, N(CH3)2, OCH3, and a conjugate group; R4 is selected from OCH3, OH, C1-C6 alkyl, substituted C1-C6 alkyl, and a conjugate group; R5 is selected from OCH3, OH, C1-C6 alkyl, and substituted C1-C6 alkyl; J R1 and G 1 But, J R1 From G 1 or J R1 is H and G 1 is H, OH, halogen, or O-[C(R6)(R7)] n -[(C=O) m -X G ] j-R8, J R2 and G 2 But, J R2 and G 2 Form a bridge with or J R2 is H and G 2 is H, OH, halogen, or O-[C(R6)(R7)] n -[(C=O) m -X G ] j -R8, In the formula, each J R The bridge of G is -CH(CH3)-O- or -(CH2) k -O-, wherein k is 1 to 3; each R6 and R7 is independently H, halogen, C1-C6 alkyl, or substituted C1-C6 alkyl; each X G is O, S, or N(E1), 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); E1, E2, and E3 are each independently H, C1-C6 alkyl, or substituted C1-C6 alkyl; n is 1 to 6; m is 0 or 1, j is 0 or 1, each substituted group comprises one or more optionally protected substituents 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; each J1, J2, and J3 is independently H or C1-C6 alkyl; The antisense agent.

[0561] Embodiment 398. An antisense agent comprising a modified oligonucleotide, wherein at least one region of the modified oligonucleotide has the structure C:

[0562] [ka]

[0563] During the ceremony, each Bx is a heterocyclic base moiety; X is selected from O or S; each of Y1 and Y2 is independently selected from OH or SH; Z 2 and Z 3 each independently represents -(CH2) p -X Z -(CH2) q -Selected from wherein p is 0 or 1, q is 0 or 1, and X Z is O, S, or N(E1), R1 is selected from H, C1-C6 alkyl, and substituted C1-C6 alkyl; T is selected from SO2R2, C(=O)R3, and P(=O)R4R5, wherein: R2 is selected from aryl, substituted aryl, heterocycle, substituted heterocycle, aromatic heterocycle, substituted aromatic heterocycle, diazole, substituted diazole, 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; R3 is selected from aryl, substituted aryl, CH3, N(CH3)2, OCH3, and a conjugate group; R4 is selected from OCH3, OH, C1-C6 alkyl, substituted C1-C6 alkyl, and a conjugate group; R5 is selected from OCH3, OH, C1-C6 alkyl, and substituted C1-C6 alkyl; J R2 and G 2 But, J R2 and G2 Form a bridge with or J R2 is H and G 2 is H, OH, halogen, or O-[C(R6)(R7)] n -[(C=O) m -X G ] j -R8, J R3 and G 3 But, J R3 and G 3 Form a bridge with or J R3 is H and G 3 is H, OH, halogen, or O-[C(R6)(R7)] n -[(C=O) m -X G ] j -R8, In the formula, each J R The bridge of G is -CH(CH3)-O- or -(CH2) k -O-, wherein k is 1 to 3; each R6 and R7 is independently H, halogen, C1-C6 alkyl, or substituted C1-C6 alkyl; each X G is O, S, or N(E1), 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); E1, E2, and E3 are each independently H, C1-C6 alkyl, or substituted C1-C6 alkyl; n is 1 to 6; m is 0 or 1, j is 0 or 1, each substituted group comprises one or more optionally protected substituents 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; each J1, J2, and J3 is independently H or C1-C6 alkyl; The antisense agent.

[0564] Embodiment 399. An antisense agent comprising a modified oligonucleotide, wherein at least one region of the modified oligonucleotide has the structure D:

[0565] [ka]

[0566] During the ceremony, each Bx is a heterocyclic base moiety; X is selected from O or S; each of Y1 and Y2 is independently selected from OH or SH; Z 2 and Z 3 each independently represents -(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), R1 is selected from H, C1-C6 alkyl, and substituted C1-C6 alkyl; T is selected from SO2R2, C(=O)R3, and P(=O)R4R5, wherein: R2 is selected from aryl, substituted aryl, heterocycle, substituted heterocycle, aromatic heterocycle, substituted aromatic heterocycle, diazole, substituted diazole, 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; R3 is selected from aryl, substituted aryl, CH3, N(CH3)2, OCH3, and a conjugate group; R4 is selected from OCH3, OH, C1-C6 alkyl, substituted C1-C6 alkyl, and a conjugate group; R5 is selected from OCH3, OH, C1-C6 alkyl, and substituted C1-C6 alkyl; J R1 and G 1 But, J R1 From G 1 or J R1 is H and G 1 is H, OH, halogen, or O-[C(R6)(R7)] n -[(C=O) m -X G ] j -R8, J R2 and G 2 But, J R2 and G 2 Form a bridge with or J R2 is H, G 2 is H, OH, halogen, or O-[C(R6)(R7)] n -[(C=O) m -X G ] j -R8, J R3 and G 3 But, J R3 and G 3 Form a bridge with or J R3 is H and G 3 is H, OH, halogen, or O-[C(R6)(R7)] n -[(C=O) m -X G ] j -R8, In the formula, each J R The bridge of G is -CH(CH3)-O- or -(CH2) k -O-, wherein k is 1 to 3; each R6 and R7 is independently H, halogen, C1-C6 alkyl, or substituted C1-C6 alkyl; each X G is O, S, or N(E1), 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); E1, E2, and E3 are each independently H, C1-C6 alkyl, or substituted C1-C6 alkyl; n is 1 to 6; m is 0 or 1, j is 0 or 1, each substituted group comprises one or more optionally protected substituents 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; each J1, J2, and J3 is independently H or C1-C6 alkyl; The antisense agent.

[0567] Embodiment 400. An antisense agent comprising a modified oligonucleotide, wherein at least one region of the modified oligonucleotide has the structure E:

[0568] [ka]

[0569] During the ceremony, each Bx is a heterocyclic base moiety; X is selected from O or S; each of Y1 and Y2 is independently selected from OH or SH; Z 2 and Z 3 each independently represents -(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), R1 is selected from H, C1-C6 alkyl, and substituted C1-C6 alkyl; T is selected from SO2R2, C(=O)R3, and P(=O)R4R5, wherein: R2 is selected from aryl, substituted aryl, heterocycle, substituted heterocycle, aromatic heterocycle, substituted aromatic heterocycle, diazole, substituted diazole, 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; R3 is selected from aryl, substituted aryl, CH3, N(CH3)2, OCH3, and a conjugate group; R4 is selected from OCH3, OH, C1-C6 alkyl, substituted C1-C6 alkyl, and a conjugate group; R5 is selected from OCH3, OH, C1-C6 alkyl, and substituted C1-C6 alkyl; J R1 and G 1 But, J R1 From G 1 or J R1 is H and G 1 is H, OH, halogen, or O-[C(R6)(R7)] n -[(C=O) m -X G ] j -R8, J R2 and G 2 But, J R2 and G 2 Form a bridge with or J R2 is H and G 2 is H, OH, halogen, or O-[C(R6)(R7)] n -[(C=O) m -X G ] j -R8, J R3 and G 3 But, J R3 and G 3 Form a bridge with or J R3 is H and G 3 is H, OH, halogen, or O-[C(R6)(R7)] n -[(C=O) m -X G ] j -R8, In the formula, each J R The bridge of G is -CH(CH3)-O- or -(CH2) k -O-, wherein k is 1 to 3; each R6 and R7 is independently H, halogen, C1-C6 alkyl, or substituted C1-C6 alkyl; each X G is O, S, or N(E1), 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); E1, E2, and E3 are each independently H, C1-C6 alkyl, or substituted C1-C6 alkyl; n is 1 to 6; m is 0 or 1, j is 0 or 1, each substituted group comprises one or more optionally protected substituents 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; each J1, J2, and J3 is independently H or C1-C6 alkyl; The antisense agent.

[0570] Embodiment 401. The modified oligonucleotide of any of embodiments 396-400, wherein each Z is O.

[0571] Embodiment 402. The modified oligonucleotide of any of embodiments 396 to 401, wherein at least one G is selected from H, OH, halogen, C1-C6 alkoxy, —O(CH2)2OCH3, or —OCH2(C═O)NHCH3.

[0572] Embodiment 403. The modified oligonucleotide of any of embodiments 396 to 401, wherein each G is selected from H, OH, halogen, C1-C6 alkoxy, —O(CH2)2OCH3, or —OCH2(C═O)NHCH3.

[0573] Embodiment 404. At least one J R forms a bridge with at least one G, and the J R From the bridge of G, 4CH(CH3)-O- or -(CH2) k -O', wherein k is 1 to 3.

[0574] Embodiment 405. Each J R and G form a bridge, and the J R The bridge of G is -CH(CH3)-O- or -(CH2) k The modified oligonucleotide of any of embodiments 396-402, having a formula selected from: -O-, wherein k is 1 to 3.

[0575] Embodiment 406. At least one Z is O and the corresponding J R Therefore, the bridge of G is a compound of the formula (CH2) k 406. The modified oligonucleotide of any of embodiments 404 or 405, having -O-, wherein k is 1.

[0576] Embodiment 407. Each nucleoside of structure A, B, C, D, or E is a stereostandard nucleoside. The modified oligonucleotide of any of embodiments 396 to 406, which is a thiol.

[0577] Embodiment 408. The modified oligonucleotide of any of embodiments 396 to 406, wherein at least one nucleoside of structure A, B, C, D, or E is a stereo-nonstandard nucleoside.

[0578] Embodiment 409.J R The modified oligonucleotide of any of embodiments 404 to 406 or 408, wherein at least one nucleoside having a bridge from G to G is in the α-L-ribosyl configuration.

[0579] Embodiment 410. The modified oligonucleotide of any of embodiments 396 to 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 the structure A, B, C, D, or E.

[0580] Embodiment 411. The modified oligonucleotide of any of embodiments 396 to 410, wherein at least one region having structure A, B, C, D, or E is at the 5' end of the modified oligonucleotide.

[0581] Embodiment 412. The modified oligonucleotide of any of embodiments 396 to 410, wherein at least one region having structure A, B, C, D, or E is at the 3' end of the modified oligonucleotide.

[0582] Embodiment 413. The modified oligonucleotide of any of embodiments 396 to 410, wherein at least one region having structure A, B, C, D, or E is internal to the modified oligonucleotide.

[0583] Embodiment 414. An antisense agent comprising a modified oligonucleotide consisting of 10 to 30 linked nucleosides, wherein a region of the modified oligonucleotide has the formula (N g1 ) L1 (N g2 ) L2 (N g3 ) L3 and each N g is a nucleoside, each L is an internucleoside linking group, and each of L and L is a phosphodiester internucleoside linking group, a phosphorothioate internucleoside linking group, or an internucleoside linking group of formula XVII;

[0584] [ka]

[0585] 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 is an internucleoside linking group of Formula XVII, and at least one of L1, L2, and L3 is a phosphorothioate or phosphodiester internucleoside linking group; wherein, independently for each internucleoside linking group of said modified oligonucleotide having Formula XVII: X is selected from O or S; R1 is selected from H, C1-C6 alkyl, and substituted C1-C6 alkyl; T is selected from SO2R2, C(=O)R3, and P(=O)R4R5, wherein: R2 is selected from aryl, substituted aryl, heterocycle, substituted heterocycle, aromatic heterocycle, substituted aromatic heterocycle, diazole, substituted diazole, 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; R3 is selected from aryl, substituted aryl, CH3, N(CH3)2, OCH3, and a conjugate; R4 is selected from OCH3, OH, C1-C6 alkyl, substituted C1-C6 alkyl, and conjugates; R5 is selected from OCH3, OH, C1-C6 alkyl, and substituted C1-C6 alkyl; The antisense agent.

[0586] Embodiment 415. The modified oligonucleotide has the formula (N g1 ) L1 (N g2 ) L2 (N g3 ) L3 415. The modified oligonucleotide of embodiment 414, comprising 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 following structure:

[0587] Embodiment 416. The compound of the formula (N g1 ) L1 (N g2 ) L2 (N g3 ) L3 415. The modified oligonucleotide of embodiment 414, wherein at least one region having the following is at the 5' end of the oligonucleotide.

[0588] Embodiment 417. The compound of the formula (N g1 ) L1 (N g2 ) L2 (N g3 ) L3 415. The modified oligonucleotide of embodiment 414, wherein at least one region having

[0589] Embodiment 418. The compound of the formula (N g1 ) L1 (N g2 ) L2 (N g3 ) L3415. The modified oligonucleotide of embodiment 414, wherein at least one region having the following is at the 3' end of the oligonucleotide.

[0590] Embodiment 419. The modified oligonucleotide of any of embodiments 311 to 418, wherein at least one nucleoside of the modified oligonucleotide is a modified nucleoside.

[0591] 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.

[0592] Embodiment 421. The modified oligonucleotide of any of embodiments 311 to 420, wherein at least one nucleoside of the modified oligonucleotide is selected from β-D-LNA nucleosides, α-L-LNA nucleosides, ENA nucleosides, cEt nucleosides, 2'-MOE nucleosides, 2'-OMe nucleosides, 2'-F nucleosides, 2'-NMA nucleosides, 5'-Me nucleosides, DNA nucleosides, and RNA nucleosides.

[0593] Embodiment 422. Each nucleoside of the modified oligonucleotide is a β-D-LNA nucleoside. 422. The modified oligonucleotide of any of embodiments 311 to 421, wherein the modified oligonucleotide is selected from nucleosides, α-L-LNA nucleosides, ENA nucleosides, cEt nucleosides, 2'-MOE nucleosides, 2'-OMe nucleosides, 2'-F nucleosides, 2'-NMA nucleosides, 5'-Me nucleosides, DNA nucleosides, and RNA nucleosides.

[0594] Embodiment 423. The modified oligonucleotide of any of embodiments 311 to 422, wherein at least one nucleoside of the modified oligonucleotide is a stereo-nonstandard nucleoside.

[0595] Embodiment 424. The modified oligonucleotide of embodiment 423, wherein the internucleoside linking group connecting at least one stereononstandard nucleoside to an adjacent nucleoside is an internucleoside linking group of Formula XVII.

[0596] Embodiment 425. The modified oligonucleotide of embodiment 423 or 424, wherein at least two nucleosides of the modified oligonucleotide are stereo-nonstandard nucleosides.

[0597] Embodiment 426. The modified oligonucleotide of embodiment 425, wherein at least two stereononstandard nucleosides of the modified oligonucleotide are adjacent to each other.

[0598] Embodiment 427. The modified oligonucleotide of embodiment 426, wherein at least two stereononstandard nucleosides of said modified oligonucleotide are linked to each other by an internucleoside linking group of Formula XVII.

[0599] Embodiment 428. The modified oligonucleotide of any of embodiments 423 to 427, wherein at least one stereononstandard nucleoside of the modified oligonucleotide is a stereononstandard DNA nucleoside.

[0600] Embodiment 429. The modified oligonucleotide of embodiment 428, wherein the stereo-nonstandard DNA nucleoside is selected from stereo-nonstandard DNA nucleosides having Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, and Formula VII.

[0601] Embodiment 430. The modified oligonucleotide of embodiment 429, wherein the stereo-nonstandard DNA nucleoside is selected from stereo-nonstandard DNA nucleosides having Formula V and Formula II:

[0602] Embodiment 431. The modified oligonucleotide of any of embodiments 423 to 427, wherein at least one stereotypical nucleoside of the modified oligonucleotide is a substituted stereotypical nucleoside or a stereotypical RNA nucleoside.

[0603] Embodiment 432. The modified oligonucleotide of embodiment 431, wherein the 2' substituent of said at least one substituted stereononstandard nucleoside of said modified oligonucleotide is selected from 2'-MOE, 2'-OMe, 2'-F, or 2'-OH.

[0604] Embodiment 433. The modified oligonucleotide of any of embodiments 311 to 432, wherein the modified oligonucleotide consists of 12 to 30 linked nucleosides.

[0605] Embodiment 434. The modified oligonucleotide of any of embodiments 311 to 433, wherein the modified oligonucleotide consists of 16 to 24 linked nucleosides.

[0606] Embodiment 435. The modified oligonucleotide of any of embodiments 311 to 434, wherein the modified oligonucleotide consists of 18 to 22 linked nucleosides.

[0607] Embodiment 436. The modified oligonucleotide of any of embodiments 311 to 434, wherein the modified oligonucleotide consists of 16 linked nucleosides.

[0608] Embodiment 437. The modified oligonucleotide of any of embodiments 311 to 434, wherein the modified oligonucleotide consists of 17 linked nucleosides.

[0609] Embodiment 438. The modified oligonucleotide of any of embodiments 311 to 435, wherein the modified oligonucleotide consists of 18 linked nucleosides.

[0610] Embodiment 439. The modified oligonucleotide of any of embodiments 311 to 435, wherein the modified oligonucleotide consists of 19 linked nucleosides.

[0611] Embodiment 440. The modified oligonucleotide of any of embodiments 311 to 435, wherein the modified oligonucleotide consists of 20 linked nucleosides.

[0612] Embodiment 441. The modified oligonucleotide of any of embodiments 311 to 435, wherein the modified oligonucleotide consists of 21 linked nucleosides.

[0613] Embodiment 442. The modified oligonucleotide of any of embodiments 311 to 435, wherein the modified oligonucleotide consists of 22 linked nucleosides.

[0614] Embodiment 443. The modified oligonucleotide of any of embodiments 311 to 434, wherein the modified oligonucleotide consists of 23 linked nucleosides.

[0615] Embodiment 444. The modified oligonucleotide of any of embodiments 311 to 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.

[0616] Embodiment 445. The modified oligonucleotide of any of embodiments 311 to 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.

[0617] 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, where each A is a stereostandard nucleoside of a first type and each B is a stereostandard nucleoside of a second type, and the first type and the second type are different from each other.

[0618] Embodiment 447. The modified oligonucleotide of embodiment 446, wherein A and B are selected from 2'-F substituted nucleosides, 2'-OMe substituted nucleosides, and stereostandard RNA nucleosides.

[0619] Embodiment 448. The modified oligonucleotide of any of embodiments 311 to 447, wherein the 5' end of the modified oligonucleotide comprises a stabilizing phosphate group.

[0620] Embodiment 449. The modified oligonucleotide of embodiment 448, wherein the stabilizing phosphate group is 5'-vinylphosphonate or 5'-cyclopropylphosphonate.

[0621] Embodiment 450. An RNAi agent comprising a modified oligonucleotide according to any one of embodiments 311 to 449.

[0622] Embodiment 451. The RNAi agent of embodiment 450, wherein the RNAi agent is a single-stranded RNAi agent comprising an RNAi antisense modified oligonucleotide, and the RNAi antisense modified oligonucleotide is a modified oligonucleotide described in any of embodiments 311 to 449.

[0623] 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, and the RNAi antisense modified oligonucleotide and / or the RNAi sense modified oligonucleotide is a modified oligonucleotide described in any of embodiments 311 to 449.

[0624] Embodiment 453. The RNAi agent of embodiment 451 or 452, wherein at least one internucleoside linkage group of said RNAi antisense modified oligonucleotide is an internucleoside linkage group of Formula XVII:

[0625] Embodiment 454. The RNAi agent of embodiment 451 or 452, wherein at least two internucleoside linkage groups of said RNAi antisense modified oligonucleotide are independently selected internucleoside linkage groups described in any of embodiments 311 to 385.

[0626] Embodiment 455. The RNAi agent of any of embodiments 450-454, wherein at least one of the five 3'-most internucleoside linkage groups of said RNAi antisense modified oligonucleotide is an internucleoside linkage group of Formula XVII.

[0627] Embodiment 456. The RNAi agent of any of embodiments 450-454, wherein at least two of the five 3'-most internucleoside linkage groups of the RNAi antisense modified oligonucleotide are internucleoside linkage groups of Formula XVII.

[0628] Embodiment 457. The RNAi agent of any of embodiments 450-454, wherein at least one internucleoside linkage group in the seed region of the RNAi antisense modified oligonucleotide is an internucleoside linkage group of Formula XVII.

[0629] Embodiment 458. An RNAi agent described in any of embodiments 450 to 457, wherein at least one region of the RNAi antisense modified oligonucleotide has the structure A, B, C, D, or E.

[0630] 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.

[0631] Embodiment 460. The RNAi agent of embodiment 458, wherein at least one region having the structure A, B, C, D, or E is at the 3' end of the RNAi antisense modified oligonucleotide.

