Key-modified oligomeric compounds and uses thereof

Abstract

This disclosure provides oligomeric compounds comprising modified oligonucleotides having at least one modified internucleotide linking group (including oligomeric compounds as antisense agents or portions thereof).

Description

[0001] sequence list

[0002] This application is submitted together with the electronic sequence listing. The sequence listing is provided as a file named CHEM0101WOSEQ_ST25.txt, created on August 14, 2020, and is 593kb in size. The information in the electronic sequence listing is incorporated herein by reference in its entirety. Technical Field

[0003] This disclosure provides oligomeric compounds comprising modified oligonucleotides having at least one modified internucleotide linking group (including oligomeric compounds as antisense agents or portions thereof). Background Technology

[0004] The principle behind antisense technology is that antisense compounds hybridize with target nucleic acids and modulate the amount, activity, and / or function of said target nucleic acids. For example, in some cases, antisense compounds cause alterations in the transcription or translation of the target. This regulation of expression can be achieved, for example, through target RNA degradation or site-based inhibition. One example of regulating RNA target function through degradation is the degradation of target RNA based on RNase H upon hybridization with DNA-like antisense compounds.

[0005] Another example of regulating gene expression through target degradation is RNA interference (RNAi). RNAi refers to antisense-mediated gene silencing via a mechanism utilizing the RNA-induced silencing complex (RISC). Another example of regulating RNA target function is through site-based mechanisms, such as those naturally employed by microRNAs. MicroRNAs are small non-coding RNAs that regulate the expression of protein-coding RNAs. The binding of antisense compounds to microRNAs prevents them from binding to their messenger RNA targets, thus interfering with their function. MicroRNA mimics can enhance the function of natural microRNAs. Some antisense compounds alter the splicing of pre-mRNA. Another example of regulating gene expression is the use of antisense compounds in CRISPR systems. Regardless of the specific mechanism, sequence specificity makes antisense compounds worth considering as tools for target identification and gene functionalization, as well as as therapeutic agents for selectively regulating the expression of genes involved in disease pathogenesis.

[0006] Antisense technology is an effective means of regulating the expression of one or more specific gene products, thus demonstrating its unique value in many therapeutic, diagnostic, and research applications. Chemically modified nucleosides can be bound to antisense compounds to enhance one or more properties, such as nuclease resistance, tolerance, pharmacokinetics, or affinity for target nucleic acids. Summary of the Invention

[0007] This disclosure provides oligomeric compounds comprising modified oligonucleotides (including oligomeric compounds as antisense agents or portions thereof), said modified oligonucleotides being composed of linked nucleosides connected by internucleotide linking groups, wherein at least one of said internucleotide linking groups has the formula VIII:

[0008]

[0009] For each nucleoside linker of formula VIII in the modified oligonucleotide, independently:

[0010] R1 is selected from H, C1-C6 alkyl groups, and substituted C1-C6 alkyl groups; and

[0011] T is selected from SO2R2, C(=O)R3 and P(=O)R4R5, where:

[0012] R2 is selected from aryl, substituted aryl, heterocyclic, substituted heterocyclic, aromatic heterocyclic, substituted aromatic heterocyclic, diazole, substituted diazole, C1-C6 alkoxy, C1-C6 alkyl and substituted C1-C6 alkyl.

[0013] R3 is selected from aryl, substituted aryl, CH3, N(CH3)2 and OCH3;

[0014] R4 is selected from OCH3, OH, C1-C6 alkyl, and substituted C1-C6 alkyl; and

[0015] R5 is selected from OCH3, OH, C1-C6 alkyl, and substituted C1-C6 alkyl.

[0016] This disclosure provides oligomeric compounds comprising modified oligonucleotides (including oligomeric compounds as antisense agents or portions thereof), said modified oligonucleotides being composed of linked nucleosides connected by internucleotide linking groups, wherein at least one of said internucleotide linking groups has the formula VIII:

[0017]

[0018] For each nucleoside linker of formula VIII in the modified oligonucleotide, independently:

[0019] R1 is selected from H, C1-C6 alkyl groups, and substituted C1-C6 alkyl groups; and

[0020] T is selected from SO2R2, C(=O)R3 and P(=O)R4R5, where:

[0021] R2 is selected from aryl, substituted aryl, heterocyclic, substituted heterocyclic, aromatic heterocyclic, substituted aromatic heterocyclic, diazole, substituted diazole, C1-C6 alkoxy, C1-C6 alkyl and substituted C1-C6 alkyl.

[0022] R3 is selected from aryl, substituted aryl, CH3, N(CH3)2 and OCH3;

[0023] R4 is selected from OCH3, OH, C1-C6 alkyl, and substituted C1-C6 alkyl; and

[0024] R5 is selected from OCH3, OH, C1-C6 alkyl, and substituted C1-C6 alkyl;

[0025] The condition is that if R1 is H, then T is not:

[0026]

[0027] This disclosure provides oligomeric compounds comprising modified oligonucleotides (including oligomeric compounds as antisense agents or portions thereof), said modified oligonucleotides being composed of linked nucleosides connected by internucleotide linking groups, wherein at least one of said internucleotide linking groups has the formula XVII:

[0028]

[0029] For each nucleoside linker of formula XVII in the modified oligonucleotide, independently:

[0030] X is selected from O or S;

[0031] R1 is selected from H, C1-C6 alkyl groups, and substituted C1-C6 alkyl groups; and

[0032] T is selected from SO2R2, C(=O)R3 and P(=O)R4R5, where:

[0033] 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 conjugate groups.

[0034] R3 is selected from aryl, substituted aryl, CH3, N(CH3)2, OCH3 and conjugate groups;

[0035] R4 is selected from OCH3, OH, C1-C6 alkyl, substituted C1-C6 alkyl, and conjugate groups; and

[0036] R5 is selected from OCH3, OH, C1-C6 alkyl, and substituted C1-C6 alkyl.

[0037] In some embodiments, oligomers having at least one nucleoside linker group of formula VIII or XVII (including oligomers as antisense agents or portions thereof) have an increased maximum tolerated dose when administered to animals compared to other oligomers of the same nature, except that the other oligomers of the same nature lack the nucleoside linker group of formula VIII or XVII.

[0038] In some embodiments, modified oligonucleotides having at least one nucleoside linker group of formula VIII or XVII have an increased therapeutic index compared to other equally identical oligomeric compounds, except that the other equally identical oligomeric compounds lack the at least one nucleoside linker group of formula VIII or XVII. Attached Figure Description

[0039] Figure 1 Describe isomers having the 2'-deoxyfuranosyl sugar moiety of formulas I-VII.

[0040] Figure 2 Describe isomers having the 2'-O-methylfuranosyl sugar moiety of formulas I-VII.

[0041] Figure 3 Describe isomers having the 2'-fluorofuranosyl sugar moiety of formulas I-VII. Detailed Implementation

[0042] It should be understood that the foregoing general description and the following detailed description are exemplary and illustrative only, and are not intended to limit the claimed embodiments. In this document, the singular is used to include the plural unless otherwise specified. As used herein, unless otherwise specified, the use of "or" means "and / or". Furthermore, the use of the term "comprising" and other forms (including / includes / included) is not restrictive.

[0043] The section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described. All references or portions thereof cited in this application, including but not limited to patents, patent applications, articles, books, papers, and GenBank and NCBI reference sequence records, are hereby expressly incorporated by reference in whole or in part.