[0632] Embodiment 461. At least one of the RNAi antisense modified oligonucleotides The region of the formula (N g1 ) L1 (N g2 ) L2 (N g3 ) L3 wherein each N g is a nucleoside, each L is an internucleoside linking group, and each of L and L is a phosphodiester internucleoside linking group, a phosphorothioate internucleoside linking group, or an internucleoside linking group of formula XVII;

[0633] [ka]

[0634] 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 is an internucleoside linking group of Formula XVII, and at least one of L1, L2, and L3 is a phosphorothioate or phosphodiester internucleoside linking group; wherein, independently for each internucleoside linking group of said modified oligonucleotide having Formula XVII: X is selected from O or S; R1 is selected from H, C1-C6 alkyl, and substituted C1-C6 alkyl; T is selected from SO2R2, C(=O)R3, and P(=O)R4R5, wherein: R2 is selected from aryl, substituted aryl, heterocycle, substituted heterocycle, aromatic heterocycle, substituted aromatic heterocycle, diazole, substituted diazole, 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; R3 is selected from aryl, substituted aryl, CH3, N(CH3)2, OCH3, and a conjugate; R4 is selected from OCH3, OH, C1-C6 alkyl, substituted C1-C6 alkyl, and conjugates; R5 is selected from OCH3, OH, C1-C6 alkyl, and substituted C1-C6 alkyl; An RNAi agent according to any one of embodiments 450 to 457.

[0635] Embodiment 462. The formula (N g1 ) L1 (N g2 ) L2 (N g3 ) L3 462. The RNAi agent of embodiment 461, wherein at least one region having the following is at the 3' end of the RNAi antisense modified oligonucleotide.

[0636] Embodiment 463. The compound of the formula (N g1 ) L1 (N g2 ) L2 (N g3 ) L3 462. The RNAi agent of embodiment 461, wherein at least one region having the following structure is within the seed region of the RNAi antisense modified oligonucleotide:

[0637] Embodiment 464. The RNAi agent of any one of embodiments 450 or 452 to 463, wherein at least one internucleoside linkage group of said RNAi sense modified oligonucleotide is an internucleoside linkage group of Formula XVII:

[0638] Embodiment 465. The RNAi agent of embodiment 464, wherein at least one of the first five internucleoside linkage groups from the 5' end of said RNAi sense modified oligonucleotide is an internucleoside linkage group of Formula XVII.

[0639] Embodiment 466. The RNAi agent of any of embodiments 464-465, wherein at least one of the five 3'-most internucleoside linkage groups of said RNAi sense modified oligonucleotide is an internucleoside linkage group of Formula XVII.

[0640] Embodiment 467. The RNAi agent of any of embodiments 464-466, wherein at least one of the first five internucleoside linkage groups from the 5' end of the RNAi sense modified oligonucleotide and at least one of the five 3'-most linkage groups of the RNAi sense modified oligonucleotide is an internucleoside linkage group of Formula XVII.

[0641] Embodiment 468. An RNAi agent described in any of embodiments 464 to 467, wherein at least one region of the RNAi sense modified oligonucleotide has the structure A, B, C, D, or E.

[0642] Embodiment 469. The RNAi agent of embodiment 468, wherein at least one region having the structure A, B, C, D, or E is at the 3' end of the RNAi sense-modified oligonucleotide.

[0643] Embodiment 470. The RNAi agent of embodiment 468, wherein at least one region having the structure A, B, C, D, or E is at the 5' end of the RNAi sense-modified oligonucleotide.

[0644] Embodiment 471. At least one region of the RNAi sense modified oligonucleotide has the formula (N g1 ) L1 (N g2 ) L2 (N g3 ) L3 wherein each Ng is a nucleoside, each L is an internucleoside linking group, and each of L and L is a phosphodiester internucleoside linking group, a phosphorothioate internucleoside linking group, or an internucleoside linking group of formula XVII;

[0645] [ka]

[0646] 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 is an internucleoside linking group of Formula XVII, and at least one of L1, L2, and L3 is a phosphorothioate or phosphodiester internucleoside linking group; wherein, independently for each internucleoside linking group of said modified oligonucleotide having Formula XVII: X is selected from O or S; R1 is selected from H, C1-C6 alkyl, and substituted C1-C6 alkyl; T is selected from SO2R2, C(=O)R3, and P(=O)R4R5, wherein: R2 is selected from aryl, substituted aryl, heterocycle, substituted heterocycle, aromatic heterocycle, substituted aromatic heterocycle, diazole, substituted diazole, 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; R3 is selected from aryl, substituted aryl, CH3, N(CH3)2, OCH3, and a conjugate; R4 is selected from OCH3, OH, C1-C6 alkyl, substituted C1-C6 alkyl, and conjugates; R5 is selected from OCH3, OH, C1-C6 alkyl, and substituted C1-C6 alkyl; An RNAi agent according to any one of embodiments 464 to 467.

[0647] Embodiment 472. The formula (N g1 ) L1 (N g2 ) L2 (N g3 ) L3 472. The RNAi agent of embodiment 471, wherein at least one region having the following is at the 3' end of the RNAi sense modified oligonucleotide.

[0648] Embodiment 473. The compound of the formula (N g1 ) L1 (N g2 ) L2 (N g3 ) L3 472. The RNAi agent of embodiment 471, wherein at least one region having the following is at the 5' end of the RNAi sense modified oligonucleotide.

[0649] Embodiment 474. The modified oligonucleotide of any of embodiments 311 to 443, wherein each nucleoside of the modified oligonucleotide is a modified nucleoside comprising a modified sugar moiety.

[0650] 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.

[0651] Embodiment 476. The modified oligonucleotide of embodiment 474 or 475, wherein each modified sugar moiety contains the same modification.

[0652] Embodiment 477. The modified oligonucleotide of any of embodiments 474 to 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.

[0653] 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.

[0654] 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.

[0655] 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.

[0656] Embodiment 481. The method of embodiment 476 or 477, wherein the six 3'-most nucleosides contain a bicyclic sugar moiety and the remaining nucleosides contain a 2'-substituted furanosyl sugar moiety. Modified oligonucleotides.

[0657] 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.

[0658] Embodiment 483. The modified oligonucleotide of embodiment 482, wherein the bicyclic sugar moiety is cEt.

[0659] 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.

[0660] Embodiment 485. The modified oligonucleotide of any of embodiments 474-484, wherein at least one of the 10 5'-most linkage groups of said modified oligonucleotide is an internucleoside linkage group of Formula XVII.

[0661] Embodiment 486. The modified oligonucleotide of embodiment 485, wherein at least two of the ten 5'-most linkage groups of said modified oligonucleotide are internucleoside linkage groups of Formula XVII.

[0662] Embodiment 487. The modified oligonucleotide of embodiment 485, wherein at least three of the ten 5'-most linkage groups of said modified oligonucleotide are internucleoside linkage groups of Formula XVII.

[0663] Embodiment 488. The modified oligonucleotide of embodiment 485, wherein at least four of the ten 5'-most linkage groups of said modified oligonucleotide are internucleoside linkage groups of Formula XVII.

[0664] Embodiment 489. The modified oligonucleotide of embodiment 485, wherein at least 5 of the 10 5'-most linkage groups of said modified oligonucleotide are internucleoside linkage groups of Formula XVII.

[0665] Embodiment 490. The modified oligonucleotide of embodiment 485, wherein at least six of the ten 5'-most linkage groups of said modified oligonucleotide are internucleoside linkage groups of Formula XVII.

[0666] Embodiment 491. The modified oligonucleotide of embodiment 485, wherein the two 5'-most internucleoside linking groups are internucleoside linking groups of Formula XVII.

[0667] Embodiment 492. The modified oligonucleotide of any of embodiments 478-491, wherein at least one of the 10 3'-most internucleoside linkage groups of said modified oligonucleotide is an internucleoside linkage group of Formula XVII.

[0668] Embodiment 493. The modified oligonucleotide of embodiment 492, wherein at least two of the 10 3'-most internucleoside linkage groups of said modified oligonucleotide are internucleoside linkage groups of Formula XVII.

[0669] Embodiment 494. The modified oligonucleotide of embodiment 492, wherein at least three of the ten 3'-most internucleoside linkage groups are internucleoside linkage groups of Formula XVII.

[0670] Embodiment 495. The modified oligonucleotide of embodiment 492, wherein at least four of the ten 3'-most internucleoside linkage groups are internucleoside linkage groups of Formula XVII.

[0671] Embodiment 496. The modified oligonucleotide of embodiment 492, wherein at least 5 of the 10 3'-most internucleoside linkage groups are internucleoside linkage groups of Formula XVII.

[0672] Embodiment 497. The modified oligonucleotide of embodiment 492, wherein at least 6 of the 10 3'-most internucleoside linkage groups are internucleoside linkage groups of Formula XVII.

[0673] Embodiment 498. The modified oligonucleotide of embodiment 492, wherein the two 3'-most internucleoside linking groups of said modified oligonucleotide are internucleoside linking groups of Formula XVII.

[0674] Embodiment 499. The modified oligonucleotide of any of embodiments 474-484, wherein the modified oligonucleotide comprises at least one block of at least three consecutive internucleoside linking groups of Formula XVII.

[0675] Embodiment 500. The modified oligonucleotide of any of embodiments 474-484, wherein the modified oligonucleotide comprises at least one block of at least four consecutive internucleoside linking groups of Formula XVII.

[0676] Embodiment 501. The modified oligonucleotide of any of embodiments 474-484, wherein the modified oligonucleotide comprises at least one block of at least five contiguous internucleoside linking groups of Formula XVII.

[0677] Embodiment 502. The modified oligonucleotide of any of embodiments 474-484, wherein the modified oligonucleotide comprises at least one block of at least six contiguous internucleoside linking groups of Formula XVII.

[0678] Embodiment 503. The modified oligonucleotide of any of embodiments 499-502, wherein at least one block of contiguous internucleoside linking groups of Formula XVII is at the 5' end of the modified oligonucleotide.

[0679] Embodiment 504. The modified oligonucleotide of any of embodiments 499-502, wherein at least one block of contiguous internucleoside linking groups of Formula XVII is at the 3' end of the modified oligonucleotide.

[0680] Embodiment 505. The modified oligonucleotide of any of embodiments 311 to 443, wherein the modified oligonucleotide comprises a deoxy region consisting of 6 to 11 linked nucleosides, each nucleoside in the deoxy region being either a modified nucleoside or a stereostandard DNA nucleoside, at least three consecutive nucleosides in the deoxy region being stereostandard DNA nucleosides, and no more than three nucleosides in the deoxy region being modified nucleosides.

[0681] Embodiment 506. The modified oligonucleotide of embodiment 505, wherein at least four consecutive nucleosides of the deoxy region are stereostandard DNA nucleosides.

[0682] Embodiment 507. The modified oligonucleotide of embodiment 505, wherein at least five consecutive nucleosides of the deoxy region are stereostandard DNA nucleosides.

[0683] Embodiment 508. The modified oligonucleotide of embodiment 505, wherein at least 6 consecutive nucleosides of the deoxy region are stereostandard DNA nucleosides.

[0684] Embodiment 509. The modified oligonucleotide of embodiment 505, wherein at least 7 consecutive nucleosides of the deoxy region are stereostandard DNA nucleosides.

[0685] Embodiment 510. The modified oligonucleotide of embodiment 505, wherein at least 8 consecutive nucleosides of the deoxy region are stereostandard DNA nucleosides.

[0686] Embodiment 511. The modified oligonucleotide of any of embodiments 505 to 510, wherein the deoxy region consists of 8 to 10 linked nucleosides.

[0687] Embodiment 512. The modified oligonucleotide of any of embodiments 505-510, wherein the deoxy region consists of 9 linked nucleosides.

[0688] Embodiment 513. The modified oligonucleotide of any of embodiments 505-510, wherein the deoxy region consists of 10 linked nucleosides.

[0689] Embodiment 514. The modified oligonucleotide of any of embodiments 505-510, wherein the deoxy region consists of 11 linked nucleosides.

[0690] Embodiment 515. The modified oligonucleotide of any of embodiments 505-510, wherein at least six nucleosides of the deoxy region are stereostandard DNA nucleosides.

[0691] Embodiment 516. The modified oligonucleotide of any of embodiments 505 to 510, wherein at least 7 nucleosides of the deoxy region are stereostandard DNA nucleosides.

[0692] Embodiment 517. The modified oligonucleotide of any of embodiments 505 to 510, wherein at least 8 nucleosides of the deoxy region are stereostandard DNA nucleosides.

[0693] Embodiment 518. The modified oligonucleotide of any of embodiments 505 to 510, wherein at least 9 nucleosides of the deoxy region are stereostandard DNA nucleosides.

[0694] Embodiment 519. The modified oligonucleotide of any of embodiments 505 to 518, wherein two nucleosides of the deoxy region are modified nucleosides.

[0695] Embodiment 520. The modified oligonucleotide of any of embodiments 505-518, wherein one nucleoside of the deoxy region is a modified nucleoside.

[0696] Embodiment 521. At least one modified nucleoside in the deoxy region is a β-D-LNA nucleoside, an α-L-LNA nucleoside, an ENA nucleoside, a cEt nucleoside, a 2'-MOE nucleoside, a 2'-OMe nucleoside, or a 2'-F nucleoside. 521. The modified oligonucleotide of any of embodiments 505-520, wherein the stereostandard modified nucleoside or bicyclic nucleoside is selected from:

[0697] Embodiment 522. The modified oligonucleotide of any of embodiments 505 to 520, wherein at least one modified nucleoside in the deoxy region is a stereo-nonstandard nucleoside.

[0698] Embodiment 523. The modified oligonucleotide of embodiment 522, wherein said at least one stereononstandard nucleoside of said deoxy region is a stereononstandard DNA nucleoside.

[0699] Embodiment 524. The modified oligonucleotide of embodiment 523, wherein the stereo-nonstandard DNA nucleoside is selected from stereo-nonstandard DNA nucleosides having Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, and Formula VII.

[0700] Embodiment 525. The modified oligonucleotide of embodiment 524, wherein the stereo-nonstandard DNA nucleoside is selected from stereo-nonstandard DNA nucleosides having formula V and formula II:

[0701] Embodiment 526. The modified oligonucleotide of embodiment 525, wherein at least one stereononstandard nucleoside in the deoxy region is a substituted stereononstandard nucleoside.

[0702] Embodiment 527. The modified oligonucleotide of embodiment 526, wherein at least one substituted stereononstandard nucleoside has a 2' substituent selected from 2'-MOE, 2'-OMe, 2'-F, or 2'-OH.

[0703] Embodiment 528. The modified oligonucleotide of any of embodiments 505 to 527, wherein the second nucleoside from the 5' end of the deoxy region is a modified nucleoside.

[0704] Embodiment 529. The modified oligonucleotide of any of embodiments 505 to 527, wherein the third nucleoside from the 5' end of the deoxy region is a modified nucleoside.

[0705] Embodiment 530. The modified oligonucleotide of any of embodiments 505 to 527, wherein the fourth nucleoside from the 5' end of the deoxy region is a modified nucleoside.

[0706] Embodiment 531. The modified oligonucleotide of any of embodiments 528-530, wherein the modified nucleoside in the deoxy region is a 2'-OMe nucleoside.

[0707] Embodiment 532. The modified oligonucleotide of any of embodiments 505 to 518, wherein each nucleoside of the deoxy region is a stereostandard DNA nucleoside.

[0708] Embodiment 533. The modified oligonucleotide of any of embodiments 505-532, wherein at least one internucleoside linking group in said deoxy region is an internucleoside linking group of Formula XVII.

[0709] Embodiment 534. The internucleoside linking group connecting the first and second nucleosides of the deoxy region, counting from the 5' end of the deoxy region, is a nucleoside of Formula XVII. The modified oligonucleotide of any of embodiments 505 to 532, wherein the interleukin-1 linking group is an olefin.

[0710] Embodiment 535. The modified oligonucleotide of any of embodiments 505-534, wherein the internucleoside linking group connecting the second and third nucleosides of the deoxy region, counting from the 5' end of the deoxy region, is an internucleoside linking group of Formula XVII.

[0711] Embodiment 536. The modified oligonucleotide of any of embodiments 505 to 535, wherein the internucleoside linking group connecting the third and fourth nucleosides of the deoxy region, counting from the 5' end of the deoxy region, is an internucleoside linking group of Formula XVII.

[0712] Embodiment 537. The modified oligonucleotide of any of embodiments 505-536, wherein the internucleoside linking group connecting the fourth and fifth nucleosides of the deoxy region, counting from the 5' end of the deoxy region, is an internucleoside linking group of Formula XVII.

[0713] Embodiment 538. The modified oligonucleotide of any of embodiments 505-537, wherein one internucleoside linkage group in the deoxy region is a linkage group of Formula XVII, and each of the other internucleoside linkage groups in the deoxy region is a respective phosphodiester or phosphorothioate internucleoside linkage group.

[0714] Embodiment 539. The modified oligonucleotide of any of embodiments 505-537, wherein two internucleoside linkage groups in the deoxy region are linkage groups of Formula XVII, and each other internucleoside linkage group in the deoxy region is a phosphodiester or phosphorothioate internucleoside linkage group.

[0715] Embodiment 540. The modified oligonucleotide of any of embodiments 505-537, wherein three internucleoside linkage groups in the deoxy region are linkage groups of Formula XVII, and each remaining internucleoside linkage group in the deoxy region is a phosphodiester or phosphorothioate internucleoside linkage group.

[0716] Embodiment 541. The modified oligonucleotide of any of embodiments 505 to 540, wherein the deoxy region comprises at least one region having the structure A, B, C, D, or E.

[0717] Embodiment 542. The modified oligonucleotide of embodiment 541, wherein the region having the structure A, B, C, D, or E is at the 3' end of the deoxy region.

[0718] Embodiment 543. The modified oligonucleotide of embodiment 541, wherein the region having the structure A, B, C, D, or E is at the 5' end of the deoxy region.

[0719] Embodiment 544. The deoxy region is selected from the group consisting of the formula (N g1 ) L1 (N g2 ) L2 (N g3 )L3 wherein each N g is a nucleoside, each L is an internucleoside linking group, and each of L and L is a phosphodiester internucleoside linking group, a phosphorothioate internucleoside linking group, or an internucleoside linking group of formula XVII;

[0720] [ka]

[0721] 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 is an internucleoside linking group of Formula XVII, and at least one of L1, L2, and L3 is a phosphorothioate or phosphodiester internucleoside linking group; wherein, independently for each internucleoside linking group of said modified oligonucleotide having Formula XVII: X is selected from O or S; R1 is selected from H, C1-C6 alkyl, and substituted C1-C6 alkyl; T is selected from SO2R2, C(=O)R3, and P(=O)R4R5, wherein: R2 is selected from aryl, substituted aryl, heterocycle, substituted heterocycle, aromatic heterocycle, substituted aromatic heterocycle, diazole, substituted diazole, 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; R3 is selected from aryl, substituted aryl, CH3, N(CH3)2, OCH3, and a conjugate; R4 is selected from OCH3, OH, C1-C6 alkyl, substituted C1-C6 alkyl, and conjugates; R5 is selected from OCH3, OH, C1-C6 alkyl, and substituted C1-C6 alkyl; The modified oligonucleotide according to any of embodiments 505 to 540.

[0722] Embodiment 545. The compound of the formula (N g1 ) L1 (N g2 ) L2 (N g3 ) L3 545. The modified oligonucleotide of any of embodiments 544, wherein the region having:

[0723] Embodiment 546. The compound of the formula (N g1 ) L1 (N g2 ) L2 (N g3 ) L3 545. The modified oligonucleotide of any of embodiments 544, wherein the region having:

[0724] Embodiment 547. The deoxy region is flanked on the 5' side by a 5' region consisting of 1 to 6 linked 5' region nucleosides and on the 3' side by a 3' region consisting of 1 to 6 linked 3' region nucleosides; the 3'-most nucleoside of the 5' region is a modified nucleoside; the 5'-most nucleoside of the 3' region is a modified nucleoside; The modified oligonucleotide according to any of embodiments 505 to 546.

[0725] Embodiment 548. The deoxy region consists of 7 to 11 linked nucleosides and has the formula: (N d1 ) L1 (N d2 ) L2 (N d3 ) L3 (N d4 ) L4 [(N d ) L5 ] q , In the formula, N d1 , N d2 , N d3 , N d4 But independently, a stereostandard DNA nucleoside, a stereononstandard DNA nucleoside, or a 2'-substituted nucleoside, with the proviso that N d1 , N d2 , N d3 , or N d4 is a 2'-substituted nucleoside; each N d are independently selected from stereostandard and stereononstandard DNA nucleosides; q is 3 to 8; each of L1, L2, L3, L4, and each L5 is an internucleoside linkage; At least two of L1, L2, L3, and L4 are internucleoside linkages of formula XVII. The modified oligonucleotide described in embodiment 547.

[0726] Embodiment 549.N d1 , N d2 , N d3 , or N d4 The modified oligonucleotide of embodiment 548, wherein one of the following is a 2'-substituted nucleoside:

[0727] Embodiment 550. The modified oligonucleotide of embodiment 549, wherein the 2'-substituted nucleoside is a 2'-OMe nucleoside.