[0044] It is to be understood that the sequence listed in each SEQ ID NO contained herein is independent of any modification to the sugar moiety, nucleoside internucleotide, or nucleobase. Therefore, a compound defined by SEQ ID NO may independently contain one or more modifications to the sugar moiety, nucleoside internucleotide, or nucleobase. Although the sequence listing accompanying this application identifies each sequence as “RNA” or “DNA” as needed, in practice, these sequences can be modified with any combination of chemical modifications. It will be readily understood by those skilled in the art that the names of modified oligonucleotides, such as “RNA” or “DNA,” are arbitrary in some cases. For example, an oligonucleotide containing a nucleoside with a 2'-OH(H) sugar moiety and a thymine base may be described as DNA with a modified sugar (2'-OH replacing a 2'-H in DNA) or RNA with a modified base (thymine (methylated uracil) replacing uracil in RNA). Therefore, the nucleic acid sequences provided herein, including but not limited to those in the sequence listing, are intended to cover nucleic acids containing any combination of native or modified RNA and / or DNA, including but not limited to such nucleic acids with modified nucleobases. As a further example, and not a limitation, the modified oligonucleotide having the nucleobase sequence “ATCGATCG” encompasses any modified oligonucleotide having such a nucleobase sequence (whether modified or unmodified), including but not limited to such compounds containing RNA bases, such as those having the sequence “AUCGAUCG”, and those having some DNA bases and some RNA bases such as “AUCGATCG”, and those having other modified nucleobases such as “AT”. m "CGAUCG" modified oligonucleotides, in which m C indicates a cytosine base containing a methyl group at position 5.

[0045] As used herein, “2’-substituted” in relation to the furanylose moiety or a nucleotide containing the furanylose moiety means that the furanylose moiety or a nucleotide containing the furanylose moiety contains a substituent other than H or OH at the 2’ position, and that it is a non-bicyclic furanylose moiety. In the case of oligonucleotides, the 2’-substituted furanylose moiety does not contain any additional substituents at any position on the furanylose moiety other than the nucleobase and / or the internucleotide bond.

[0046] As used herein, “4’-substituted” in relation to the furanylose moiety or a nucleotide containing the furanylose moiety means that the furanylose moiety or a nucleotide containing the furanylose moiety contains a substituent other than H at the 4’ position and is a non-bicyclic furanylose moiety. In the case of oligonucleotides, the 4’-substituted furanylose moiety does not contain any additional substituents at any other position on the furanylose moiety except for nucleobases and / or internucleotide bonds.

[0047] As used herein, "5'-substituted" in relation to the furanylose moiety or a nucleotide containing the furanylose moiety means that the furanylose moiety or a nucleotide containing the furanylose moiety contains a substituent other than H at the 5' position and is a non-bicyclic furanylose moiety. In the case of oligonucleotides, the 5'-substituted furanylose moiety does not contain any additional substituents at positions other than nucleobases and / or internucleotide bonds.

[0048] As used herein, “administration” means the means by which a compound or composition provided herein is introduced into a subject to achieve its intended function. Examples of possible administration methods include, but are not limited to, administration by inhalation, subcutaneous injection, intrathecal injection, and oral administration.

[0049] As used herein, “antisense activity” means any detectable and / or measurable change attributable to the hybridization of an antisense oligonucleotide with its target nucleic acid. In some embodiments, antisense activity is a reduction in the amount or expression of the target nucleic acid or the protein encoded by such target nucleic acid compared to the target nucleic acid or target protein level in the absence of an antisense oligonucleotide.

[0050] As used in this article, "antisense agent" means antisense oligonucleotide or oligonucleotide duplex containing antisense oligonucleotide.

[0051] As used in this article, "antisense compound" means antisense oligonucleotide or oligonucleotide duplex containing antisense oligonucleotide.

[0052] As used herein, "antisense oligonucleotide" means an oligonucleotide that is complementary to a target nucleic acid and capable of performing at least one antisense activity. Antisense oligonucleotides include, but are not limited to, RNAi antisense modified oligonucleotides and RNase H antisense modified oligonucleotides. In some embodiments, the antisense oligonucleotide pairs with a sense oligonucleotide to form an oligonucleotide duplex. In some embodiments, the antisense oligonucleotide is unpaired and is a single-stranded antisense oligonucleotide. In some embodiments, the antisense oligonucleotide contains a conjugation group.

[0053] As used herein, “artificial mRNA compound” is an oligonucleotide or a portion thereof that has a modified nucleobase sequence containing one or more codons.

[0054] As used herein, "bicyclic nucleoside" or "BNA" refers to a nucleoside comprising a bicyclic sugar moiety. As used herein, "bicyclic sugar" or "bicyclic sugar moiety" refers to a modified sugar moiety comprising two rings, wherein the second ring is formed via a bridge connecting two atoms in the first ring, thereby forming a bicyclic structure. In some embodiments, the first ring of the bicyclic sugar moiety is a furanyl sugar moiety, and the bicyclic sugar moiety is a modified bicyclic furanyl sugar moiety. In some embodiments, the bicyclic sugar moiety does not contain a furanyl sugar moiety.

[0055] As used herein, “cEt” or “restricted ethyl” or “cEt sugar moiety” refers to a bicyclic sugar moiety in which the first ring is a ribosyl sugar moiety, and the second ring of the bicyclic sugar is formed via a bridge connecting the 4'-carbon and the 2'-carbon, 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.

[0056] As used herein, the term "complementary" in the context of oligonucleotides means that at least 70% of the nucleobases of such oligonucleotide or one or more regions thereof are hydrogen-bonded to each other with the nucleobases of another nucleic acid or one or more regions thereof (when the nucleobase sequences of the oligonucleotide and the other nucleic acid are aligned in opposite directions). Complementary nucleobase pairs are nucleobase pairs that are capable of forming 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 (… m C) and guanine (G). Complementary oligonucleotides and / or nucleic acids do not need to be complementary at every nucleoside. Instead, some mismatches are tolerated. As used herein, “perfectly complementary” or “100% complementary” with respect to oligonucleotides means that such oligonucleotides are complementary to another oligonucleotide or nucleic acid at each nucleoside of the oligonucleotide.

[0057] As used in this article, "conjugate group" refers to a group of atoms consisting of a conjugate portion and a conjugate linker.

[0058] As used herein, “conjugated moiety” means a group of atoms that modifies one or more properties of a molecule compared to an identical molecule lacking a conjugated moiety, including but not limited to pharmacodynamics, pharmacokinetics, stability, binding, absorption, tissue distribution, cellular distribution, cellular uptake, charge, and clearance.

[0059] As used in this article, "combination junction" refers to a group of atoms that contains at least one bond.

[0060] As used herein, “CRISPR compound” refers to an oligonucleotide modified to include both a DNA recognition portion and a tracrRNA recognition portion. As used herein, “DNA recognition portion” is a nucleobase sequence complementary to a DNA target. As used herein, “tracrRNA recognition portion” is a nucleobase sequence that binds to or is capable of binding to tracrRNA. The tracrRNA recognition portion of crRNA can bind to tracrRNA via hybridization or covalent linkage.

[0061] As used herein, "cytotoxic" or "cytotoxic" in the context of the effect of the oligomer or parent oligomer on cultured cells means that, after administration of 10 μM or less of the oligomer or parent oligomer to cultured cells, caspase activation is increased at least 2-fold compared to cells cultured under the same conditions without administration of the oligomer or parent oligomer. In some embodiments, cytotoxicity is measured using a standard in vitro cytotoxicity assay.

[0062] As used herein, "deoxygenated region" refers to a region of 5-12 consecutive nucleotides in which at least 70% of the nucleosides are stereo-standard DNA nucleosides. In some embodiments, each nucleoside is selected from stereo-standard DNA nucleosides (nucleosides containing the β-D-2'-deoxyribosyl sugar moiety), stereonon-standard nucleosides of formulas I-VII, bicyclic nucleosides, and substituted stereo-standard nucleosides. In some embodiments, the deoxygenated region supports RNase H activity. In some embodiments, the deoxygenated region is a gap in a gapmer.

[0063] As used herein, "double-stranded antisense compound" means an antisense compound comprising two complementary oligomers that form a double strand, wherein one of the two oligomers comprises an antisense oligonucleotide.

[0064] As used herein, “expression” includes all functions that translate the coding information of a gene into structures that are present and function in the cell. These structures include, but are not limited to, the products of transcription and translation. As used herein, “regulation of expression” means any change in the amount or activity of the transcriptional or translational products of a gene. Such a change can be any increase or decrease relative to the expression level prior to regulation.