[0728] Embodiment 551. The modified oligonucleotide of embodiment 550, wherein the 2'-OMe nucleoside is a stereostandard 2'-OMe nucleoside.

[0729] Embodiment 552. The 2'-substituted nucleoside is N d2 The modified oligonucleotide according to any of embodiments 548 to 551, wherein

[0730] Embodiment 553.N d1 , N d2 , N d3 , N d4 Each of the above, and each N d The modified oligonucleotide of embodiment 548, wherein

[0731] Embodiment 554. The modified oligonucleotide of embodiment 553, wherein each DNA nucleoside is a stereostandard DNA nucleoside.

[0732] Embodiment 555. The modified oligonucleotide according to any of embodiments 548 to 554, wherein L1 and L2 are internucleoside linkages of formula XVII.

[0733] Embodiment 556. The modified oligonucleotide according to any of embodiments 548 to 554, wherein L2 and L3 are internucleoside linkages of formula XVII.

[0734] Embodiment 557. The modified oligonucleotide according to any of embodiments 548 to 554, wherein L3 and L4 are internucleoside linkages of formula XVII.

[0735] Embodiment 558. The modified oligonucleotide of any of embodiments 548 to 554, wherein L1, L2, and L3 are internucleoside linkages of formula XVII.

[0736] Embodiment 559. The modified oligonucleotide of any of embodiments 548 to 554, wherein L2, L3, and L4 are internucleoside linkages of formula XVII.

[0737] Embodiment 560. The modified oligonucleotide of any of embodiments 548 to 554, wherein L1, L2, L3, and L4 are internucleoside linkages of formula XVII.

[0738] Embodiment 561. The 5' region of embodiment 5 consists of 2 to 5 linked nucleosides. 47 to 560. A modified oligonucleotide according to any one of 47 to 560.

[0739] Embodiment 562. The modified oligonucleotide of embodiment 561, wherein the 5' region consists of 3 linked nucleosides.

[0740] Embodiment 563. The modified oligonucleotide of embodiment 561, wherein the 5' region consists of 5 linked nucleosides.

[0741] Embodiment 564. The modified oligonucleotide of any of embodiments 547 to 563, wherein each nucleoside of the 5' region is a modified nucleoside.

[0742] Embodiment 565. The modified oligonucleotide of any of embodiments 547-564, wherein each nucleoside in the 5' region is a modified nucleoside comprising a modified sugar.

[0743] 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.

[0744] 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.

[0745] Embodiment 568. The modified oligonucleotide of any of embodiments 547 to 567, wherein each 2'-substituted furanosyl sugar moiety in the 5' region has a 2'-substituent selected from among 2'-MOE, 2'-OMe, and 2'-NMA.

[0746] 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.

[0747] 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.

[0748] Embodiment 571. The modified oligonucleotide of embodiment 569 or 570, wherein each bicyclic sugar moiety in the 5' region is selected from among cEt, LNA, and ENA.

[0749] Embodiment 572. The modified oligonucleotide of embodiment 571, wherein each bicyclic sugar moiety in the 5' region is a cEt sugar moiety.

[0750] Embodiment 573. The modified oligonucleotide of any of embodiments 547 to 563, 566, or 569, wherein at least one nucleoside of the 5' region is a stereostandard DNA nucleoside.

[0751] Embodiment 574. The modified oligonucleotide of any of embodiments 547 to 572, wherein at least one nucleoside in the 5' region is a stereo-nonstandard nucleoside.

[0752] Embodiment 575. The modified oligonucleotide of any of embodiments 547 to 574, wherein each nucleobase of the 5' region is independently selected from among thymine, uracil, guanine, cytosine, 5-methylcytosine, and adenine.

[0753] Embodiment 576. The 3' region of embodiment 5 consists of 2 to 5 linked nucleosides. 47 to 575. A modified oligonucleotide according to any one of claims 47 to 575.

[0754] Embodiment 577. The modified oligonucleotide of embodiment 576, wherein the 3' region consists of 3 linked nucleosides.

[0755] Embodiment 578. The modified oligonucleotide of embodiment 576, wherein the 3' region consists of 5 linked nucleosides.

[0756] Embodiment 579. The modified oligonucleotide of any of embodiments 547 to 578, wherein each nucleoside of the 3' region is a modified nucleoside.

[0757] Embodiment 580. The modified oligonucleotide of any of embodiments 547-578, wherein each nucleoside in the 3' region is a modified nucleoside comprising a modified sugar.

[0758] 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.

[0759] 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.

[0760] Embodiment 583. The modified oligonucleotide of any of embodiments 547 to 582, wherein each 2'-substituted furanosyl sugar moiety in the 3' region has a 2'-substituent selected from among 2'-MOE, 2'-OMe, and 2'-NMA.

[0761] 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.

[0762] 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.

[0763] Embodiment 586. The modified oligonucleotide of embodiment 584 or 585, wherein each bicyclic sugar moiety in the 3' region is selected from among cEt, LNA, and ENA.

[0764] Embodiment 587. The modified oligonucleotide of embodiment 586, wherein each bicyclic sugar moiety in the 3' region is a cEt sugar moiety.

[0765] 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 stereostandard DNA nucleoside.

[0766] Embodiment 589. The modified oligonucleotide of any of embodiments 547 to 588, wherein at least one nucleoside in the 3' region is a stereo-nonstandard nucleoside.

[0767] Embodiment 590. The modified oligonucleotide of any of embodiments 547 to 589, wherein each nucleobase of the 3' region is independently selected from among thymine, uracil, guanine, cytosine, 5-methylcytosine, and adenine.

[0768] Embodiment 591. The modified oligonucleotide of any of embodiments 547 to 590, wherein the modified oligonucleotide is a gapmer.

[0769] Embodiment 592. The modified oligonucleotide of any of embodiments 311 to 432, wherein the modified oligonucleotide is a CRISPR compound.

[0770] Embodiment 593. The modified oligonucleotide of embodiment 592, wherein the CRISPR compound consists of 20 to 50 linked nucleosides.

[0771] Embodiment 594. The modified oligonucleotide of embodiment 592, wherein the CRISPR compound consists of 29 to 32 linked nucleosides.

[0772] Embodiment 595. The modified oligonucleotide of any of embodiments 311 to 432, wherein the modified oligonucleotide is an artificial mRNA compound.

[0773] Embodiment 596. The artificial mRNA compound of embodiment 595, wherein the artificial mRNA oligonucleotide consists of 17 to 3000 linked nucleosides.

[0774] Embodiment 597. The artificial mRNA compound of embodiment 595 or 596, wherein the artificial mRNA oligonucleotide encodes a protein.

[0775] Embodiment 598. The modified oligonucleotide of any of embodiments 396 to 597, wherein each X is O.

[0776] Embodiment 599. The modified oligonucleotide of any of embodiments 396 to 597, wherein each X is S.

[0777] Embodiment 600. The modified oligonucleotide of any of embodiments 396 to 599, wherein at least one R1 is H.

[0778] Embodiment 601. The modified oligonucleotide of any of embodiments 396 to 599, wherein at least one R1 is C1-C6 alkyl.

[0779] Embodiment 602. The modified oligonucleotide of embodiment 601, wherein at least one R1 is methyl.

[0780] Embodiment 603. The modified oligonucleotide of any of embodiments 396-602, wherein at least one R1 is substituted C1-C6 alkyl.

[0781] Embodiment 604. The modified oligonucleotide of any of embodiments 396 to 603, wherein at least one T comprises a conjugate group.

[0782] Embodiment 605. The modified oligonucleotide of embodiment 604, wherein the conjugate group comprises a carbohydrate or carbohydrate cluster.

[0783] Embodiment 606. The modified oligonucleotide of embodiment 604 or 605, wherein the conjugate group comprises at least one GalNAc.

[0784] Embodiment 607. The conjugate group is C 10 ~C 20 The modified oligonucleotide of embodiment 604, comprising an alkyl chain.

[0785] Embodiment 608. The conjugate group is C 16 In embodiment 607, containing alkyl The modified oligonucleotide described.

[0786] Embodiment 609. The modified oligonucleotide of any of embodiments 396 to 603, wherein at least one T does not comprise a conjugate group.

[0787] Embodiment 610. The modified oligonucleotide of any of embodiments 396 to 603, wherein each T does not comprise a conjugate group.

[0788] Embodiment 611. The modified oligonucleotide of any of embodiments 396 to 603, wherein at least one T is SO2R2.

[0789] Embodiment 612. The modified oligonucleotide of embodiment 611, wherein R2 is aryl.

[0790] Embodiment 613. The modified oligonucleotide of embodiment 611, wherein R2 is substituted aryl.

[0791] Embodiment 614. The modified oligonucleotide of embodiment 611, wherein R2 is a heterocycle.

[0792] Embodiment 615. The modified oligonucleotide of embodiment 611, wherein R2 is a substituted heterocycle.

[0793] Embodiment 616. The modified oligonucleotide of embodiment 611, wherein R2 is an aromatic heterocycle.

[0794] Embodiment 617. The modified oligonucleotide of embodiment 611, wherein R2 is a substituted aromatic heterocycle.

[0795] Embodiment 618. The modified oligonucleotide of embodiment 611, wherein R2 is diazole.

[0796] Embodiment 619. The modified oligonucleotide of embodiment 611, wherein R2 is a substituted diazole.

[0797] Embodiment 620. The modified oligonucleotide according to embodiment 611, wherein R2 is an amine.

[0798] Embodiment 621. The modified oligonucleotide of embodiment 611, wherein R2 is a substituted amine.

[0799] Embodiment 622. The modified oligonucleotide of embodiment 611, wherein R2 is C1-C6 alkoxy, C1-C6 alkenyl, or C1-C6 alkynyl.

[0800] Embodiment 623.R2 is C1 to C 20 , C1~C6, C2~C 20 , C2 to C6, or C 10 ~C 20 The modified oligonucleotide of embodiment 611, which is alkyl.

[0801] In the embodiment 624.R2, substitutions C1 to C 20 , C1~C6, C2~C 20 , C2 to C6, or C 10 ~C 20 The modified oligonucleotide of embodiment 611, which is alkyl.

[0802] Embodiment 625. The modified oligonucleotide according to embodiment 611, wherein R2 comprises a carbohydrate or carbohydrate cluster.

[0803] Embodiment 626. The modified oligonucleotide of embodiment 611, wherein R2 comprises at least one GalNAc.

[0804] Embodiment 627. The modified oligonucleotide of embodiment 611, wherein T is:

[0805] [ka]

[0806] Embodiment 628. The modified oligonucleotide of embodiment 611, wherein T is:

[0807] [ka]

[0808] Embodiment 629. The modified oligonucleotide of embodiment 611, wherein T is:

[0809] [ka]

[0810] Embodiment 630. The modified oligonucleotide of embodiment 611, wherein T is:

[0811] [ka]

[0812] Embodiment 631. The modified oligonucleotide of embodiment 611, wherein T is:

[0813] [ka]

[0814] Embodiment 632. The modified oligonucleotide of embodiment 611, wherein T is:

[0815] [ka]

[0816] Embodiment 633. The modified oligonucleotide of embodiment 611, wherein T is:

[0817] [ka]

[0818] Embodiment 634. The modified oligonucleotide of embodiment 611, wherein T is:

[0819] [ka]

[0820] Embodiment 635. The modified oligonucleotide of embodiment 611, wherein T is:

[0821] [ka]

[0822] In an embodiment 636.T,

[0823] [ka]

[0824] 612. The modified oligonucleotide of embodiment 611, wherein n is 2 to 20.

[0825] Embodiment 637. The modified oligonucleotide of embodiment 636, wherein n is 15.

[0826] Embodiment 638. The modified oligonucleotide of any of embodiments 396 to 603, wherein at least one T is C(=O)R3.

[0827] Embodiment 639. The modified oligonucleotide of embodiment 638, wherein R3 is aryl.

[0828] Embodiment 640. The modified oligonucleotide of embodiment 638, wherein R3 is substituted aryl.

[0829] Embodiment 641. The modified oligonucleotide of embodiment 638, wherein R3 is CH3.

[0830] Embodiment 642. The modified oligonucleotide of embodiment 638, wherein R3 is N(CH3)2.

[0831] Embodiment 643. The modified oligonucleotide of embodiment 638, wherein R3 is OCH3.

[0832] Embodiment 644. The modified oligonucleotide of embodiment 638, wherein R3 is C1-C6 alkoxy.

[0833] Embodiment 645.R3 is C1 to C 20 , C1~C6, C2~C 20 , C2 to C6, or C 10 ~C 20 The modified oligonucleotide of embodiment 638, which is alkyl.

[0834] In the embodiment 646.R3, substitutions C1 to C 20 , C1~C6, C2~C 20 , C2 to C6, or C 10 ~C 20 The modified oligonucleotide of embodiment 638, which is alkyl.

[0835] Embodiment 647. The modified oligonucleotide of embodiment 638, wherein R3 comprises a carbohydrate or carbohydrate cluster.

[0836] Embodiment 648.R 23 The modified oligonucleotide of embodiment 638, wherein said modified oligonucleotide comprises at least one GalNAc.

[0837] Embodiment 649. The modified oligonucleotide of embodiment 638, wherein T is:

[0838] [ka]

[0839] Embodiment 650. The modified oligonucleotide of embodiment 638, wherein T is:

[0840] [ka]

[0841] Embodiment 651. The modified oligonucleotide of embodiment 638, wherein T is:

[0842] [ka]

[0843] Embodiment 652. The modified oligonucleotide of embodiment 638, wherein T is:

[0844] [ka]

[0845] In an embodiment 653.T,

[0846] [ka]

[0847] The modified oligonucleotide of embodiment 638, wherein n is 2 to 20.

[0848] Embodiment 654. The modified oligonucleotide of embodiment 653, wherein n is 15.

[0849] Embodiment 655. The modified oligonucleotide of any of embodiments 396 to 603, wherein at least one T is P(=O)R4R5.

[0850] Embodiment 656. The modified oligonucleotide of embodiment 655, wherein R4 is OCH3.

[0851] Embodiment 657. The modified oligonucleotide of embodiment 655, wherein R4 is OH.

[0852] Embodiment 658. The modified oligonucleotide of embodiment 655, wherein R4 is C1-C6 alkyl.

[0853] Embodiment 659. The modified oligonucleotide of embodiment 655, wherein R4 is substituted C1-C6 alkyl.

[0854] Embodiment 660.R4 is C1 to C 20 , C1~C6, C2~C 20 , C2 to C6, or C 10 ~C 20 The modified oligonucleotide of embodiment 655, which is alkyl.

[0855] In the embodiment 661.R4, substitutions C1 to C 20 , C1~C6, C2~C 20 , C2 to C6, or C 10 ~C 20 The modified oligonucleotide of embodiment 655, which is alkyl.

[0856] Embodiment 662. The modified oligonucleotide of embodiment 655, wherein R4 comprises a carbohydrate or carbohydrate cluster.

[0857] Embodiment 663. The modified oligonucleotide of embodiment 655, wherein R4 comprises at least one GalNAc.

[0858] Embodiment 664. The modified oligonucleotide according to any of embodiments 655 to 663, wherein R5 is OCH3.

[0859] Embodiment 665. The modified oligonucleotide according to any of embodiments 655 to 663, wherein R5 is OH.

[0860] Embodiment 666. The modified oligonucleotide according to any of embodiments 655 to 663, wherein R5 is C1 to C6 alkyl.

[0861] Embodiment 667. The modified oligonucleotide according to any of embodiments 655 to 663, wherein R5 is substituted C1-C6 alkyl.

[0862] Embodiment 668. The modified oligonucleotide of embodiment 655, wherein T is:

[0863] [ka]

[0864] Embodiment 669. The modified oligonucleotide of embodiment 655, wherein T is:

[0865] [ka]

[0866] In an embodiment 670.T,

[0867] [ka]

[0868] 656. The modified oligonucleotide of embodiment 655, wherein n is 2 to 20.

[0869] Embodiment 671. The modified oligonucleotide of embodiment 670, wherein n is 15.

[0870] Embodiment 672. A chirally enriched population of modified oligonucleotides described in any of embodiments 311 to 671, wherein the population is enriched for modified oligonucleotides comprising at least one particular internucleoside linkage group having a particular stereochemical configuration.

[0871] Embodiment 673. A chirally enriched population of modified oligonucleotides according to embodiment 672, wherein the particular internucleoside linking group having a particular stereochemical configuration is an internucleoside linking group of formula XVIII, as shown in formulas XVIIIa and XVIIIb below.

[0872] [ka]

[0873] Embodiment 674. A chirally enriched population of modified oligonucleotides according to embodiment 672, wherein said particular internucleoside linking group having a particular stereochemical configuration is a phosphorothioate internucleoside linking group.

[0874] Embodiment 675. A chirally enriched population according to any of embodiments 672 to 674, wherein the population is enriched for modified oligonucleotides comprising at least one particular internucleoside linkage having an (Sp) configuration.

[0875] Embodiment 676. A chirally enriched population according to any of embodiments 672 to 675, wherein the population is enriched for modified oligonucleotides comprising at least one particular internucleoside linkage having an (Rp) configuration.

[0876] Embodiment 677. The chiral enriched population of embodiment 672, wherein the population is enriched for modified oligonucleotides having a specific, independently selected stereochemical configuration at each chiral internucleoside linkage.

[0877] Embodiment 678. The chiral enriched population of any of embodiments 672 to 677, wherein the population is enriched for modified oligonucleotides having the (Sp) configuration at each chiral internucleoside linkage.

[0878] Embodiment 679. The chiral enriched population of any of embodiments 672 to 677, wherein the population is enriched for modified oligonucleotides having the (Rp) configuration at each chiral internucleoside linkage.

[0879] Embodiment 680. The chiral enriched population of any of embodiments 672 to 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.

[0880] Embodiment 681. The chirally enriched population of embodiment 673, wherein each phosphorothioate internucleoside linkage is stereorandom.

[0881] Embodiment 682. The modified oligonucleotide of any of embodiments 311 to 681, wherein the nucleobase sequence of the modified oligonucleotide is complementary to a target nucleic acid.

[0882] 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.

[0883] 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.

[0884] 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.

[0885] 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.

[0886] Embodiment 687. The modified oligonucleotide of embodiment 682, wherein the nucleobase sequence of the modified oligonucleotide is 100% complementary to the target nucleic acid.

[0887] Embodiment 688. The modified oligonucleotide of any of embodiments 682 to 687, wherein the target nucleic acid is a target RNA.

[0888] Embodiment 689. The modified oligonucleotide of embodiment 688, wherein the target RNA is selected from mRNA, pre-mRNA, microRNA, and non-coding RNA.

[0889] Embodiment 690. The modified oligonucleotide of embodiment 688, wherein the target RNA is not a microRNA.

[0890] Embodiment 691. The modified oligonucleotide of any of embodiments 311 to 690, wherein the modified oligonucleotide is not complementary to miR-21.

[0891] Embodiment 692. A modified oligonucleotide according to any one of embodiments 311 to 691, comprising a conjugate group.

[0892] Embodiment 693. The modified oligonucleotide of embodiment 692, wherein the conjugate group comprises at least one GalNAc.

[0893] Embodiment 694. The modified oligonucleotide of embodiment 692 or 693, wherein the conjugate group comprises 1 to 5 linker nucleosides.

[0894] Embodiment 695. A pharmaceutical composition comprising a modified oligonucleotide according to any of embodiments 311 to 694 and a pharmaceutically acceptable carrier or diluent.

[0895] Embodiment 696. A method comprising contacting a cell with a modified oligonucleotide or pharmaceutical composition according to any one of embodiments 311 to 695.

[0896] Embodiment 697. A method for modulating the amount or activity of a target nucleic acid in a cell, comprising contacting the cell with a modified oligonucleotide or pharmaceutical composition described in any of embodiments 311 to 695, thereby modulating the amount or activity of the target nucleic acid.

[0897] Embodiment 698. A method for modulating the amount or activity of a target nucleic acid in a cell, comprising contacting the cell with a modified oligonucleotide or pharmaceutical composition described in any of embodiments 311 to 695.

[0898] Embodiment 699. The method of embodiments 696 to 698, wherein the amount or activity of the target nucleic acid is reduced.

[0899] Embodiment 700. The method of embodiments 696-698, wherein the amount or activity of the target nucleic acid is increased.

[0900] Embodiment 701. The method of embodiment 700, wherein the target protein is encoded by a target nucleic acid comprising at least one translational repression element, and the modified oligonucleotide is complementary to a target site within the translational repression element region of the target nucleic acid.

[0901] Embodiment 702. The method of embodiment 701, wherein the translational repression element region comprises at least one stem-loop structure.

[0902] Embodiment 703. Any of embodiments 311 to 695 for the treatment of a disease or condition. Use of a modified oligonucleotide or composition as described in claim 1.

[0903] Embodiment 704. Use of a modified oligonucleotide or composition according to any of embodiments 311 to 695 for the preparation of a medicament for the treatment of a disease or pathological condition.

[0904] Embodiment 705. An antisense agent comprising a modified oligonucleotide consisting of 12 to 70 linked nucleosides linked via internucleoside linking groups, wherein at least one nucleoside comprises a modified sugar moiety, and at least one of the internucleoside linking groups has Formula XVII:

[0905] [ka]

[0906] wherein, independently for each internucleoside linking group of said modified oligonucleotide having Formula XVII: X is selected from O or S; R1 is selected from H, C1-C6 alkyl, and substituted C1-C6 alkyl; T is selected from SO2R2, C(=O)R3, and P(=O)R4R5, wherein: R2 is selected from aryl, substituted aryl, heterocycle, substituted heterocycle, aromatic heterocycle, substituted aromatic heterocycle, diazole, substituted diazole, 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; R3 is selected from aryl, substituted aryl, CH3, N(CH3)2, OCH3, and a conjugate group; R4 is selected from OCH3, OH, C1-C6 alkyl, substituted C1-C6 alkyl, and a conjugate group; R5 is selected from OCH3, OH, C1-C6 alkyl, and substituted C1-C6 alkyl; The antisense agent.

[0907] Embodiment 706. An antisense agent comprising a modified oligonucleotide consisting of 12 to 70 linked nucleosides linked via internucleoside linking groups, wherein at least one nucleoside comprises a modified sugar moiety, and at least one of the internucleoside linking groups has the formula XVII:

[0908] [ka]

[0909] wherein, independently for each internucleoside linking group of said modified oligonucleotide having Formula XVII: X is selected from O or S; R1 is selected from H, C1-C6 alkyl, and substituted C1-C6 alkyl; T is selected from SO2R2, C(=O)R3, and P(=O)R4R5, wherein: R2 is selected from aryl, substituted aryl, heterocycle, substituted heterocycle, aromatic heterocycle, substituted aromatic heterocycle, diazole, substituted diazole, 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; R3 is selected from aryl, substituted aryl, CH3, N(CH3)2, OCH3, and a conjugate group; R4 is selected from OCH3, OH, C1-C6 alkyl, substituted C1-C6 alkyl, and a conjugate group; R5 is selected from OCH3, OH, C1-C6 alkyl, and substituted C1-C6 alkyl; However, when X is O and R1 is H, T is

[0910] [ka]

[0911] provided that it is not The antisense agent.

[0912] Embodiment 707. The antisense agent of embodiment 705 or embodiment 706, wherein at least one internucleoside linkage group is a phosphodiester or phosphorothioate internucleoside linkage group.

[0913] Embodiment 708. The antisense agent of any of embodiments 705-707, wherein at least one nucleoside comprises a 2'-β-D-deoxyribosyl sugar moiety.

[0914] 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.

[0915] 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.

[0916] Embodiment 711. The modified oligonucleotide of embodiment 705 or 706, wherein for at least one internucleoside linking group of Formula XVII, R1 is H.

[0917] Embodiment 712. For at least one internucleoside linking group of Formula XVII, R The modified oligonucleotide of embodiment 705 or 706, wherein is C1-C6 alkyl.

[0918] Embodiment 713. The modified oligonucleotide of embodiment 710, wherein R1 is methyl.

[0919] Embodiment 714. The modified oligonucleotide of embodiment 705 or 706, wherein for at least one internucleoside linking group of Formula XVII, R1 is substituted C1-C6 alkyl.

[0920] 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.

[0921] Embodiment 716. The modified oligonucleotide of embodiment 715, wherein the conjugate group comprises a cell targeting moiety.

[0922] Embodiment 717. The modified oligonucleotide of embodiment 715, wherein the conjugate group comprises a carbohydrate or carbohydrate cluster.

[0923] Embodiment 718. The modified oligonucleotide of any of embodiments 715 to 717, wherein the conjugate group comprises at least one GalNAc.

[0924] Embodiment 719. The conjugate group is C 10 ~C 20 The modified oligonucleotide of embodiment 715, comprising an alkyl chain.

[0925] Embodiment 720. The conjugate group is C 16 The modified oligonucleotide of embodiment 719, comprising an alkyl.

[0926] 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.

[0927] 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.

[0928] 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.

[0929] Embodiment 724. The modified oligonucleotide of embodiment 723, wherein R2 is aryl.

[0930] Embodiment 725. The modified oligonucleotide of embodiment 723, wherein R2 is substituted aryl.

[0931] Embodiment 726. The modified oligonucleotide of embodiment 723, wherein R2 is a heterocycle.

[0932] Embodiment 727. The modified oligonucleotide of embodiment 723, wherein R2 is a substituted heterocycle.

[0933] Embodiment 728. The modified oligonucleotide of embodiment 723, wherein R2 is an aromatic heterocycle.

[0934] Embodiment 729. The modified oligonucleotide of embodiment 723, wherein R2 is a substituted aromatic heterocycle.

[0935] Embodiment 730. The modified oligonucleotide of embodiment 723, wherein R2 is diazole.

[0936] Embodiment 731. The modified oligonucleotide of embodiment 723, wherein R2 is a substituted diazole.

[0937] Embodiment 732. The modified oligonucleotide of embodiment 723, wherein R2 is an amine.

[0938] Embodiment 733. The modified oligonucleotide of embodiment 723, wherein R2 is a substituted amine.

[0939] Embodiment 734. R2 is C1-C6 alkoxy, C1-C6 alkenyl, or C 1~ The modified oligonucleotide of embodiment 723, which is C6-alkynyl.

[0940] Embodiment 735.R2 is C1 to C 20 , C1~C6, C2~C 20 , C2 to C6, or C 10 ~C 20 The modified oligonucleotide of embodiment 723, which is alkyl.

[0941] In the embodiment 736.R2, substitutions C1 to C 20 , C1~C6, C2~C 20 , C2 to C6, or C 10 ~C 20 The modified oligonucleotide of embodiment 723, which is alkyl.

[0942] Embodiment 737. The modified oligonucleotide according to embodiment 723, wherein R2 comprises a carbohydrate or carbohydrate cluster.

[0943] Embodiment 738. The modified oligonucleotide of embodiment 723, wherein R2 comprises at least one GalNAc.

[0944] Embodiment 739. The modified oligonucleotide of embodiment 723, wherein T is:

[0945] [ka]

[0946] Embodiment 740. The modified oligonucleotide of embodiment 723, wherein T is:

[0947] [ka]

[0948] Embodiment 741. The modified oligonucleotide of embodiment 723, wherein T is:

[0949] [ka]

[0950] Embodiment 742. The modified oligonucleotide of embodiment 723, wherein T is:

[0951] [ka]

[0952] Embodiment 743. The modified oligonucleotide of embodiment 723, wherein T is:

[0953] [ka]

[0954] Embodiment 744. The modified oligonucleotide of embodiment 723, wherein T is:

[0955] [ka]

[0956] Embodiment 745. The modified oligonucleotide of embodiment 723, wherein T is:

[0957] [ka]

[0958] Embodiment 746. The modified oligonucleotide of embodiment 723, wherein T is:

[0959] [ka]

[0960] Embodiment 747. The modified oligonucleotide of embodiment 723, wherein T is:

[0961] [ka]

[0962] In an embodiment 748.T,

[0963] [ka]

[0964] The modified oligonucleotide of embodiment 723, wherein n is 2 to 20.

[0965] Embodiment 749. The modified oligonucleotide of embodiment 748, wherein n is 15.

[0966] 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.

[0967] Embodiment 751. The modified oligonucleotide of embodiment 750, wherein R3 is aryl.

[0968] Embodiment 752. The modified oligonucleotide according to embodiment 750, wherein R3 is substituted aryl. Cleotide.

[0969] Embodiment 753. The modified oligonucleotide of embodiment 750, wherein R3 is CH3.

[0970] Embodiment 754. The modified oligonucleotide of embodiment 750, wherein R3 is N(CH3)2.

[0971] Embodiment 755. The modified oligonucleotide of embodiment 750, wherein R3 is OCH3.

[0972] Embodiment 756. The modified oligonucleotide of embodiment 750, wherein R3 is C1-C6 alkoxy.

[0973] Embodiment 757.R3 is C1 to C 20 , C1~C6, C2~C 20 , C2 to C6, or C 10 ~C 20 The modified oligonucleotide of embodiment 750, which is alkyl.

[0974] In the embodiment 758.R3, substitutions C1 to C 20 , C1~C6, C2~C 20 , C2 to C6, or C 10 ~C 20 The modified oligonucleotide of embodiment 750, which is alkyl.

[0975] Embodiment 759. The modified oligonucleotide of embodiment 750, wherein R3 comprises a carbohydrate or carbohydrate cluster.

[0976] Embodiment 760.R 23 The modified oligonucleotide of embodiment 750, wherein said modified oligonucleotide comprises at least one GalNAc.

[0977] Embodiment 761. The modified oligonucleotide of embodiment 750, wherein T is:

[0978] [ka]

[0979] Embodiment 762. The modified oligonucleotide of embodiment 750, wherein T is:

[0980] [ka]

[0981] Embodiment 763. The modified oligonucleotide of embodiment 750, wherein T is:

[0982] [ka]

[0983] Embodiment 764. The modified oligonucleotide of embodiment 750, wherein T is:

[0984] [ka]

[0985] In embodiment 765.T,

[0986] [ka]

[0987] The modified oligonucleotide of embodiment 750, wherein n is 2 to 20.

[0988] Embodiment 766. The modified oligonucleotide of embodiment 765, wherein n is 15.

[0989] 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.

[0990] Embodiment 768. The modified oligonucleotide of embodiment 767, wherein R4 is OCH3.

[0991] Embodiment 769. The modified oligonucleotide of embodiment 767, wherein R4 is OH.

[0992] Embodiment 770. The modified oligonucleotide of embodiment 767, wherein R4 is C1-C6 alkyl.

[0993] Embodiment 771. The modified oligonucleotide of embodiment 767, wherein R4 is a substituted C1-C6 alkyl.

[0994] Embodiment 772.R4 is C1 to C 20 , C1~C6, C2~C 20 , C2 to C6, or C 10 ~C 20 The modified oligonucleotide of embodiment 767, which is alkyl.

[0995] In the embodiment 773.R4, substitutions C1 to C 20 , C1~C6, C2~C 20 , C2 to C6, or C 10 ~C 20 The modified oligonucleotide of embodiment 767, which is alkyl.

[0996] Embodiment 774. The modified oligonucleotide of embodiment 767, wherein R4 comprises a carbohydrate or carbohydrate cluster.

[0997] Embodiment 775. The modified oligonucleotide of embodiment 767, wherein R4 comprises at least one GalNAc.

[0998] Embodiment 776. The modified oligonucleotide according to any of embodiments 767 to 775, wherein R5 is OCH3.

[0999] Embodiment 777. The modified oligonucleotide according to any of embodiments 767 to 775, wherein R5 is OH.

[1000] Embodiment 778. The modified oligonucleotide according to any of embodiments 767 to 775, wherein R5 is C1-C6 alkyl.

[1001] Embodiment 779. The modified oligonucleotide according to any of embodiments 767 to 775, wherein R5 is substituted C1-C6 alkyl.

[1002] Embodiment 780. The modified oligonucleotide of embodiment 767, wherein T is:

[1003] [ka]

[1004] Embodiment 781. The modified oligonucleotide of embodiment 767, wherein T is:

[1005] [ka]

[1006] In embodiment 782.T,

[1007] [ka]

[1008] 768. The modified oligonucleotide of embodiment 767, wherein n is 2 to 20.

[1009] Embodiment 783. The modified oligonucleotide of embodiment 782, wherein n is 15.

[1010] Embodiment 784. The modified oligonucleotide of any of embodiments 705 to 783, wherein at least one internucleoside linkage group of the modified oligonucleotide is not a linkage group of Formula XVII.

[1011] Embodiment 785. The modified oligonucleotide of any of embodiments 705 to 784, wherein exactly one internucleoside linking group of the modified oligonucleotide is an internucleoside linking group of Formula XVII.

[1012] Embodiment 786. The modified oligonucleotide of any of embodiments 705 to 784, wherein exactly two internucleoside linking groups of said modified oligonucleotide are internucleoside linking groups of Formula XVII.

[1013] Embodiment 787. The modified oligonucleotide of any of embodiments 705-784, wherein exactly three internucleoside linking groups of said modified oligonucleotide are internucleoside linking groups of Formula XVII.

[1014] Embodiment 788. The modified oligonucleotide of any of embodiments 705 to 784, wherein exactly four internucleoside linking groups of said modified oligonucleotide are internucleoside linking groups of Formula XVII.

[1015] Embodiment 789. The modified oligonucleotide of any of embodiments 705 to 784, wherein exactly five internucleoside linking groups of said modified oligonucleotide are internucleoside linking groups of Formula XVII.

[1016] 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.

[1017] Embodiment 791. The modified oligonucleotide of any of embodiments 705-783 or 785-787, having at least two linking groups of Formula XVII, wherein at least two of said linking groups of Formula XVII are the same as each other.

[1018] Embodiment 792. The modified oligonucleotide of any of embodiments 705-791, wherein each internucleoside linkage group of the modified oligonucleotide that is not an internucleoside linkage group of Formula XVII is either a phosphodiester internucleoside linkage group or a phosphorothioate internucleoside linkage group.

[1019] 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.

[1020] Embodiment 794. An antisense agent comprising a modified oligonucleotide, wherein at least one region of the modified oligonucleotide has the structure A:

[1021] [ka]

[1022] During the ceremony, each Bx is a heterocyclic base moiety; X is selected from O or S; each of Y1 and Y2 is independently selected from OH or SH; Z 1 , Z 2 , and Z 3 each independently represents -(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), R1 is selected from H, C1-C6 alkyl, and substituted C1-C6 alkyl; T is selected from SO2R2, C(=O)R3, and P(=O)R4R5, wherein: R2 is selected from aryl, substituted aryl, heterocycle, substituted heterocycle, aromatic heterocycle, substituted aromatic heterocycle, diazole, substituted diazole, 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; R3 is selected from aryl, substituted aryl, CH3, N(CH3)2, OCH3, and a conjugate group; R4 is selected from OCH3, OH, C1-C6 alkyl, substituted C1-C6 alkyl, and a conjugate group; R5 is selected from OCH3, OH, C1-C6 alkyl, and substituted C1-C6 alkyl; J R1 and G 1 But, J R1 From G 1 or J R1 is H and G 1 is H, OH, halogen, or O-[C(R6)(R7)] n -[(C=O) m -X G ] j -R8, J R2 and G 2 But, J R2 and G 2 Form a bridge with or J R2 is H and G 2 is H, OH, halogen, or O-[C(R6)(R7)] n -[(C=O) m -X G ] j -R8, J R3 and G 3 But, J R3 and G 3 Form a bridge with or J R3 is H and G 3 is H, OH, halogen, or O-[C(R6)(R7)] n -[(C=O) m -X G] j -R8, In the formula, each J R The bridge of G is -CH(CH3)-O- or -(CH2) k -O-, wherein k is 1 to 3; each R6 and R7 is independently H, halogen, C1-C6 alkyl, or substituted C1-C6 alkyl; each X G is O, S, or N(E1), 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); E1, E2, and E3 are each independently H, C1-C6 alkyl, or substituted C1-C6 alkyl; n is 1 to 6; m is 0 or 1, j is 0 or 1, each substituted group comprises one or more optionally protected substituents 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; each J1, J2, and J3 is independently H or C1-C6 alkyl; The antisense agent.

[1023] Embodiment 795. An antisense agent comprising a modified oligonucleotide, wherein at least one region of the modified oligonucleotide has the structure B:

[1024] [ka]

[1025] During the ceremony, each Bx is a heterocyclic base moiety; X is selected from O or S; each of Y1 and Y2 is independently selected from OH or SH; Z 1 and Z 2 each independently represents -(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), R1 is selected from H, C1-C6 alkyl, and substituted C1-C6 alkyl; T is selected from SO2R2, C(=O)R3, and P(=O)R4R5, wherein: R2 is selected from aryl, substituted aryl, heterocycle, substituted heterocycle, aromatic heterocycle, substituted aromatic heterocycle, diazole, substituted diazole, 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; R3 is selected from aryl, substituted aryl, CH3, N(CH3)2, OCH3, and a conjugate group; R4 is selected from OCH3, OH, C1-C6 alkyl, substituted C1-C6 alkyl, and a conjugate group; R5 is selected from OCH3, OH, C1-C6 alkyl, and substituted C1-C6 alkyl; J R1 and G 1 But, J R1 From G 1 or J R1 is H and G 1 is H, OH, halogen, or O-[C(R6)(R7)] n -[(C=O) m -X G ] j -R8, J R2 and G 2 But, J R2and G 2 Form a bridge with or J R2 is H and G 2 is H, OH, halogen, or O-[C(R6)(R7)] n -[(C=O) m -X G ] j -R8, In the formula, each J R The bridge of G is -CH(CH3)-O- or -(CH2) k -O-, wherein k is 1 to 3; each R6 and R7 is independently H, halogen, C1-C6 alkyl, or substituted C1-C6 alkyl; each X G is O, S, or N(E1), 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); E1, E2, and E3 are each independently H, C1-C6 alkyl, or substituted C1-C6 alkyl; n is 1 to 6; m is 0 or 1, j is 0 or 1, each substituted group comprises one or more optionally protected substituents 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; each J1, J2, and J3 is independently H or C1-C6 alkyl; The antisense agent.

[1026] Embodiment 796. An antisense agent comprising a modified oligonucleotide, wherein at least one region of the modified oligonucleotide has the structure C:

[1027] [ka]

[1028] During the ceremony, each Bx is a heterocyclic base moiety; X is selected from O or S; each of Y1 and Y2 is independently selected from OH or SH; Z 2 and Z 3 each independently represents -(CH2) p -X Z -(CH2) q -, wherein p is 0 or 1, q is 0 or 1, and X Z But O, S, and is N(E1), R1 is selected from H, C1-C6 alkyl, and substituted C1-C6 alkyl; T is selected from SO2R2, C(=O)R3, and P(=O)R4R5, wherein: R2 is selected from aryl, substituted aryl, heterocycle, substituted heterocycle, aromatic heterocycle, substituted aromatic heterocycle, diazole, substituted diazole, 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; R3 is selected from aryl, substituted aryl, CH3, N(CH3)2, OCH3, and a conjugate group; R4 is selected from OCH3, OH, C1-C6 alkyl, substituted C1-C6 alkyl, and a conjugate group; R5 is selected from OCH3, OH, C1-C6 alkyl, and substituted C1-C6 alkyl; J R2 and G 2 But, J R2 and G 2 Form a bridge with or J R2 is H and G 2 is H, OH, halogen, or O-[C(R6)(R7)]n -[(C=O) m -X G ] j -R8, J R3 and G 3 But, J R3 and G 3 Form a bridge with or J R3 is H and G 3 is H, OH, halogen, or O-[C(R6)(R7)] n -[(C=O) m -X G ] j -R8, In the formula, each J R The bridge of G is -CH(CH3)-O- or -(CH2) k -O-, wherein k is 1 to 3; each R6 and R7 is independently H, halogen, C1-C6 alkyl, or substituted C1-C6 alkyl; each X G is O, S, or N(E1), 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); E1, E2, and E3 are each independently H, C1-C6 alkyl, or substituted C1-C6 alkyl; n is 1 to 6; m is 0 or 1, j is 0 or 1, each substituted group comprises one or more optionally protected substituents 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; each J1, J2, and J3 is independently H or C1-C6 alkyl; The antisense agent.