[0065] As used herein, a “gap polymer” refers to an oligonucleotide having a central region containing multiple nucleotides located between the 5' and 3' regions that support RNase H cleavage. In this context, the nucleotides in the 5' and 3' regions each contain a 2'-substituted furanyl glycan moiety or a bicyclic glycan moiety, and the 3' and 5' nucleotides in the central region each contain a glycan moiety independently selected from the 2'-deoxyfuranyl glycan moiety or the glycan substitution. The position of the central region refers to the sequence of the nucleotides in the central region and is counted starting from the 5' end. Thus, the 5' nucleotide in the central region is at position 1. The “central region” may be referred to as the “gap,” and the “5' region” and “3' region” may be referred to as “wings.” The gap in the gap polymer is the deoxygenated region.

[0066] As used herein, “hepatotoxicity” in the mouse context refers to plasma ALT levels above 300 units per liter. Hepatotoxicity of the oligomeric compound or the parent oligomeric compound administered to mice is determined by measuring plasma ALT levels in mice 24 hours to 2 weeks after at least one dose of the compound at 1–150 mg / kg.

[0067] As used herein, “hepatotoxicity” in the human context refers to plasma ALT levels above 150 units per liter. Hepatotoxicity of oligomeric compounds or parent oligomeric compounds administered to humans is determined by measuring plasma ALT levels in humans 24 hours to 2 weeks after at least one dose of the compound (10–300 mg).

[0068] As used herein, “hybridization” refers to the pairing or annealing of complementary oligonucleotides and / or nucleic acids. While not limited to a specific mechanism, the most common hybridization mechanisms involve hydrogen bonding between complementary nucleobases, which can be Watson-Crick, Hoogsteen, or reverse Hoogsteen hydrogen bonding.

[0069] As used in this article, “inhibition of expression or activity” means a reduction or blockage of expression or activity relative to untreated or control samples, and does not necessarily mean complete elimination of expression or activity.

[0070] As used herein, “internucleotide bond” or “internucleotide linking group” refers to a group or bond that forms a covalent bond between adjacent nucleosides in an oligonucleotide. As used herein, “modified internucleotide bond” refers to any internucleotide bond other than a naturally occurring phosphodiester internucleotide bond. “Thiophosphate bond” refers to a modified internucleotide bond in which one of the non-bridging oxygen atoms of the phosphodiester is replaced by a sulfur atom. Modified internucleotide bonds may or may not contain a phosphorus atom. “Neutral internucleotide bond” is a modified internucleotide bond that does not have a negatively charged phosphate ester in a buffered aqueous solution at pH 7.0. Modified internucleotide bonds may optionally contain a conjugation group.

[0071] As used in this article, “linked nucleosides” are nucleosides linked by a continuous sequence (i.e., there are no other nucleosides between the linked nucleosides).

[0072] As used herein, “maximum tolerated dose” means the highest dose of a compound that will not cause unacceptable side effects. In some embodiments, the maximum tolerated dose is the highest dose of a modified oligonucleotide that will not cause an ALT increase of three times the upper limit of normal as measured by standard assays.

[0073] As used in this article, “mismatch” or “non-complementary” means that when the first and second oligonucleotides are matched, the nucleobases of the first oligonucleotide are not complementary to the corresponding nucleobases of the second oligonucleotide or target nucleic acid.

[0074] As used in this article, “regulation” refers to altering or adjusting characteristics in cells, tissues, organs, or organisms.

[0075] As used herein, “MOE” means O-methoxyethyl. “2'-MOE” or “2'-O-methoxyethyl” means the 2'-OCH2CH2OCH3 group at the 2' position of the furanyl ring. In some embodiments, the 2'-OCH2CH2OCH3 group replaces the 2'-OH group of the ribosyl ring or replaces the 2'-H in the 2'-deoxyribosyl ring. The “2'-MOE sugar moiety” is the sugar moiety in which the 2'-OCH2CH2OCH3 group replaces the 2'-OH group of the furanyl sugar moiety. Unless otherwise noted, the 2'-MOE sugar moiety is β-D ribosyl.

[0076] As used herein, the “2'-OMe sugar moiety” is a sugar moiety in which the 2'-OH group of the furanyl sugar moiety is replaced by the 2'-CH3 group. Unless otherwise noted, the 2'-OMe sugar moiety is β-D ribosyl and is a “stereostandard 2'OMe sugar moiety”.

[0077] As used herein, the “2’-F sugar moiety” is a sugar moiety in which the 2’-F group replaces the 2’-OH group of the furanyl sugar moiety. Unless otherwise noted, the 2’-F sugar moiety is β-D ribosyl and is a “stereostandard 2’-F sugar moiety”.

[0078] As used in this article, "motif" refers to the pattern of unmodified and / or modified sugar moieties, nucleobases, and / or nucleoside bonds in an oligonucleotide.

[0079] As used in this article, “naturally occurring” means found in nature.

[0080] As used herein, "nucleobase" means an unmodified nucleobase or a modified nucleobase. As used herein, an "unmodified nucleobase" is adenine (A), thymine (T), cytosine (C), uracil (U), or guanine (G). As used herein, a modified nucleobase is a group of atoms capable of pairing with at least one unmodified nucleobase. A universal base is a nucleobase capable of pairing with any of the five unmodified nucleobases. 5-Methylcytosine ( m C) is an example of a modified nucleobase.

[0081] As used in this article, "nucleobase sequence" refers to the sequence of consecutive nucleobases in a nucleic acid or oligonucleotide that is independent of any sugar moiety or nucleoside internucleotide modification.

[0082] As used herein, "nucleoside" means a moiety comprising a nucleobase and a sugar moiety. The nucleobase and sugar moiety are either unmodified or modified independently. As used herein, "modified nucleoside" means a nucleoside comprising a modified nucleobase and / or a modified sugar moiety. Modified nucleosides may contain conjugate groups.

[0083] As used herein, “oligomeric compound” means a compound consisting of: (1) an oligonucleotide (single-stranded oligomeric compound) or two oligonucleotides hybridized with each other (double-stranded oligomeric compound); and (2) optionally one or more additional features, such as conjugation groups or terminal groups that can be attached to the oligonucleotide of the single-stranded oligomeric compound or one or two oligonucleotides of the double-stranded oligomeric compound.

[0084] As used herein, “oligonucleotide” means a chain of linking nucleosides connected by internucleotide bonds, wherein each nucleoside and internucleotide bond may be modified or unmodified. Unless otherwise indicated, an oligonucleotide consists of 12-3000 linking nucleosides and optionally conjugation groups or terminal groups. As used herein, “modified oligonucleotide” means an oligonucleotide in which at least one nucleoside or internucleotide bond is modified. As used herein, “unmodified oligonucleotide” means an oligonucleotide that does not contain any nucleoside or internucleotide modifications.

[0085] As used herein, “parent antisense agent” means an antisense agent other than an RNAi agent that is the same as an antisense agent having at least one nucleoside inter-bond of formula XVII, except that the parent antisense agent has a thiophosphate nucleoside inter-bond instead of each nucleoside inter-bond of formula XVII in the antisense agent having at least one nucleoside inter-bond of formula XVII.

[0086] As used herein, “parent RNAi agent” means the same RNAi agent as an RNAi agent having at least one nucleoside bond of formula XVII, the difference being that the parent RNAi agent has a phosphodiester nucleoside bond instead of each nucleoside bond of formula XVII in the RNAi agent having at least one nucleoside bond of formula XVII.

[0087] As used herein, "pharmaceutically acceptable carrier or diluent" means any substance suitable for administration to animals. Certain such carriers enable pharmaceutical compositions to be formulated as, for example, liquids, powders, or suspensions, which can be atomized or otherwise dispersed for inhalation by a subject. In some embodiments, a pharmaceutically acceptable carrier or diluent is sterile water; sterile saline; or a sterile buffer solution.

[0088] As used herein, “pharmaceutically acceptable salt” means a physiologically and pharmaceutically acceptable salt of a compound such as an oligomer (including oligomers that are antisense agents or a portion thereof), i.e., a salt that retains the desired biological activity of the compound without conferring adverse toxicological effects upon it.

[0089] As used herein, "pharmaceutical composition" means a mixture of substances suitable for administration to a subject. For example, a pharmaceutical composition may comprise an antisense compound and an aqueous solution.

[0090] As used herein, "RNAi agent" means an antisense agent that acts at least partially via RISC or Ago2 to regulate a target nucleic acid and / or the 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 contain conjugation groups and / or terminal groups. In some embodiments, RNAi agents regulate the amount, activity, and / or splicing of the target nucleic acid. The term RNAi agent does not include antisense agents that act via RNase H.