[1029] Embodiment 797. An antisense agent comprising a modified oligonucleotide, wherein at least one region of the modified oligonucleotide has the structure D:

[1030] [ka]

[1031] During the ceremony, each Bx is a heterocyclic base moiety; X is selected from O or S; each of Y1 and Y2 is independently selected from OH or SH; Z 2 and Z 3 each independently represents -(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), R1 is selected from H, C1-C6 alkyl, and substituted C1-C6 alkyl; T is selected from SO2R2, C(=O)R3, and P(=O)R4R5, wherein: R2 is selected from aryl, substituted aryl, heterocycle, substituted heterocycle, aromatic heterocycle, substituted aromatic heterocycle, diazole, substituted diazole, 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; R3 is selected from aryl, substituted aryl, CH3, N(CH3)2, OCH3, and a conjugate group; R4 is selected from OCH3, OH, C1-C6 alkyl, substituted C1-C6 alkyl, and a conjugate group; R5 is selected from OCH3, OH, C1-C6 alkyl, and substituted C1-C6 alkyl; J R1and G 1 But, J R1 From G 1 or J R1 is H and G 1 is H, OH, halogen, or O-[C(R6)(R7)] n -[(C=O) m -X G ] j -R8, J R2 and G 2 But, J R2 and G 2 Form a bridge with or J R2 But H , G 2 is H, OH, halogen, or O-[C(R6)(R7)] n -[(C=O) m -X G ] j -R8, J R3 and G 3 But, J R3 and G 3 Form a bridge with or J R3 is H and G 3 is H, OH, halogen, or O-[C(R6)(R7)] n -[(C=O) m -X G ] j -R8, In the formula, each J R The bridge of G is -CH(CH3)-O- or -(CH2) k -O-, wherein k is 1 to 3; each R6 and R7 is independently H, halogen, C1-C6 alkyl, or substituted C1-C6 alkyl; each X G is O, S, or N(E1), 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); E1, E2, and E3 are each independently H, C1-C6 alkyl, or substituted C1-C6 alkyl; n is 1 to 6; m is 0 or 1, j is 0 or 1, each substituted group comprises one or more optionally protected substituents 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; each J1, J2, and J3 is independently H or C1-C6 alkyl; The antisense agent.

[1032] Embodiment 798. An antisense agent comprising a modified oligonucleotide, wherein at least one region of the modified oligonucleotide has the structure E:

[1033] [ka]

[1034] During the ceremony, each Bx is a heterocyclic base moiety; X is selected from O or S; each of Y1 and Y2 is independently selected from OH or SH; Z 2 and Z 3 each independently represents -(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), R1 is selected from H, C1-C6 alkyl, and substituted C1-C6 alkyl; T is selected from SO2R2, C(=O)R3, and P(=O)R4R5, wherein: R2 is selected from aryl, substituted aryl, heterocycle, substituted heterocycle, aromatic heterocycle, substituted aromatic heterocycle, diazole, substituted diazole, 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; R3 is selected from aryl, substituted aryl, CH3, N(CH3)2, OCH3, and a conjugate group; R4 is selected from OCH3, OH, C1-C6 alkyl, substituted C1-C6 alkyl, and a conjugate group; R5 is selected from OCH3, OH, C1-C6 alkyl, and substituted C1-C6 alkyl; J R1 and G 1 But, J R1 From G 1 or J R1 is H and G 1 is H, OH, halogen, or O-[C(R6)(R7)] n -[(C=O) m -X G ] j -R8, J R2 and G 2 But, J R2 and G 2 Form a bridge with or J R2 is H and G 2 is H, OH, halogen, or O-[C(R6)(R7)] n -[(C=O) m -X G ] j -R8, J R3 and G 3 But, J R3 and G 3Form a bridge with or J R3 is H and G 3 is H, OH, halogen, or O-[C(R6)(R7)] n -[(C=O) m -X G ] j -R8, In the formula, each J R The bridge of G is -CH(CH3)-O- or -(CH2) k -O-, wherein k is 1 to 3; each R6 and R7 is independently H, halogen, C1-C6 alkyl, or substituted C1-C6 alkyl; each X G is O, S, or N(E1), 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); E1, E2, and E3 are each independently H, C1-C6 alkyl, or substituted C1-C6 alkyl; n is 1 to 6; m is 0 or 1, j is 0 or 1, each substituted group comprises one or more optionally protected substituents 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; each J1, J2, and J3 is independently H or C1-C6 alkyl; The antisense agent.

[1035] Embodiment 799. The modified oligonucleotide of any of embodiments 794 to 798, wherein each Z is O.

[1036] Embodiment 800. The modified oligonucleotide of any of embodiments 794 to 799, wherein at least one G is selected from H, OH, halogen, C1-C6 alkoxy, —O(CH2)2OCH3, or —OCH2(C═O)NHCH3.

[1037] 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.

[1038] Embodiment 802. At least one J R forms a bridge with at least one G, and the J R The bridge of G is -CH(CH3)-O- or -(CH2) k The modified oligonucleotide of any of embodiments 794 to 801, having a formula selected from: —O′, wherein k is 1 to 3.

[1039] Embodiment 803. Each J R and G form a bridge, and the J R The bridge of G is -CH(CH3)-O- or -(CH2) k The modified oligonucleotide of any of embodiments 794 to 802, having a formula selected from: -O-, wherein k is 1 to 3.

[1040] Embodiment 804. At least one Z is O and the corresponding J R Therefore, the bridge of G is a compound of the formula (CH2) k The modified oligonucleotide of any of embodiments 802 or 803, having -O-, wherein k is 1.

[1041] Embodiment 805. Each nucleoside of structure A, B, C, D, or E is a stereostandard nucleoside. The modified oligonucleotide of any of embodiments 794 to 804, which is a thiol.

[1042] Embodiment 806. The modified oligonucleotide of any of embodiments 794 to 804, wherein at least one nucleoside of structure A, B, C, D, or E is a stereo-nonstandard nucleoside.

[1043] Embodiment 807.J R The modified oligonucleotide of any of embodiments 802 to 804 or 806, wherein at least one nucleoside having a bridge from G to G is in the α-L-ribosyl configuration.

[1044] Embodiment 808. The modified oligonucleotide of any of embodiments 794 to 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 the structure A, B, C, D, or E.

[1045] Embodiment 809. The modified oligonucleotide of any of embodiments 794 to 807, wherein at least one region having structure A, B, C, D, or E is at the 5' end of the modified oligonucleotide.

[1046] Embodiment 810. The modified oligonucleotide of any of embodiments 794 to 807, wherein at least one region having structure A, B, C, D, or E is at the 3' end of the modified oligonucleotide.

[1047] Embodiment 811. The modified oligonucleotide of any of embodiments 794 to 807, wherein at least one region having structure A, B, C, D, or E is internal to the modified oligonucleotide.

[1048] Embodiment 812. An antisense agent comprising a modified oligonucleotide consisting of 10 to 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, each L is an internucleoside linking group, and each of L and L is a phosphodiester internucleoside linking group, a phosphorothioate internucleoside linking group, or an internucleoside linking group of formula XVII;

[1049] [ka]

[1050] 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 is an internucleoside linking group of Formula XVII, and at least one of L1, L2, and L3 is a phosphorothioate or phosphodiester internucleoside linking group; wherein, independently for each internucleoside linking group of said modified oligonucleotide having Formula XVII: X is selected from O or S; R1 is selected from H, C1-C6 alkyl, and substituted C1-C6 alkyl; T is selected from SO2R2, C(=O)R3, and P(=O)R4R5, wherein: R2 is selected from aryl, substituted aryl, heterocycle, substituted heterocycle, aromatic heterocycle, substituted aromatic heterocycle, diazole, substituted diazole, 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; R3 is selected from aryl, substituted aryl, CH3, N(CH3)2, OCH3, and a conjugate; R4 is selected from OCH3, OH, C1-C6 alkyl, substituted C1-C6 alkyl, and conjugates; R5 is selected from OCH3, OH, C1-C6 alkyl, and substituted C1-C6 alkyl; The antisense agent.

[1051] Embodiment 813. The modified oligonucleotide has the formula (N g1 ) L1 (N g2 ) L2 (N g3 ) L3 813. The modified oligonucleotide of embodiment 812, comprising 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 following structure:

[1052] Embodiment 814. The compound of the formula (N g1 ) L1 (N g2 ) L2 (N g3 ) L3 The modified oligonucleotide of embodiment 812 or 813, wherein at least one region having

[1053] Embodiment 815. The compound of the formula (N g1 ) L1 (N g2 ) L2 (N g3 ) L3 The modified oligonucleotide of embodiment 812 or 813, wherein at least one region having

[1054] Embodiment 816. The compound of formula (N g1 ) L1 (N g2 ) L2 (N g3 ) L3 The modified oligonucleotide of embodiment 812 or 813, wherein at least one region having

[1055] Embodiment 817. The modified oligonucleotide of any of embodiments 705 to 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.

[1056] Embodiment 818. The modified oligonucleotide of any of embodiments 705 to 817, wherein at least one nucleoside of the modified oligonucleotide is selected from β-D-LNA nucleosides, α-L-LNA nucleosides, ENA nucleosides, cEt nucleosides, 2'-MOE nucleosides, 2'-OMe nucleosides, 2'-F nucleosides, 2'-NMA nucleosides, 5'-Me nucleosides, DNA nucleosides, and RNA nucleosides.

[1057] Embodiment 819. The modified oligonucleotide of any of embodiments 705 to 818, wherein each nucleoside of the modified oligonucleotide is selected from β-D-LNA nucleosides, α-L-LNA nucleosides, ENA nucleosides, cEt nucleosides, 2'-MOE nucleosides, 2'-OMe nucleosides, 2'-F nucleosides, 2'-NMA nucleosides, 5'-Me nucleosides, DNA nucleosides, and RNA nucleosides. Chid.

[1058] Embodiment 820. The modified oligonucleotide of any of embodiments 705 to 819, wherein at least one nucleoside of the modified oligonucleotide is a stereo-nonstandard nucleoside.

[1059] Embodiment 821. The modified oligonucleotide of embodiment 820, wherein the internucleoside linking group connecting at least one stereononstandard nucleoside to an adjacent nucleoside is an internucleoside linking group of Formula XVII.

[1060] Embodiment 822. The modified oligonucleotide of embodiment 820 or 821, wherein at least two nucleosides of the modified oligonucleotide are stereo-nonstandard nucleosides.

[1061] Embodiment 823. The modified oligonucleotide of embodiment 822, wherein at least two stereononstandard nucleosides of the modified oligonucleotide are adjacent to each other.

[1062] Embodiment 824. The modified oligonucleotide of embodiment 823, wherein at least two stereononstandard nucleosides of the modified oligonucleotide are linked to each other by an internucleoside linking group of Formula XVII.

[1063] Embodiment 825. The modified oligonucleotide of any of embodiments 820 to 824, wherein at least one stereononstandard nucleoside of the modified oligonucleotide is a stereononstandard DNA nucleoside.

[1064] Embodiment 826. The modified oligonucleotide of embodiment 825, wherein the stereo-nonstandard DNA nucleoside is selected from stereo-nonstandard DNA nucleosides having Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, and Formula VII.

[1065] Embodiment 827. The modified oligonucleotide of embodiment 826, wherein the stereo-nonstandard DNA nucleoside is selected from stereo-nonstandard DNA nucleosides having formula V and formula II:

[1066] Embodiment 828. The modified oligonucleotide of any of embodiments 820 to 827, wherein at least one stereotypical nucleoside of the modified oligonucleotide is a substituted stereotypical nucleoside or a stereotypical RNA nucleoside.

[1067] Embodiment 829. The modified oligonucleotide of embodiment 828, wherein the 2' substituent of the at least one substituted stereononstandard nucleoside of the modified oligonucleotide is selected from 2'-MOE, 2'-OMe, 2'-F, or 2'-OH.

[1068] Embodiment 830. The modified oligonucleotide of any of embodiments 705 to 819, wherein each nucleoside is a stereostandard nucleoside.

[1069] Embodiment 831. The modified oligonucleotide of any of embodiments 705 to 829, wherein the modified oligonucleotide consists of 12 to 30 linked nucleosides.

[1070] Embodiment 832. The modified oligonucleotide of any of embodiments 705 to 829, wherein the modified oligonucleotide consists of 16 to 24 linked nucleosides.

[1071] Embodiment 833. The modified oligonucleotide of any of embodiments 705 to 829, wherein the modified oligonucleotide consists of 18 to 22 linked nucleosides.

[1072] Embodiment 834. The modified oligonucleotide of any of embodiments 705 to 832, wherein the modified oligonucleotide consists of 16 linked nucleosides.

[1073] Embodiment 835. The modified oligonucleotide of any of embodiments 705 to 832, wherein the modified oligonucleotide consists of 17 linked nucleosides.

[1074] Embodiment 836. The modified oligonucleotide of any of embodiments 705 to 833, wherein the modified oligonucleotide consists of 18 linked nucleosides.

[1075] Embodiment 837. The modified oligonucleotide of any of embodiments 705 to 833, wherein the modified oligonucleotide consists of 19 linked nucleosides.

[1076] Embodiment 838. The modified oligonucleotide of any of embodiments 705 to 833, wherein the modified oligonucleotide consists of 20 linked nucleosides.

[1077] Embodiment 839. The modified oligonucleotide of any of embodiments 705 to 833, wherein the modified oligonucleotide consists of 21 linked nucleosides.

[1078] Embodiment 840. The modified oligonucleotide of any of embodiments 705 to 833, wherein the modified oligonucleotide consists of 22 linked nucleosides.

[1079] Embodiment 841. The modified oligonucleotide of any of embodiments 705 to 832, wherein the modified oligonucleotide consists of 23 linked nucleosides.

[1080] Embodiment 842. The modified oligonucleotide of any of embodiments 705 to 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.

[1081] Embodiment 843. The modified oligonucleotide of any of embodiments 705 to 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.

[1082] 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.

[1083] Embodiment 845. The modified oligonucleotide of any of embodiments 705 to 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.

[1084] Embodiment 846. The modified oligonucleotide of embodiment 845, wherein each nucleoside of the modified oligonucleotide is selected from 2'-OMe nucleosides, 2'-F nucleosides, and nucleosides containing sugar surrogates.

[1085] Embodiment 847. The nucleoside containing a sugar substitute is

[1086] [ka]

[1087] The modified oligonucleotide of any of embodiments 845-846, wherein Bx is selected from the group consisting of:

[1088] Embodiment 848. The modified oligonucleotide of embodiment 847, wherein the nucleoside comprising a sugar surrogate is GNA.

[1089] Embodiment 849. The modified oligonucleotide of any of embodiments 842 to 848, wherein the modified oligonucleotide has a region of alternating nucleoside types having the motif ABABA, where each A is a stereostandard nucleoside of a first type and each B is a stereostandard nucleoside of a second type, and the first type and the second type are different from each other.

[1090] Embodiment 850. The modified oligonucleotide of embodiment 849, wherein A and B are selected from 2'-F substituted nucleosides, 2'-OMe substituted nucleosides, and stereostandard RNA nucleosides.

[1091] Embodiment 851. The modified oligonucleotide of any of embodiments 705 to 850, wherein the 5' end of the modified oligonucleotide comprises a terminal group.

[1092] Embodiment 852. The modified oligonucleotide of embodiment 851, wherein the terminal group is a stabilizing phosphate group.

[1093] Embodiment 853. The modified oligonucleotide of embodiment 852, wherein the stabilizing phosphate group is 5'-vinylphosphonate or 5'-cyclopropylphosphonate.

[1094] Embodiment 854. The terminal group is:

[1095] [ka]

[1096] is selected from In the formula, R A is OH, OP(=O)OH, OP(=O)SH, or a stabilized phosphate group; G A is H, OH, OMe, MOE, or a halogen; X is OH, SH, or NSO2R2; R2 is selected from aryl, substituted aryl, heterocycle, substituted heterocycle, aromatic heterocycle, substituted aromatic heterocycle, diazole, substituted diazole, 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; The modified oligonucleotide described in embodiment 851.

[1097] Embodiment 855.G A The modified oligonucleotide of embodiment 854, wherein X is selected from H or OH, and X is SH.

[1098] Embodiment 856. The antisense agent of any of embodiments 705 to 855, wherein the antisense agent is an RNAi agent.

[1099] Embodiment 857. The RNAi agent of embodiment 856, wherein the RNAi agent is a single-stranded RNAi agent comprising an RNAi antisense modified oligonucleotide, and the RNAi antisense modified oligonucleotide is a modified oligonucleotide described in any of embodiments 705 to 855.

[1100] 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, and the RNAi antisense modified oligonucleotide and / or the RNAi sense modified oligonucleotide is a modified oligonucleotide described in any of embodiments 705 to 855.

[1101] Embodiment 859. The RNAi agent of embodiment 857 or 858, wherein at least one internucleoside linkage group of the RNAi antisense modified oligonucleotide is an internucleoside linkage group of Formula XVII.

[1102] Embodiment 860. The RNAi agent of embodiment 857 or 858, wherein at least two internucleoside linkage groups of said RNAi antisense modified oligonucleotide are independently selected internucleoside linkage groups of Formula XVII.

[1103] Embodiment 861. The 3'-most 5'-terminal end of the RNAi antisense modified oligonucleotide The RNAi agent of any of embodiments 857-860, wherein at least one of the internucleoside linking groups is an internucleoside linking group of Formula XVII.

[1104] Embodiment 862. The RNAi agent of any of embodiments 857-861, wherein at least two of the five 3'-most internucleoside linkage groups of the RNAi antisense modified oligonucleotide are internucleoside linkage groups of Formula XVII.

[1105] Embodiment 863. The RNAi agent of any of embodiments 857-862, wherein one to three of the three 3'-most internucleoside linkage groups are internucleoside linkage groups of Formula XVII, and each of those three internucleoside linkage groups that is not an internucleoside linkage group of Formula XVII is a phosphodiester or phosphorothioate internucleoside linkage group.

[1106] Embodiment 864. The RNAi agent of embodiment 863, wherein the two 3'-most internucleoside linking groups are internucleoside linking groups of formula XVII.

[1107] Embodiment 865. The RNAi agent of any of embodiments 857 to 864, wherein exactly one of the 5'-most and the 5'-most penultimate internucleoside linking groups is an internucleoside linking group of Formula XVII.

[1108] Embodiment 866. The RNAi agent of any of embodiments 857 to 865, wherein exactly one of the 5'-most and 5'-most penultimate internucleoside linkages of said RNAi antisense oligonucleotide is an internucleoside linkage group of Formula XVII, and the other of the 5'-most and 5'-most penultimate internucleoside linkage groups of said RNAi antisense oligonucleotide is selected from phosphodiester and phosphorothioate internucleoside linkages, and the two 3'-most internucleoside linkages of said RNAi antisense oligonucleotide are internucleoside linkage groups of Formula XVII, and the remaining internucleoside linkages of said RNAi antisense oligonucleotide are phosphodiester internucleoside linkages.

[1109] Embodiment 867. The RNAi agent of any of embodiments 857 to 866, wherein the antisense modified oligonucleotide comprises a 3' overhang.

[1110] Embodiment 868. The RNAi agent of embodiment 867, wherein the 3' overhang consists of two nucleosides.

[1111] Embodiment 869. The RNAi agent of any of embodiments 857-865 or 867-868, wherein at least one internucleoside linkage group in the seed region of the RNAi antisense modified oligonucleotide is an internucleoside linkage group of Formula XVII.

[1112] 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.

[1113] Embodiment 871. The RNAi antisense modified oligonucleotide consists of 23 linked nucleosides and the internucleoside linkage motifs are: ooooooooooooooooooooaa, aaoooooooooooooooooooo, aaooooooooooooooooooaa, asooooooooooooooooooss, saoooooooooooooooooo, oooooooooooooooooaaa, ​​ooooooooooooooooaaaoss, oooooooooooooaaaooooss, ooooooooooaaaoooooooss, oooooooooooaaaoooooooss, ooooooo The RNAi agent of any of embodiments 857-870, wherein the RNAi agent is selected from aaaooooooooooss, ooooaaaoooooooooooooss, saoooaoooooooaooooss, ssoooaoooooooaooooooss, 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.

[1114] Embodiment 872. The RNAi agent of embodiment 871, wherein the internucleoside linkage motif of the RNAi antisense modified oligonucleotide is selected from ooooooooooooooooooooaa, asooooooooooooooooooooss, or saoooooooooooooooooooo.

[1115] 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 yfyyyfyyyyyyyfyfyyyyyy, wherein "y" represents a 2'-OMe sugar moiety and "f" represents a 2'-F sugar moiety.

[1116] Embodiment 874. The RNAi antisense modified oligonucleotide consists of 21 linked nucleosides and the internucleoside linkage motifs are aaososososossssss, ssaaosososososssssss, ssosaaosososossssss, ssososaaososossssss, ssosososaaosossssss, ssosososaaosossssss, ssosososaaosossssss, ssososososaaossssss, ssososososaaossssss, ssos The RNAi agent of any of embodiments 857-870, wherein the internucleoside linkage is selected from: ososososaassssss, 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.

[1117] Embodiment 875. The RNAi agent of embodiment 874, wherein the internucleoside linkage motif of the RNAi antisense modified oligonucleotide is selected from aaososososossssss, ssaaososososossssss, ssososaaososossssss, ssosososaaosossssss, ssososososossssaass, or ssosososososssssaa, 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.

[1118] 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.

[1119] Embodiment 877. An RNAi agent according to any of embodiments 873 to 876, wherein each "a" is a mesyl phosphoramidate linkage.