[0091] As used in this article, “RNAi oligonucleotide” refers to an RNAi antisense modified oligonucleotide or an RNAi sense modified oligonucleotide.

[0092] As used herein, “RNAi antisense modified oligonucleotide” means an oligonucleotide that contains a region complementary to the target sequence and includes at least one chemical modification suitable for RNAi.

[0093] As used herein, “RNAi antisense oligomer” means a single-stranded oligomer that contains a region complementary to the target sequence and includes at least one chemical modification suitable for RNAi.

[0094] As used herein, “RNAi positive-modified oligonucleotide” means an oligonucleotide that contains a region complementary to the region of an RNAi antisense-modified oligonucleotide and is capable of forming a double strand with such an RNAi antisense-modified oligonucleotide.

[0095] As used herein, "RNAi positive oligomer" means a single-stranded oligomer containing a region complementary to the region of an RNAi antisense modified oligonucleotide and / or an RNAi antisense oligomer and capable of forming a double strand with such RNAi antisense modified oligonucleotide and / or RNAi antisense oligomer.

[0096] The double strand formed by an RNAi antisense modified oligonucleotide and / or an RNAi antisense oligomer with an RNAi sense modified oligonucleotide and / or an RNAi sense oligomer is called a double-stranded RNAi compound (dsRNAi) or short interfering RNA (siRNA).

[0097] As used herein, "RNase H agent" means an antisense agent that functions at least partially via RNase H to regulate a target nucleic acid and / or the protein encoded by the target nucleic acid. In some embodiments, the RNase H agent is single-stranded. In some embodiments, the RNase H agent is double-stranded. RNase H compounds may contain conjugation groups and / or terminal groups. In some embodiments, the RNase H agent regulates the amount or activity of the target nucleic acid. The term RNase H agent does not include antisense agents that function primarily via RISC / Ago2.

[0098] As used herein, "RNase H antisense modified oligonucleotide" means an oligonucleotide that contains a region complementary to the target sequence and includes at least one chemically modified oligonucleotide suitable for RNase H-mediated nucleic acid reduction.

[0099] As used herein, "RNAi compound" means an antisense compound that functions at least partially via RISC or Ago2 to regulate a target nucleic acid and / or the protein encoded by the target nucleic acid. RNAi compounds include, but are not limited to, double-stranded siRNA, single-stranded RNA (ssRNA), and microRNA, including microRNA mimics. In some embodiments, RNAi compounds regulate the amount, activity, and / or splicing of the target nucleic acid. The term RNAi compound does not include antisense oligonucleotides that function via RNase H.

[0100] As used herein, the term "single-chain" in relation to an antisense compound means a compound consisting of an oligomer that does not pair with a second oligomer to form a duplex. The term "self-complementary" in relation to an oligonucleotide means an oligonucleotide that hybridizes at least partially with itself. A compound consisting of an oligomer (in which the oligonucleotides are self-complementary) is a single-chain compound. A single-chain antisense or oligomer may be able to combine with a complementary oligomer to form a duplex, in which case the compound will no longer be single-chain.

[0101] As used herein, a “stable phosphate group” refers to the 5’-chemical moiety that stabilizes the 5’-phosphate portion of the 5’-terminal nucleoside of the oligonucleotide, relative to the stability of the unmodified 5’-phosphate ester of the unmodified nucleoside under biological conditions. This stabilization of the 5’-phosphate group includes, but is not limited to, resistance to removal by phosphatases. Stabilized phosphate groups include, but are not limited to, 5’-vinylphosphonate and 5’-cyclopropylphosphonate.