[1120] Embodiment 878. An RNAi agent described in any of embodiments 857 to 878, wherein at least one region of the RNAi antisense modified oligonucleotide has the structure A, B, C, D, or E.

[1121] Embodiment 879. At least one region having structure A, B, C, D, or E is The RNAi agent of embodiment 878, which is within the seed region of the RNAi antisense modified oligonucleotide.

[1122] Embodiment 880. The RNAi agent of embodiment 878, wherein at least one region having the structure A, B, C, D, or E is at the 3' end of the RNAi antisense modified oligonucleotide.

[1123] Embodiment 881. 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, each L is an internucleoside linking group, and each of L and L is a phosphodiester internucleoside linking group, a phosphorothioate internucleoside linking group, or an internucleoside linking group of formula XVII;

[1124] [ka]

[1125] 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 is an internucleoside linking group of Formula XVII, and at least one of L1, L2, and L3 is a phosphorothioate or phosphodiester internucleoside linking group; wherein, independently for each internucleoside linking group of said modified oligonucleotide having Formula XVII: X is selected from O or S; R1 is selected from H, C1-C6 alkyl, and substituted C1-C6 alkyl; T is selected from SO2R2, C(=O)R3, and P(=O)R4R5, wherein: R2 is selected from aryl, substituted aryl, heterocycle, substituted heterocycle, aromatic heterocycle, substituted aromatic heterocycle, diazole, substituted diazole, C1-C6 alkoxy, C1-C6 alkyl, substituted C1-C6 alkyl, and conjugates; R3 is selected from aryl, substituted aryl, CH3, N(CH3)2, OCH3, and a conjugate; R4 is selected from OCH3, OH, C1-C6 alkyl, substituted C1-C6 alkyl, and conjugates; R5 is selected from OCH3, OH, C1-C6 alkyl, and substituted C1-C6 alkyl; An RNAi agent described in any of embodiments 857 to 880.

[1126] Embodiment 882. The compound of the formula (N g1 ) L1 (N g2 ) L2 (N g3 ) L3 882. The RNAi agent of embodiment 881, wherein the region having the formula:

[1127] Embodiment 883. The compound of the formula (N g1 ) L1 (N g2 ) L2 (N g3 ) L3 Having less The RNAi agent of embodiment 881, wherein both regions are at the 3' end of the RNAi antisense modified oligonucleotide.

[1128] Embodiment 884. An RNAi agent according to embodiment 883, wherein L1 and L2 are internucleoside linkages of formula XVII, wherein R1 is H, T is SO2Me, and L3 is a phosphodiester internucleoside linkage.

[1129] Embodiment 885. The compound of formula (N g1 ) L1 (N g2 ) L2 (N g3 ) L3 The RNAi agent of embodiment 881, wherein at least one region having the following is at the 5' end of the RNAi antisense modified oligonucleotide.

[1130] Embodiment 886. An RNAi agent according to embodiment 885, wherein one of L1 or L2 is an internucleoside linkage 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.

[1131] Embodiment 887. The compound of the formula (N g1 ) L1 (N g2 ) L2 (N g3 ) L3 882. The RNAi agent of embodiment 881, wherein at least one region having the following structure is within the seed region of the RNAi antisense modified oligonucleotide:

[1132] Embodiment 888. The RNAi agent of any of embodiments 857 to 887, wherein the region of the RNAi antisense oligonucleotide that is complementary to the target is at least 15 nucleobases.

[1133] Embodiment 889. The RNAi agent of any of embodiments 857 to 888, wherein the region of the RNAi antisense oligonucleotide that is complementary to the target is at least 17 nucleobases.

[1134] Embodiment 890. The RNAi agent of any of embodiments 857 to 889, wherein said region of said RNAi antisense oligonucleotide that is complementary to a target is at least 19 nucleobases.

[1135] Embodiment 891. The RNAi agent of any of embodiments 857 to 890, wherein the region of the RNAi antisense oligonucleotide that is complementary to the target is at least 21 nucleobases.

[1136] Embodiment 892. An RNAi agent described in any of embodiments 857 to 890, wherein the region of the RNAi antisense oligonucleotide that is complementary to the target is exactly 19 nucleobases.

[1137] Embodiment 893. An RNAi agent described in any of embodiments 857 to 891, wherein the region of the RNAi antisense oligonucleotide that is complementary to the target is exactly 21 nucleobases.

[1138] Embodiment 894. An RNAi agent described in any of embodiments 857 to 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.

[1139] Embodiment 895. 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'-OMe nucleoside. The RNAi agent of any of embodiments 857-894, wherein the nucleoside is an RNA nucleoside.

[1140] Embodiment 896. An RNAi agent described in any of embodiments 857 to 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.

[1141] 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.

[1142] Embodiment 898. The RNAi agent of any of embodiments 887 to 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, and at least one nucleoside of the modified oligonucleotide comprises a sugar surrogate.

[1143] Embodiment 899. The RNAi agent of embodiment 898, wherein each nucleoside of the RNAi antisense modified oligonucleotide is selected from 2'-OMe nucleosides, 2'-F nucleosides, and nucleosides containing sugar surrogates.

[1144] Embodiment 900. The nucleoside comprising a sugar substitute is:

[1145] [ka]

[1146] 899. The RNAi agent of any of embodiments 898-899, wherein Bx is selected from the group consisting of:

[1147] Embodiment 901. The RNAi agent of embodiment 900, wherein the nucleoside comprising a sugar surrogate is GNA.

[1148] 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 said RNAi antisense modified oligonucleotide.

[1149] Embodiment 903. The modified oligonucleotide has an alternating nucleotide sequence having the motif ABABA. 903. The RNAi agent of any of embodiments 857-902, having a region of nucleoside types, wherein each A is a stereostandard nucleoside of a first type and each B is a stereostandard nucleoside of a second type, and wherein said first type and said second type are different from each other.

[1150] Embodiment 904. The RNAi agent of embodiment 903, wherein A and B are selected from 2'-F substituted nucleosides, 2'-OMe substituted nucleosides, and stereostandard RNA nucleosides.

[1151] Embodiment 905. The RNAi agent of any of embodiments 857 to 904, wherein the 5' end of the RNAi antisense modified oligonucleotide comprises a terminal group.

[1152] Embodiment 906. The RNAi agent of embodiment 905, wherein the terminal group is a stabilizing phosphate group.

[1153] Embodiment 907. The RNAi agent of embodiment 906, wherein the stabilizing phosphate group is 5'-vinylphosphonate or 5'-cyclopropylphosphonate.

[1154] Embodiment 908. The terminal group is:

[1155] [ka]

[1156] is selected from In the formula, R A is OH, OP(=O)OH, OP(=O)SH, or a stabilized phosphate group; G A is H, OH, OMe, MOE, or a halogen; X is OH, SH, or NSO2R2; R2 is selected from aryl, substituted aryl, heterocycle, substituted heterocycle, aromatic heterocycle, substituted aromatic heterocycle, diazole, substituted diazole, 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; The RNAi agent described in embodiment 905.

[1157] Embodiment 909.G A 909. The RNAi agent of embodiment 908, wherein X is selected from H or OH, and X is SH.

[1158] Embodiment 910. The RNAi agent of any of embodiments 858-909, wherein at least one internucleoside linkage group of said RNAi sense modified oligonucleotide is an internucleoside linkage group of Formula XVII:

[1159] Embodiment 911. The RNAi agent of embodiment 910, wherein at least one of the five 5'-most internucleoside linkage groups of said RNAi sense modified oligonucleotide is an internucleoside linkage group of Formula XVII.

[1160] Embodiment 912. The RNAi agent of embodiment 910, wherein at least two of the five 5'-most internucleoside linkage groups of said RNAi sense modified oligonucleotide are internucleoside linkage groups of Formula XVII.

[1161] Embodiment 913 The RNAi agent of embodiment 910, wherein the two 5'-most internucleoside linkage groups of said RNAi sense modified oligonucleotide are internucleoside linkage groups of Formula XVII.

[1162] Embodiment 914. The RNAi agent of any of embodiments 910-913, wherein at least one of the five 3'-most internucleoside linkage groups of said RNAi sense modified oligonucleotide is an internucleoside linkage group of Formula XVII.

[1163] Embodiment 915. The RNAi agent of any of embodiments 910-913, wherein at least two of the five 3'-most internucleoside linkage groups of the RNAi sense modified oligonucleotide are internucleoside linkage groups of Formula XVII.

[1164] 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.

[1165] Embodiment 917. The RNAi agent of embodiment 910, wherein the two 3'-most and two 5'-most internucleoside linkages of said RNAi sense oligonucleotide are internucleoside linkages of Formula XVII, and the remaining internucleoside linkages of said RNAi sense oligonucleotide are phosphodiester internucleoside linkages.

[1166] 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.

[1167] Embodiment 919. The RNAi agent of any of embodiments 910 to 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.

[1168] 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.

[1169] Embodiment 921. The sugar motif of the RNAi sense modified oligonucleotide is selected from yyyyyyfyfffyyyyyyyyy or fyfyfyfyfyfyfyfyfyfyfyf, wherein "y" represents a 2'-OMe sugar moiety and "f" represents a 2'-F sugar moiety. The RNAi agent of embodiment 919 or 920, which represents a moiety.

[1170] Embodiment 922. The RNAi agent of embodiment 921, wherein the RNAi sense modified oligonucleotide has an internucleoside linkage motif of aaooooooooooooooooaa, where each "a" represents an internucleoside linkage of formula XVII, where each "s" represents a phosphorothioate internucleoside linkage, and where each "o" represents a phosphodiester internucleoside linkage, and a sugar motif of yyyyyyfyfffyyyyyyyyy, where "y" represents a 2'-OMe sugar moiety and "f" represents a 2'-F sugar moiety.

[1171] Embodiment 923. An RNAi agent according to any of embodiments 919 to 922, wherein each "a" is a mesyl phosphoramidate linkage.

[1172] Embodiment 924. An RNAi agent described in any of embodiments 910 to 923, wherein at least one region of the RNAi sense modified oligonucleotide has the structure A, B, C, D, or E.

[1173] Embodiment 925. The RNAi agent of embodiment 924, wherein at least one region having the structure A, B, C, D, or E is at the 3' end of the RNAi sense-modified oligonucleotide.

[1174] Embodiment 926. The RNAi agent of embodiment 924, wherein at least one region having the structure A, B, C, D, or E is at the 5' end of the RNAi sense-modified oligonucleotide.

[1175] Embodiment 927. 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 gis a nucleoside, each L is an internucleoside linking group, and each of L and L is a phosphodiester internucleoside linking group, a phosphorothioate internucleoside linking group, or an internucleoside linking group of formula XVII;

[1176] [ka]

[1177] 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 is an internucleoside linking group of Formula XVII, and at least one of L1, L2, and L3 is a phosphorothioate or phosphodiester internucleoside linking group; wherein, independently for each internucleoside linking group of said modified oligonucleotide having Formula XVII: X is selected from O or S; R1 is selected from H, C1-C6 alkyl, and substituted C1-C6 alkyl; T is selected from SO2R2, C(=O)R3, and P(=O)R4R5, wherein: R2 is selected from aryl, substituted aryl, heterocycle, substituted heterocycle, aromatic heterocycle, substituted aromatic heterocycle, diazole, substituted diazole, 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; R3 is selected from aryl, substituted aryl, CH3, N(CH3)2, OCH3, and a conjugate; R4 is selected from OCH3, OH, C1-C6 alkyl, substituted C1-C6 alkyl, and conjugates; R5 is selected from OCH3, OH, C1-C6 alkyl, and substituted C1-C6 alkyl; An RNAi agent described in any of embodiments 910 to 926.

[1178] Embodiment 928. The formula (N g1 ) L1 (N g2 ) L2 (N g3 ) L3 928. The RNAi agent of embodiment 927, wherein at least one region having the following is at the 3' end of the RNAi sense modified oligonucleotide.

[1179] Embodiment 929. The RNAi agent of embodiment 928, wherein L1 and L2 are internucleoside linking groups of formula XVII, R1 is H, T is SO2Me, and L3 is a phosphodiester internucleoside linkage.

[1180] Embodiment 930. The compound of the formula (N g1 ) L1 (N g2 ) L2 (N g3 ) L3 928. The RNAi agent of embodiment 927, wherein at least one region having the following is at the 5' end of the RNAi sense modified oligonucleotide.

[1181] Embodiment 931. The RNAi agent of embodiment 930, wherein L1 is a phosphodiester internucleoside linking group, L2 and L3 are each an internucleoside linking group of formula XVII, R1 is H, and T is SO2Me.

[1182] Embodiment 932. The RNAi agent of any of embodiments 858 to 931, wherein the RNAi sense modified oligonucleotide comprises a 3' end group and / or a 5' end group.

[1183] Embodiment 933. The RNAi agent of any of embodiments 858 to 932, wherein the RNAi sense strand comprises a conjugate group.

[1184] Embodiment 934. The RNAi agent of embodiment 933, wherein the conjugate group comprises a cell targeting moiety.

[1185] Embodiment 935. The RNAi agent of embodiment 933, wherein the conjugate group comprises a carbohydrate or carbohydrate cluster.

[1186] Embodiment 936. The RNAi agent of embodiment 933, wherein the conjugate group comprises at least one GalNAc.

[1187] Embodiment 937. The conjugate group is C 10 ~C 20 The RNAi agent of embodiment 933, comprising an alkyl chain.

[1188] Embodiment 938. The conjugate group is C 16 The RNAi agent of embodiment 933, comprising an alkyl.

[1189] Embodiment 939. The RNAi agent of any of embodiments 858 to 938, wherein the double-stranded region of the oligonucleotide duplex is at least 15 nucleosides.

[1190] Embodiment 940. The RNAi agent of any of embodiments 858 to 938, wherein the double-stranded region of the oligonucleotide duplex is at least 17 nucleosides.

[1191] Embodiment 941. The RNAi agent of any of embodiments 858 to 938, wherein the double-stranded region of the oligonucleotide duplex is at least 19 nucleosides.

[1192] Embodiment 942. The RNAi agent of any of embodiments 858 to 938, wherein the double-stranded region of the oligonucleotide duplex is exactly 19 nucleosides.

[1193] 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.

[1194] 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.

[1195] Embodiment 945. The modified oligonucleotide of embodiment 943 or 944, wherein each modified sugar moiety contains the same modification.

[1196] Embodiment 946. The modified oligonucleotide of any of embodiments 943 to 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.

[1197] 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.

[1198] 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.

[1199] 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.

[1200] 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.

[1201] Embodiment 951. The modified oligonucleotide of any of embodiments 947-950, wherein each bicyclic sugar moiety is selected from among cEt, LNA, and ENA.

[1202] Embodiment 952. The modified oligonucleotide of embodiment 951, wherein the bicyclic sugar moiety is cEt.

[1203] Embodiment 953. The modified oligonucleotide of any of embodiments 947 to 952, wherein the 2'-substituted furanosyl sugar moiety is selected from 2'-OMe, 2'-MOE, and 2'-F. Reotide.

[1204] Embodiment 954. The modified oligonucleotide of any of embodiments 943-953, wherein at least one of the 10 5'-most linkage groups of said modified oligonucleotide is an internucleoside linkage group of Formula XVII.

[1205] Embodiment 955. The modified oligonucleotide of embodiment 954, wherein at least two of the ten 5'-most linkage groups of said modified oligonucleotide are internucleoside linkage groups of Formula XVII.

[1206] Embodiment 956. The modified oligonucleotide of embodiment 954, wherein at least three of the ten 5'-most linkage groups of said modified oligonucleotide are internucleoside linkage groups of Formula XVII.

[1207] Embodiment 957. The modified oligonucleotide of embodiment 954, wherein at least four of the ten 5'-most linkage groups of said modified oligonucleotide are internucleoside linkage groups of Formula XVII.

[1208] Embodiment 958. The modified oligonucleotide of embodiment 954, wherein at least 5 of the 10 5'-most linkage groups of said modified oligonucleotide are internucleoside linkage groups of Formula XVII.

[1209] Embodiment 959. The modified oligonucleotide of embodiment 954, wherein at least 6 of the 10 5'-most linkage groups of said modified oligonucleotide are internucleoside linkage groups of Formula XVII.

[1210] Embodiment 960. The modified oligonucleotide of embodiment 954, wherein the two 5'-most internucleoside linking groups are internucleoside linking groups of Formula XVII.

[1211] Embodiment 961. The modified oligonucleotide of any of embodiments 943-960, wherein at least one of the 10 3'-most internucleoside linkage groups of said modified oligonucleotide is an internucleoside linkage group of Formula XVII.

[1212] Embodiment 962. The modified oligonucleotide of embodiment 961, wherein at least two of the 10 3'-most internucleoside linkage groups of said modified oligonucleotide are internucleoside linkage groups of Formula XVII.

[1213] Embodiment 963. The modified oligonucleotide of embodiment 961, wherein at least three of the ten 3'-most internucleoside linkage groups are internucleoside linkage groups of Formula XVII.

[1214] Embodiment 964. The modified oligonucleotide of embodiment 961, wherein at least four of the ten 3'-most internucleoside linkage groups are internucleoside linkage groups of Formula XVII.

[1215] Embodiment 965. The modified oligonucleotide of embodiment 961, wherein at least five of the ten 3'-most internucleoside linkage groups are internucleoside linkages 961 of Formula XVII.

[1216] Embodiment 966. At least 6 of the 10 3'-most internucleoside linking groups The modified oligonucleotide of embodiment 961, wherein

[1217] Embodiment 967. The modified oligonucleotide of embodiment 961, wherein the two 3'-most internucleoside linking groups of said modified oligonucleotide are internucleoside linking groups of Formula XVII.

[1218] Embodiment 968. The modified oligonucleotide of any of embodiments 943 to 953, wherein the modified oligonucleotide comprises at least one block of at least three consecutive internucleoside linking groups of Formula XVII.

[1219] Embodiment 969. The modified oligonucleotide of any of embodiments 943-953, wherein the modified oligonucleotide comprises at least one block of at least four consecutive internucleoside linking groups of Formula XVII.

[1220] Embodiment 970. The modified oligonucleotide of any of embodiments 943-953, wherein the modified oligonucleotide comprises at least one block of at least five consecutive internucleoside linking groups of Formula XVII.

[1221] Embodiment 971. The modified oligonucleotide of any of embodiments 943-953, wherein the modified oligonucleotide comprises at least one block of at least six contiguous internucleoside linking groups of Formula XVII.

[1222] Embodiment 972. The modified oligonucleotide of any of embodiments 968-971, wherein at least one block of contiguous internucleoside linking groups of Formula XVII is at the 5' end of the modified oligonucleotide.

[1223] Embodiment 973. The modified oligonucleotide of any of embodiments 968-971, wherein at least one block of contiguous internucleoside linking groups of Formula XVII is at the 3' end of the modified oligonucleotide.

[1224] 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.

[1225] Embodiment 975. The modified oligonucleotide of any of embodiments 943 to 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.

[1226] Embodiment 976. The modified oligonucleotide of embodiment 975, wherein each "a" represents a mesyl phosphoramidate internucleoside linkage.

[1227] Embodiment 977. The modified oligonucleotide of any of embodiments 705 to 841, wherein the modified oligonucleotide comprises a deoxy region consisting of 6 to 11 linked nucleosides, each nucleoside in the deoxy region being either a modified nucleoside or a stereostandard DNA nucleoside, at least three consecutive nucleosides in the deoxy region being stereostandard DNA nucleosides, and no more than three nucleosides in the deoxy region being modified nucleosides.

[1228] Embodiment 978. The modified oligonucleotide of embodiment 977, wherein at least five consecutive nucleosides of the deoxy region are stereostandard DNA nucleosides.

[1229] Embodiment 979. The modified oligonucleotide of embodiment 977, wherein at least 6 consecutive nucleosides of the deoxy region are stereostandard DNA nucleosides.

[1230] Embodiment 980. The modified oligonucleotide of embodiment 977, wherein at least 7 consecutive nucleosides of the deoxy region are stereostandard DNA nucleosides.

[1231] Embodiment 981. The modified oligonucleotide of embodiment 977, wherein at least 8 consecutive nucleosides of the deoxy region are stereostandard DNA nucleosides.

[1232] Embodiment 982. The modified oligonucleotide of any of embodiments 977 to 981, wherein the deoxy region consists of 8 to 10 linked nucleosides.

[1233] Embodiment 983. The modified oligonucleotide of any of embodiments 977-981, wherein the deoxy region consists of 9 linked nucleosides.

[1234] Embodiment 984. The modified oligonucleotide of any of embodiments 977 to 981, wherein the deoxy region consists of 10 linked nucleosides.

[1235] Embodiment 985. The modified oligonucleotide of any of embodiments 977 to 981, wherein the deoxy region consists of 11 linked nucleosides.

[1236] Embodiment 986. The modified oligonucleotide of any of embodiments 977 to 981, wherein at least six nucleosides of the deoxy region are stereostandard DNA nucleosides.

[1237] Embodiment 987. The modified oligonucleotide of any of embodiments 977 to 981, wherein at least 7 nucleosides of the deoxy region are stereostandard DNA nucleosides.

[1238] Embodiment 988. The modified oligonucleotide of any of embodiments 977 to 981, wherein at least 8 nucleosides of the deoxy region are stereostandard DNA nucleosides.

[1239] Embodiment 989. The modified oligonucleotide of any of embodiments 977 to 981, wherein at least 9 nucleosides of the deoxy region are stereostandard DNA nucleosides.

[1240] Embodiment 990. The modified oligonucleotide of any of embodiments 977-989, wherein exactly two nucleosides of the deoxy region are modified nucleosides.

[1241] Embodiment 991. The modified oligonucleotide of any of embodiments 977-989, wherein exactly one nucleoside of the deoxy region is a modified nucleoside.

[1242] Embodiment 992. At least one modified nucleoside in the deoxy region is a β-D-LNA nucleoside, an α-L-LNA nucleoside, an ENA nucleoside, a cEt nucleoside, a 2'-MOE nucleoside, a 2'-OMe nucleoside, or a 2'-F nucleoside. 992. The modified oligonucleotide of any of embodiments 977-991, wherein the stereostandard modified nucleoside or bicyclic nucleoside is selected from:

[1243] Embodiment 993. The modified oligonucleotide of any of embodiments 977 to 991, wherein at least one modified nucleoside in the deoxy region is a stereo-nonstandard nucleoside.

[1244] Embodiment 994. The modified oligonucleotide of embodiment 993, wherein said at least one stereononstandard nucleoside of said deoxy region is a stereononstandard DNA nucleoside.

[1245] Embodiment 995. The modified oligonucleotide of embodiment 994, wherein the stereo-nonstandard DNA nucleoside is selected from stereo-nonstandard DNA nucleosides having Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, and Formula VII.

[1246] Embodiment 996. The modified oligonucleotide of embodiment 995, wherein the stereo-nonstandard DNA nucleoside is selected from stereo-nonstandard DNA nucleosides having formula V and formula II.

[1247] Embodiment 997. The modified oligonucleotide of embodiment 996, wherein at least one stereononstandard nucleoside in the deoxy region is a substituted stereononstandard nucleoside.

[1248] Embodiment 998. The modified oligonucleotide of embodiment 997, wherein at least one substituted stereononstandard nucleoside has a 2' substituent selected from 2'-MOE, 2'-OMe, 2'-F, or 2'-OH.

[1249] Embodiment 999. The modified oligonucleotide of any of embodiments 977 to 998, wherein the second nucleoside from the 5' end of the deoxy region is a modified nucleoside.

[1250] Embodiment 1000. The modified oligonucleotide of any of embodiments 977 to 998, wherein the third nucleoside from the 5' end of the deoxy region is a modified nucleoside.

[1251] Embodiment 1001. The modified oligonucleotide of any of embodiments 977-998, wherein the fourth nucleoside from the 5' end of the deoxy region is a modified nucleoside.

[1252] Embodiment 1002. The modified oligonucleotide of any of embodiments 999-1001, wherein the modified nucleoside in the deoxy region is a 2'-OMe nucleoside.

[1253] Embodiment 1003. The modified oligonucleotide of any of embodiments 977-989, wherein each nucleoside of the deoxy region is a stereostandard DNA nucleoside.

[1254] Embodiment 1004. The modified oligonucleotide of any of embodiments 977 to 1003, wherein at least one internucleoside linking group in said deoxy region is an internucleoside linking group of Formula XVII.

[1255] Embodiment 1005. The modified oligonucleotide of any of embodiments 977 to 1004, wherein the internucleoside linking group connecting the first and second nucleosides of the deoxy region, counting from the 5' end of the deoxy region, is an internucleoside linking group of Formula XVII.

[1256] Embodiment 1006. The modified oligonucleotide of any of embodiments 977 to 1005, wherein the internucleoside linking group connecting the second and third nucleosides of the deoxy region, counting from the 5' end of the deoxy region, is an internucleoside linking group of Formula XVII.

[1257] Embodiment 1007. The modified oligonucleotide of any of embodiments 977 to 1006, wherein the internucleoside linking group connecting the third and fourth nucleosides of the deoxy region, counting from the 5' end of the deoxy region, is an internucleoside linking group of Formula XVII.

[1258] Embodiment 1008. The modified oligonucleotide of any of embodiments 977 to 1007, wherein the internucleoside linking group connecting the fourth and fifth nucleosides of the deoxy region, counting from the 5' end of the deoxy region, is an internucleoside linking group of Formula XVII.

[1259] Embodiment 1009. The modified oligonucleotide of any of embodiments 977 to 1008, wherein one internucleoside linkage group in the deoxy region is a linkage group of Formula XVII, and the other internucleoside linkage groups in the deoxy region are independently selected from phosphodiester and phosphorothioate internucleoside linkage groups.

[1260] Embodiment 1010. The modified oligonucleotide of any of embodiments 977-1008, wherein two internucleoside linkage groups in the deoxy region are linkage groups of Formula XVII, and each other internucleoside linkage group in the deoxy region is independently selected from phosphodiester and phosphorothioate internucleoside linkage groups.

[1261] Embodiment 1011. The modified oligonucleotide of any of embodiments 977-1008, wherein three internucleoside linkage groups in the deoxy region are linkage groups of Formula XVII, and each other internucleoside linkage group in the deoxy region is independently selected from phosphodiester and phosphorothioate internucleoside linkage groups.

[1262] Embodiment 1012. The modified oligonucleotide of any of embodiments 977-1008, wherein four internucleoside linkage groups in the deoxy region are linkage groups of Formula XVII, and each remaining internucleoside linkage group in the deoxy region is a phosphodiester or phosphorothioate internucleoside linkage group.

[1263] Embodiment 1013. The oligomeric compound of any of embodiments 1009-1012, wherein said internucleoside linking group of Formula XVII links the first and second, second and third, third and fourth, and / or fourth and fifth nucleosides of said deoxy region, counting from the 5' end of said deoxy region.

[1264] Embodiment 1014. The modified oligonucleotide of any of embodiments 877 to 1013, wherein the deoxy region comprises at least one region having the structure A, B, C, D, or E.

[1265] Embodiment 1015. The region having structure A, B, C, D, or E is The modified oligonucleotide of embodiment 1014, which is at the 3' end of the region.

[1266] Embodiment 1016. The modified oligonucleotide of embodiment 1014, wherein the region having the structure A, B, C, D, or E is at the 5' end of the deoxy region.

[1267] Embodiment 1017. The deoxy region is selected from the group consisting of the formula (N g1 ) L1 (N g2 ) L2 (N g3 ) L3 wherein each N g is a nucleoside, each L is an internucleoside linking group, and each of L and L is a phosphodiester internucleoside linking group, a phosphorothioate internucleoside linking group, or an internucleoside linking group of formula XVII;

[1268] [ka]

[1269] 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 is an internucleoside linking group of Formula XVII, and at least one of L1, L2, and L3 is a phosphorothioate or phosphodiester internucleoside linking group; wherein, independently for each internucleoside linking group of said modified oligonucleotide having Formula XVII: X is selected from O or S; R1 is selected from H, C1-C6 alkyl, and substituted C1-C6 alkyl; T is selected from SO2R2, C(=O)R3, and P(=O)R4R5, wherein: R2 is selected from aryl, substituted aryl, heterocycle, substituted heterocycle, aromatic heterocycle, substituted aromatic heterocycle, diazole, substituted diazole, 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; R3 is selected from aryl, substituted aryl, CH3, N(CH3)2, OCH3, and a conjugate; R4 is selected from OCH3, OH, C1-C6 alkyl, substituted C1-C6 alkyl, and conjugates; R5 is selected from OCH3, OH, C1-C6 alkyl, and substituted C1-C6 alkyl; The modified oligonucleotide according to any of embodiments 877 to 1016.

[1270] Embodiment 1018. The compound of the formula (N g1 ) L1 (N g2 ) L2 (N g3 ) L3 1018. The modified oligonucleotide of embodiment 1017, wherein the region having

[1271] Embodiment 1019. The compound of formula (N g1 ) L1 (N g2 ) L2 (N g3 ) L3 1018. The modified oligonucleotide of embodiment 1017, wherein the region having:

[1272] 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.

[1273] Embodiment 1021. The deoxy region is flanked on the 5' side by a 5' region consisting of 1 to 6 linked 5' region nucleosides and on the 3' side by a 3' region consisting of 1 to 6 linked 3' region nucleosides; the 3'-most nucleoside of said 5' region comprises a modified sugar moiety; the 5'-most nucleoside of said 3' region comprises a modified sugar moiety; The modified oligonucleotide according to any of embodiments 877 to 1020.

[1274] Embodiment 1022. The deoxy region consists of 7 to 11 linked nucleosides and has the formula: (N d1 ) L1 (N d2 ) L2 (N d3 ) L3 (N d4 ) L4 [(N d ) L5 ] q , In the formula, N d1 , N d2 , N d3 , N d4 But independently, a stereostandard DNA nucleoside, a stereononstandard DNA nucleoside, or a 2'-substituted nucleoside, with the proviso that N d1 , N d2 , N d3 , or N d4 is a 2'-substituted nucleoside; each N d are independently selected from stereostandard and stereononstandard DNA nucleosides; q is 3 to 8; each of L1, L2, L3, L4, and each L5 is an internucleoside linkage; At least two of L1, L2, L3, and L4 are internucleoside linkages of formula XVII. The modified oligonucleotide according to embodiment 1021.

[1275] Embodiment 1023.N d1 , N d2 , N d3 , or N d4 The modified oligonucleotide of embodiment 1022, wherein one of:

[1276] Embodiment 1024. The modified oligonucleotide of embodiment 1023, wherein the 2'-substituted nucleoside is a 2'-OMe nucleoside.

[1277] Embodiment 1025. The modified oligonucleotide of embodiment 1024, wherein the 2'-OMe nucleoside is a stereostandard 2'-OMe nucleoside.

[1278] Embodiment 1026. The 2'-substituted nucleoside is N d2 The modified oligonucleotide according to any of embodiments 1022 to 1025, wherein

[1279] Embodiment 1027.N d1 , N d2 , N d3 , N d4 Each of the above, and each N d is a DNA nucleoside.

[1280] Embodiment 1028. The modified oligonucleotide of embodiment 1027, wherein each DNA nucleoside is a stereostandard DNA nucleoside.

[1281] Embodiment 1029. The modified oligonucleotide according to any of embodiments 1022 to 1028, wherein L1 and L2 are internucleoside linkages of formula XVII.

[1282] Embodiment 1030. The modified oligonucleotide according to any of embodiments 1022 to 1028, wherein L2 and L3 are internucleoside linkages of formula XVII.

[1283] Embodiment 1031. The modified oligonucleotide according to any of embodiments 1022 to 1028, wherein L3 and L4 are internucleoside linkages of formula XVII.

[1284] Embodiment 1032. The modified oligonucleotide according to any of embodiments 1022 to 1028, wherein L1, L2, and L3 are internucleoside linkages of formula XVII.

[1285] Embodiment 1033. The modified oligonucleotide according to any of embodiments 1022 to 1028, wherein L2, L3, and L4 are internucleoside linkages of formula XVII.

[1286] Embodiment 1034. The modified oligonucleotide according to any of embodiments 1022 to 1028, wherein L1, L2, L3, and L4 are internucleoside linkages of formula XVII.

[1287] 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.

[1288] 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.

[1289] Embodiment 1037. The modified oligonucleotide of any of embodiments 1021 to 1036, wherein the 5' region consists of 2 to 5 linked nucleosides.

[1290] Embodiment 1038. The modified oligonucleotide of embodiment 1037, wherein the 5' region consists of 3 linked nucleosides.

[1291] Embodiment 1039. The modified oligonucleotide of embodiment 1037, wherein the 5' region consists of 5 linked nucleosides.

[1292] Embodiment 1040. The modified oligonucleotide of any of embodiments 1021 to 1039, wherein each nucleoside of the 5' region is a modified nucleoside.

[1293] Embodiment 1041. The modified oligonucleotide of any of embodiments 1021 to 1040, wherein each nucleoside in the 5' region is a modified nucleoside comprising a modified sugar.

[1294] Embodiment 1042. The modified oligonucleotide of any of embodiments 1021 to 1041, wherein at least one nucleoside of the 5' region comprises a 2'-substituted furanosyl sugar moiety.

[1295] Embodiment 1043. The modified oligonucleotide of any of embodiments 1021 to 1041, wherein each nucleoside of the 5' region comprises a 2'-substituted furanosyl sugar moiety.

[1296] Embodiment 1044. The modified oligonucleotide of any of embodiments 1021 to 1043, wherein each 2'-substituted furanosyl sugar moiety in the 5' region has a 2'-substituent selected from among 2'-MOE, 2'-OMe, and 2'-NMA.

[1297] 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.

[1298] 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.

[1299] 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.

[1300] Embodiment 1048. The modified oligonucleotide of embodiment 1047, wherein each bicyclic sugar moiety in the 5' region is a cEt sugar moiety.

[1301] Embodiment 1049. The modified oligonucleotide of any of embodiments 1021 to 1039, 1042, or 1045, wherein at least one nucleoside of the 5' region is a stereostandard DNA nucleoside.

[1302] Embodiment 1050. The modified oligonucleotide of any of embodiments 1021 to 1048, wherein at least one nucleoside in the 5' region is a stereo-nonstandard nucleoside.

[1303] Embodiment 1051. The modified oligonucleotide of any of embodiments 1021 to 1050, wherein each nucleobase of the 5' region is independently selected from among thymine, uracil, guanine, cytosine, 5-methylcytosine, and adenine.

[1304] Embodiment 1052. The modified oligonucleotide of any of embodiments 1021 to 1051, wherein the 3' region consists of 2 to 5 linked nucleosides.

[1305] Embodiment 1053. The modified oligonucleotide of embodiment 1052, wherein the 3' region consists of 3 linked nucleosides.

[1306] Embodiment 1054. The modified oligonucleotide of embodiment 1052, wherein the 3' region consists of 5 linked nucleosides.

[1307] Embodiment 1055. The modified oligonucleotide of any of embodiments 1021 to 1054, wherein each nucleoside of the 3' region is a modified nucleoside.

[1308] Embodiment 1056. The modified oligonucleotide of any of embodiments 1021 to 1055, wherein each nucleoside in the 3' region is a modified nucleoside comprising a modified sugar.

[1309] Embodiment 1057. The modified oligonucleotide of any of embodiments 1021 to 1056, wherein at least one nucleoside of the 3' region comprises a 2'-substituted furanosyl sugar moiety.

[1310] Embodiment 1058. The modified oligonucleotide of any of embodiments 1021 to 1057, wherein each nucleoside of the 3' region comprises a 2'-substituted furanosyl sugar moiety.

[1311] Embodiment 1059. The modified oligonucleotide of any of embodiments 1021 to 1058, wherein each 2'-substituted furanosyl sugar moiety in the 3' region has a 2'-substituent selected from among 2'-MOE, 2'-OMe, and 2'-NMA.

[1312] Embodiment 1060. At least one nucleoside in the 3' region is a bicyclic furanoside. The modified oligonucleotide of any of embodiments 1021 to 1057 or 1059, comprising a disaccharide moiety.

[1313] 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.

[1314] 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.

[1315] Embodiment 1063. The modified oligonucleotide of embodiment 1062, wherein each bicyclic sugar moiety in the 3' region is a cEt sugar moiety.

[1316] Embodiment 1064. The modified oligonucleotide of any of embodiments 1021 to 1054, 1057, or 1060, wherein at least one nucleoside of the 3' region is a stereostandard DNA nucleoside.

[1317] Embodiment 1065. The modified oligonucleotide of any of embodiments 1021 to 1064, wherein at least one nucleoside in the 3' region is a stereo-nonstandard nucleoside.

[1318] Embodiment 1066. The modified oligonucleotide of any of embodiments 1021 to 1065, wherein each nucleobase of the 3' region is independently selected from among thymine, uracil, guanine, cytosine, 5-methylcytosine, and adenine.

[1319] Embodiment 1067. The modified oligonucleotide of any of embodiments 1021 to 1066, wherein the modified oligonucleotide is a gapmer.

[1320] Embodiment 1068. The modified oligonucleotide of any of embodiments 1021 to 1066, wherein the modified oligonucleotide has a sugar motif selected from kkkddddddddddddkkk 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.

[1321] Embodiment 1069. がななななななななななななながが、sssssssssssssa、ssssssssssssas、sssssssssssass、sssssssssssass、ssssssssssasss、ssssssssasssss、sssssssassssss、sssssssssssss、sssssa ssssssss、s ... sssaassss、ssssssssaasssss、sssssssssaassssss、sssssssssaasssssss、ssssssssaassssssss、ssssssssaassssssss、sssssssaasssssssss、sssssaassssssssss、ssssaassssssssss、sssaasssssssssss、ssaassssssssssss、saassssssssssssss、aassssss ssssssss、aaaaaaaaaaaaaa、ssaaaaaaaaaaass、ssaaaaaaaaaaaasss、sssaaaaaaaaaaasss、aassssssssssaaa、sssaaaasssssssss、ssssaaassssssss、sssaaaaassssssss、ssaaassssssssss、ssaaaas sssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssss 、ooossssssssssoo、soosssssssssssos、aoossssssssssooa、aoassssssssssaoa、aoaaaasssssssaoa、aoosasssssssssoa、ooassssssssssoa、aooassssssssssoa、aoossssssssssssoa、aoossssssssssssoa ssaaasss、ssssaaaassssss、sssssaaaassssss、sssssssaaasssss、sssssssaaaassss、ssssssssaaaasss、sssaasssssssaass、sssaasssssaasss、sss aassssaassss、sssaasssaasssss、sssaassaassssss、sssaasaasssssss、sssaasssssssaass、ssssaassssssaass、sssssaassssaass、sssssaassssaass 、sssssssaassaass、ssssssssaasaass、ssssaaasssaassss、sssssaasaasssss、ssssssssssssss、aaasssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssThe modified oligonucleotide of any of embodiments 1021-1066, having an internucleoside linkage motif selected from 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.

[1322] Embodiment 1070. The modified oligonucleotide of embodiment 1069, wherein the modified oligonucleotide has an internucleoside linkage motif selected from sssaaaassssssss, sssaaasssssssss, ssssaaassssssss, ssssaassssssaass, sssaassssssssss, ssssaassssssss, ssssaassssssss, or ssssssssssaassss, 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.

[1323] Embodiment 1071. The modified oligonucleotide of embodiments 1069-1070, wherein each "a" represents a mesyl phosphoramidate internucleoside linkage.

[1324] Embodiment 1072. The modified oligonucleotide of any of embodiments 705 to 841, wherein the modified oligonucleotide is a CRISPR compound.

[1325] Embodiment 1073. The modified oligonucleotide of embodiment 1072, wherein the CRISPR compound consists of 20 to 50 or 29 to 32 linked nucleosides.

[1326] Embodiment 1074. The modified form of any one of embodiments 794 to 1073, wherein each X is O. Decorated oligonucleotides.

[1327] Embodiment 1075. The modified oligonucleotide of any of embodiments 794 to 1073, wherein each X is S.

[1328] Embodiment 1076. The modified oligonucleotide of any of embodiments 794 to 1075, wherein at least one R1 is H.

[1329] Embodiment 1077. The modified oligonucleotide of any of embodiments 794 to 1075, wherein at least one R1 is C1-C6 alkyl.

[1330] Embodiment 1078. The modified oligonucleotide of embodiment 1077, wherein at least one R1 is methyl.

[1331] Embodiment 1079. The modified oligonucleotide of any of embodiments 794 to 1075, wherein at least one R1 is substituted C1-C6 alkyl.

[1332] Embodiment 1080. The modified oligonucleotide of any of embodiments 794 to 1079, wherein at least one T comprises a conjugate group.

[1333] Embodiment 1081. The modified oligonucleotide of embodiment 1080, wherein the conjugate group comprises a cell-targeting moiety.

[1334] Embodiment 1082. The modified oligonucleotide of embodiment 1080, wherein the conjugate group comprises a carbohydrate or carbohydrate cluster.

[1335] Embodiment 1083. The modified oligonucleotide of any of embodiments 1080 to 1082, wherein the conjugate group comprises at least one GalNAc.

[1336] Embodiment 1084. The conjugate group is C 10 ~C 20 The modified oligonucleotide of embodiment 1080, comprising an alkyl chain.

[1337] Embodiment 1085. The conjugate group is C 16 The modified oligonucleotide of embodiment 1084, comprising an alkyl.

[1338] Embodiment 1086. The modified oligonucleotide of any of embodiments 794 to 1085, wherein at least one T does not comprise a conjugate group.

[1339] Embodiment 1087. The modified oligonucleotide of any of embodiments 794 to 1079, wherein each T does not comprise a conjugate group.

[1340] Embodiment 1088. The modified oligonucleotide of any of embodiments 794 to 1087, wherein at least one T is SO2R2.

[1341] Embodiment 1089. The modified oligonucleotide of embodiment 1088, wherein R2 is aryl.

[1342] Embodiment 1090. The modified oligonucleotide of embodiment 1088, wherein R2 is substituted aryl.

[1343] Embodiment 1091. The modified oligonucleotide of embodiment 1088, wherein R2 is a heterocycle.

[1344] Embodiment 1092. The modified oligonucleotide of embodiment 1088, wherein R2 is a substituted heterocycle.

[1345] Embodiment 1093. The modified oligonucleotide of embodiment 1088, wherein R2 is an aromatic heterocycle.

[1346] Embodiment 1094. The modified oligonucleotide of embodiment 1088, wherein R2 is a substituted aromatic heterocycle.

[1347] Embodiment 1095. The modified oligonucleotide of embodiment 1088, wherein R2 is diazole.

[1348] Embodiment 1096. The modified oligonucleotide of embodiment 1088, wherein R2 is a substituted diazole.

[1349] Embodiment 1097. The modified oligonucleotide according to embodiment 1088, wherein R2 is an amine.

[1350] Embodiment 1098. The modified oligonucleotide according to embodiment 1088, wherein R2 is a substituted amine.

[1351] Embodiment 1099. The modified oligonucleotide of embodiment 1088, wherein R2 is C1-C6 alkoxy, C1-C6 alkenyl, or C1-C6 alkynyl.

[1352] The embodiment 1100.R2 is C1 to C 20 , C1~C6, C2~C 20 , C2 to C6, or C 10 ~C 20 The modified oligonucleotide of embodiment 1088, which is alkyl.

[1353] In the embodiment 1101.R2, substitutions C1 to C 20 , C1~C6, C2~C 20 , C2 to C6, or C 10 ~C 20 The modified oligonucleotide of embodiment 1088, which is alkyl.

[1354] Embodiment 1102. The modified oligonucleotide according to embodiment 1088, wherein R2 comprises a carbohydrate or carbohydrate cluster.

[1355] Embodiment 1103. The modified oligonucleotide of embodiment 1088, wherein R2 comprises at least one GalNAc.

[1356] Embodiment 1104. The modified oligonucleotide of embodiment 1088, wherein T is:

[1357] [ka]

[1358] Embodiment 1105. The modified oligonucleotide of embodiment 1088, wherein T is:

[1359] [ka]

[1360] Embodiment 1106. The modified oligonucleotide of embodiment 1088, wherein T is:

[1361] [ka]

[1362] Embodiment 1107. The modified oligonucleotide of embodiment 1088, wherein T is:

[1363] [ka]

[1364] Embodiment 1108. The modified oligonucleotide according to embodiment 1088, wherein T is:

[1365] [ka]

[1366] Embodiment 1109. The modified oligonucleotide of embodiment 1088, wherein T is:

[1367] [ka]

[1368] Embodiment 1110. The modified oligonucleotide of embodiment 1088, wherein T is:

[1369] [ka]

[1370] Embodiment 1111. The modified oligonucleotide of embodiment 1088, wherein T is:

[1371] [ka]

[1372] Embodiment 1112. The modified oligonucleotide of embodiment 1088, wherein T is:

[1373] [ka]

[1374] In one embodiment,

[1375] [ka]

[1376] The modified oligonucleotide of embodiment 1088, wherein n is 2 to 20.

[1377] Embodiment 1114. The modified oligonucleotide according to embodiment 1113, wherein n is 15.

[1378] Embodiment 1115. The modified oligonucleotide of any of embodiments 794 to 1114, wherein at least one T is C(=O)R3.

[1379] Embodiment 1116. The modified oligonucleotide according to embodiment 1115, wherein R3 is aryl.

[1380] Embodiment 1117. The modified oligonucleotide according to embodiment 1115, wherein R3 is substituted aryl.

[1381] Embodiment 1118. The modified oligonucleotide according to embodiment 1115, wherein R3 is CH3.

[1382] Embodiment 1119. The modified oligonucleotide according to embodiment 1115, wherein R3 is N(CH3)2.

[1383] Embodiment 1120. The modified oligonucleotide according to embodiment 1115, wherein R3 is OCH3.

[1384] Embodiment 1121. The modified oligonucleotide according to embodiment 1115, wherein R3 is C1-C6 alkoxy.

[1385] Embodiment 1122.R3 is C1 to C 20 , C1~C6, C2~C 20 , C2 to C6, or C 10 ~C 20 The modified oligonucleotide of embodiment 1115, which is alkyl.

[1386] In the embodiment 1123.R3, substitutions C1 to C 20 , C1~C6, C2~C 20 , C2 to C6, or C 10 ~C 20 The modified oligonucleotide of embodiment 1115, which is alkyl.

[1387] Embodiment 1124. The modified oligonucleotide according to embodiment 1115, wherein R3 comprises a carbohydrate or carbohydrate cluster.

[1388] Embodiment 1125.R 23The modified oligonucleotide of embodiment 1115, wherein said modified oligonucleotide comprises at least one GalNAc.

[1389] Embodiment 1126. The modified oligonucleotide according to embodiment 1115, wherein T is:

[1390] [ka]

[1391] Embodiment 1127. The modified oligonucleotide according to embodiment 1115, wherein T is:

[1392] [ka]

[1393] Embodiment 1128. The modified oligonucleotide according to embodiment 1115, wherein T is:

[1394] [ka]

[1395] Embodiment 1129. The modified oligonucleotide according to embodiment 1115, wherein T is:

[1396] [ka]

[1397] Embodiment 1130.T is as follows:

[1398] [ka]

[1399] 1116. The modified oligonucleotide of embodiment 1115, wherein n is 2 to 20.

[1400] Embodiment 1131. The modified oligonucleotide according to embodiment 1130, wherein n is 15.

[1401] Embodiment 1132. The modified oligonucleotide of any of embodiments 794 to 1131, wherein at least one T is P(=O)R4R5.

[1402] Embodiment 1133. The modified oligonucleotide according to embodiment 1132, wherein R4 is OCH3.

[1403] Embodiment 1134. The modified oligonucleotide according to embodiment 1132, wherein R4 is OH.

[1404] Embodiment 1135. The modified oligonucleotide according to embodiment 1132, wherein R4 is C1-C6 alkyl.

[1405] Embodiment 1136. The modified oligonucleotide according to embodiment 1132, wherein R4 is a substituted C1-C6 alkyl.

[1406] Embodiment 1137.R4 is C1 to C 20 , C1~C6, C2~C 20 , C2~C6, or C 10 ~C 20 The modified oligonucleotide of embodiment 1132, which is alkyl.

[1407] In the embodiment 1138.R4, substitutions C1 to C 20 , C1~C6, C2~C 20 , C2 to C6, or C 10 ~C 20 The modified oligonucleotide of embodiment 1132, which is alkyl.

[1408] Embodiment 1139. The modified oligonucleotide according to embodiment 1132, wherein R4 comprises a carbohydrate or carbohydrate cluster.

[1409] Embodiment 1140. The modified oligonucleotide according to embodiment 1132, wherein R4 comprises at least one GalNAc.

[1410] Embodiment 1141. The modified oligonucleotide according to any of embodiments 1132 to 1140, wherein R5 is OCH3.

[1411] Embodiment 1142. The modified oligonucleotide according to any of embodiments 1132 to 1140, wherein R5 is OH.

[1412] Embodiment 1143. The modified oligonucleotide according to any of embodiments 1132 to 1140, wherein R5 is C1-C6 alkyl.

[1413] Embodiment 1144. The modified oligonucleotide according to any of embodiments 1132 to 1140, wherein R5 is substituted C1-C6 alkyl.

[1414] Embodiment 1145. The modified oligonucleotide according to embodiment 1132, wherein T is:

[1415] [ka]

[1416] Embodiment 1146. The modified oligonucleotide according to embodiment 1132, wherein T is:

[1417] [ka]

[1418] Embodiment 1147.T is as follows:

[1419] [ka]

[1420] The modified oligonucleotide of embodiment 1132, wherein n is 2 to 20.

[1421] Embodiment 1148. The modified oligonucleotide according to embodiment 1147, wherein n is 15.

[1422] Embodiment 1149. An antisense agent comprising a modified oligonucleotide consisting of 12 to 50 linked nucleosides linked via internucleoside linking groups, wherein at least one internucleoside linking group is a phosphodiester or phosphorothioate internucleoside linking group, and at least one of the internucleoside linking groups has the formula XX:

[1423] [ka]

[1424] wherein, independently for each internucleoside linking group of said modified oligonucleotide having formula XX, X is selected from O or S; The antisense agent.

[1425] Embodiment 1150. An antisense agent comprising a modified oligonucleotide, wherein the 5' end of the modified oligonucleotide has the structure F:

[1426] [ka]

[1427] During the ceremony, p is 0 to 6; q is 0 to 6; T is OH or a conjugate group; each Bx is an independently selected heterocyclic base moiety; each X is independently selected from OH or SH; each Z is independently selected from O, S, or NSOMe; Each J of the same furanosyl sugar moietyR and for G, J R and G, J R to form a bridge of G or J R is H and G is OH, halogen, or O—[C(R6)(R7)] n -[(C=O) m -X G ] j -R8, In the formula, each J R The bridge of G is -CH(CH3)-O- or -(CH2) k -O-, wherein k is 1 to 3; each R6 and R7 is independently H, halogen, C1-C6 alkyl, or substituted C1-C6 alkyl; each X G is O, S, or N(E1), 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), E1, E2, and E3 are each independently H, C1-C6 alkyl, or substituted C1-C6 alkyl; n is 1 to 6; m is 0 or 1, j is 0 or 1, each substituted group comprises one or more optionally protected substituents 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; each J1, J2, and J3 is independently H or C1-C6 alkyl; The antisense agent.

[1428] Embodiment 1151. An antisense agent comprising a modified oligonucleotide, wherein the 3' end of the modified oligonucleotide has the structure G,

[1429] [ka]

[1430] During the ceremony, p is 0 to 6; q is 1 to 6; T is OH or a conjugate group; each Bx is an independently selected heterocyclic base moiety; each X is independently selected from OH or SH; each Z is independently selected from O, S, or NSOMe; Each J of the same furanosyl sugar moiety R and for G, J R and G, J R to form a bridge of G or J R is H and G is OH, halogen, or O—[C(R6)(R7)] n -[(C=O) m -X G ] j -R8, In the formula, each J R The bridge of G is -CH(CH3)-O- or -(CH2) k -O-, wherein k is 1 to 3; each R6 and R7 is independently H, halogen, C1-C6 alkyl, or substituted C1-C6 alkyl; each X G is O, S, or N(E1), 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); E1, E2, and E3 are each independently H, C1-C6 alkyl, or substituted C1-C6 alkyl; n is 1 to 6; m is 0 or 1, j is 0 or 1, each substituted group comprises one or more optionally protected substituents 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; each J1, J2, and J3 is independently H or C1-C6 alkyl; The antisense agent.

[1431] Embodiment 1152. The antisense agent of embodiment 1150 or 1151, wherein the sum of p+q is selected from 2, 3, 4, or 5.

[1432] Embodiment 1153. An antisense agent comprising a modified oligonucleotide, wherein the 5' end of the modified oligonucleotide has the structure H:

[1433] [ka]

[1434] During the ceremony, p is 0 to 5; q is 1 to 4; T is OH or a conjugate group; each Bx is an independently selected heterocyclic base moiety; each X is independently selected from OH or SH; each Z is independently selected from O, S, or NSOMe; Each J of the same furanosyl sugar moiety R and for G, J R and G, J R to form a bridge of G or JR is H and G is OH, halogen, or O—[C(R6)(R7)] n -[(C=O) m -X G ] j -R8, In the formula, each J R The bridge of G is -CH(CH3)-O- or -(CH2) k -O-, wherein k is 1 to 3; each R6 and R7 is independently H, halogen, C1-C6 alkyl, or substituted C1-C6 alkyl; each X G is O, S, or N(E1), 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), E1, E2, and E3 are each independently H, C1-C6 alkyl, or substituted C1-C6 alkyl; n is 1 to 6; m is 0 or 1, j is 0 or 1, each substituted group comprises one or more optionally protected substituents 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; each J1, J2, and J3 is independently H or C1-C6 alkyl; The antisense agent.

[1435] Embodiment 1154. An antisense agent comprising a modified oligonucleotide, wherein the 5' end of the modified oligonucleotide has the structure I:

[1436] [ka]

[1437] During the ceremony, p is 0 to 5; q is 1 to 4; T is OH or a conjugate group; each Bx is an independently selected heterocyclic base moiety; each X is independently selected from OH or SH; each Z is independently selected from O, S, or NSOMe; Each R q is H or exactly one R q is OMe and other R q is H, Each J of the same furanosyl sugar moiety R and for G, J R and G, J R to form a bridge of G or J R is H and G is OH, halogen, or O—[C(R6)(R7)] n -[(C=O) m -X G ] j -R8, In the formula, each J R The bridge of G is -CH(CH3)-O- or -(CH2) k -O-, wherein k is 1 to 3; each R6 and R7 is independently H, halogen, C1-C6 alkyl, or substituted C1-C6 alkyl; each X G is O, S, or N(E1), 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); E1, E2, and E3 are each independently H, C1-C6 alkyl, or substituted C1-C6 alkyl; n is 1 to 6; m is 0 or 1, j is 0 or 1, each substituted group comprises one or more optionally protected substituents 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; each J1, J2, and J3 is independently H or C1-C6 alkyl; The antisense agent.

[1438] Embodiment 1155. Exactly one R q The antisense agent of embodiment 1154, wherein is -OMe.

[1439] Embodiment 1156. An antisense agent according to any one of embodiments 1153 to 1155, wherein the sum of p+q is 2, 3, or 4.

[1440] Embodiment 1157. An antisense agent comprising a modified oligonucleotide, wherein the 3' end of the modified oligonucleotide has the structure J:

[1441] [ka]

[1442] During the ceremony, p is 0 to 6; T is OH or a conjugate group; each Bx is an independently selected heterocyclic base moiety; each X is independently selected from OH or SH; each Z is independently selected from O, S, or NSOMe; Each J of the same furanosyl sugar moiety R and for G, J R and G, J R to form a bridge of G or JR is H and G is OH, halogen, or O—[C(R6)(R7)] n -[(C=O) m -X G ] j -R8, In the formula, each J R The bridge of G is -CH(CH3)-O- or -(CH2) k -O-, wherein k is 1 to 3; each R6 and R7 is independently H, halogen, C1-C6 alkyl, or substituted C1-C6 alkyl; each X G is O, S, or N(E1), 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); E1, E2, and E3 are each independently H, C1-C6 alkyl, or substituted C1-C6 alkyl; n is 1 to 6; m is 0 or 1, j is 0 or 1, each substituted group comprises one or more optionally protected substituents 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; each J1, J2, and J3 is independently H or C1-C6 alkyl; The antisense agent.

[1443] Embodiment 1158. The antisense agent of embodiment 1157, wherein p is 2, 3, or 4.

[1444] Embodiment 1159. Each J RThe antisense agent of any of embodiments 1150-1158, wherein is H and each G is OCH2CH2OCH3.

[1445] Embodiment 1160. Each J R The a...

Claims

1. An oligomeric compound comprising a modified oligonucleotide consisting of 12 to 30 linked nucleosides linked via internucleoside linking groups, wherein at least one of the internucleoside linking groups has formula XVII, 【Chemistry 1】 In the formula, each nucleoside linking group of the modified oligonucleotide having formula XVII is independently considered, X is selected from O or S, R １ However, H, C １ ~C ６ Alkyl and substituted C １ ~C ６ Selected from alkyl groups, T is SO ２ R ２ And, R ２ is selected from aryl, substituted aryl, heterocyclic ring, substituted heterocyclic ring, aromatic heterocyclic ring, substituted aromatic heterocyclic ring, diazol, substituted diazol, C １ to C ６ alkoxy, C １ to C ６ alkyl, C １ to C ６ alkenyl, C １ to C ６ alkynyl, substituted C １ to C ６ alkyl, substituted C １ to C ６ alkenyl, and substituted C １ to C ６ alkynyl, Each nucleoside of the modified oligonucleotide is a modified nucleoside containing a modified sugar moiety. The above-mentioned oligomer compound.

2. The oligomer compound according to claim 1, which modulates the splicing of a target premRNA.

3. The oligomer compound according to claim 1 or 2, wherein each modified sugar moiety of the modified oligonucleotide is independently selected from a bicyclic sugar moiety and a 2'-substituted furanosyl sugar moiety.

4. The oligomer compound according to any one of claims 1 to 3, wherein each modified sugar moiety of the modified oligonucleotide contains the same modification.

5. The oligomer compound according to any one of claims 1 to 4, wherein each modified sugar moiety of the modified oligonucleotide is selected from a 2'-OMe sugar moiety, a 2'-MOE sugar moiety, and a 2'-NMA sugar moiety.

6. The oligomer compound according to claim 5, wherein each modified sugar moiety of the modified oligonucleotide is a 2'-MOE sugar moiety.

7. The oligomer compound according to claim 5, wherein each modified sugar moiety of the modified oligonucleotide is selected from a 2'-MOE sugar moiety and a 2'-NMA sugar moiety.

8. Modified oligonucleotides, formula (N ｇ１ ) Ｌ１ (N ｇ２ ) Ｌ２ (N ｇ３ ) Ｌ３ Includes at least one region having, In the formula, each N ｇ However, it is a modified nucleoside containing a modified sugar moiety, and each L is a nucleoside linking group. In the ceremony, L １ , L ２ , and L ３ Each of these is a phosphodiester nucleoside linking group, a phosphorothioate nucleoside linking group, or a nucleoside linking group of formula XVII, In the ceremony, L １ and L ２ Each of these is a phosphodiester nucleoside linking group, a phosphorothioate nucleoside linking group, or a nucleoside linking group of formula XVII, In the ceremony, L ３ However, it is either absent, or it is a phosphodiester nucleoside linking group, a phosphorothioate nucleoside linking group, or a nucleoside linking group of formula XVII. In the ceremony, L １ , L ２ , and L ３ At least one of them is the internucleoside linking group of formula XVII, and L １ , L ２ , and L ３ At least one of them is a phosphorothioate or phosphodiester nucleoside linking group. The oligomer compound according to any one of claims 1 to 7.

9. L １ and L ２ Each of these is a nucleoside linking group of formula XVII, or L ２ and L ３ The oligomer compound according to claim 8, wherein each of them is a nucleoside linking group of formula XVII.

10. Formula (N ｇ１ ) Ｌ１ (N ｇ２ ) Ｌ２ (N ｇ３ ) Ｌ３ The oligomer compound according to claim 8 or 9, wherein at least one region having is located at the 5' end of the oligonucleotide.

11. Formula (N ｇ１ ) Ｌ１ (N ｇ２ ) Ｌ２ (N ｇ３ ) Ｌ３ The oligomer compound according to any one of claims 8 to 10, wherein at least one region having is located at the 3' end of the oligonucleotide.

12. The oligomer compound according to any one of claims 1 to 7, wherein at least one of the ten linking groups at the 5' end of the modified oligonucleotide is an internucleoside linking group of formula XVII.

13. The oligomer compound according to any one of claims 1 to 7 or 12, wherein the modified oligonucleotide comprises at least one block of at least three consecutive internucleoside linking groups of formula XVII.

14. The oligomer compound according to any one of claims 1 to 7 or 12, wherein the modified oligonucleotide comprises at least one block of at least four consecutive internucleoside linking groups of formula XVII.

15. The oligomer compound according to any one of claims 12 to 14, wherein at least one block of consecutive internucleoside linking groups of formula XVII is located at the 5' end of the modified oligonucleotide.

16. The oligomer compound according to any one of claims 12 to 14, wherein at least one block of consecutive internucleoside linking groups of formula XVII is located at the 3' end of the modified oligonucleotide.

17. For each nucleoside linking group of formula XVII of the modified oligonucleotide, R １ However, H is, and T is, SO ２ The oligomer compound according to any one of claims 1 to 16, wherein the compound is Me.

18. A pharmaceutical composition comprising an oligomer compound according to any one of claims 1 to 17 and a pharmaceutically acceptable carrier or diluent.

19. A pharmaceutical composition according to claim 18 for treating a disease or condition.

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