[0102] As used herein, “stereostandard nucleoside” means a nucleoside comprising a non-bicyclic furanyl sugar moiety having the configurations of naturally occurring DNA and RNA as shown below. “Stereostandard DNA nucleoside” is a nucleoside comprising a β-D-2'-deoxyribosyl sugar moiety. “Stereostandard RNA nucleoside” is a nucleoside comprising a β-D-ribosyl sugar moiety. “Substituted stereostandard nucleoside” is a stereostandard nucleoside other than stereostandard DNA or stereostandard RNA nucleoside. In some embodiments, R1 is a 2'-substituent, and R2-R5 are each H. In some embodiments, the 2'-substituent is selected from OMe, F, OCH2CH2OCH3, O-alkyl, SMe, or NMA. In some embodiments, R1-R4 are H, and R5 is a 5'-substituent selected from methyl, allyl, or ethyl. In some embodiments, the heterocyclic base moiety Bx is selected from uracil, thymine, cytosine, 5-methylcytosine, adenine, or guanine. In some embodiments, the heterocyclic base moiety Bx is not uracil, thymine, cytosine, 5-methylcytosine, adenine, or guanine.

[0103]

[0104] As used herein, "stereotypical nonstandard nucleoside" means a nucleoside comprising a non-bicyclic furanyl sugar moiety having a configuration different from that of a stereostandard sugar moiety. In some embodiments, "stereotypical nonstandard nucleoside" is represented by formulas I-VII. In some embodiments, J1-J 14 Independently selected from H, OH, F, OCH3, OCH2CH2OCH3, O-C1-C6 alkoxy groups, and SCH3. The “stereo-non-standard RNA nucleoside” has one of formulas I-VII, wherein J1, J3, J5, J7, J9, J 11 and J 13 Each of them is H, and J2, J4, J6, J8, J 10 J 12 and J 14 Each of them is OH. "Stereotypical non-standard DNA nucleosides" have one of the following formulas I-VII, where each J is H. "2'-substituted stereotypical non-standard nucleosides" have one of the following formulas I-VII, where J1, J3, J5, J7, J9, J... 11 and J13 Not H, and / or J2, J4, J6, J8, J 10 J 12 and J 14 Not H or OH. In some embodiments, the heterocyclic base moiety Bx is selected from uracil, thymine, cytosine, 5-methylcytosine, adenine, or guanine. In some embodiments, the heterocyclic base moiety Bx is not uracil, thymine, cytosine, 5-methylcytosine, adenine, or guanine.

[0105]

[0106]

[0107]

[0108] As used in this article, "stereostandard sugar fraction" refers to the sugar fraction of stereostandard nucleosides.

[0109] As used in this article, "stereotypical non-standard sugar fraction" refers to the sugar fraction of stereotypical non-standard nucleosides.

[0110] As used herein, “substituted stereononstandard nucleosides” means stereononstandard nucleosides containing substituents other than those corresponding to substituents in native RNA or DNA. Substituted stereononstandard nucleosides include, but are not limited to, nucleosides of formulas I-VII, wherein the J group is not: (1) all of them are H, or (2) one is H and the other is OH.

[0111] As used in this article, “subject” means a human or non-human animal selected for treatment or therapy.

[0112] As used herein, “glycan moiety” means an unmodified or modified sugar moiety. As used herein, “unmodified sugar moiety” means, for example, the β-D-ribosyl moiety found in naturally occurring RNA, or the β-D-2'-deoxyribosyl sugar moiety found in naturally occurring DNA. As used herein, “modified sugar moiety” or “modified sugar” means a sugar substitute or a furanyl sugar moiety other than β-D-ribosyl or β-D-2'-deoxyribosyl. Modified furanyl sugar moieties may be modified, substituted, or unsubstituted at specific positions within the sugar moiety, and they may or may not be stereochemical non-standard sugar moieties. Modified furanyl sugar moieties include bicyclic and non-bicyclic sugars. As used herein, “sugar substitute” means a modified sugar moiety that does not contain a furanyl or tetrahydrofuranyl ring (not a “furanyl sugar moiety”) and may have a nucleobase linked to another group, such as an internucleotide bond, conjugation group, or terminal group in an oligonucleotide. Nucleosides modified with sugar substitutes can bind to one or more sites within oligonucleotides, and these oligonucleotides can hybridize with complementary oligomers or nucleic acids.

[0113] As used herein, “target nucleic acid,” “target RNA,” “target RNA transcript,” and “nucleic acid target” refer to nucleic acids to which oligomeric compounds, such as antisense compounds, are designed to influence. In some embodiments, the oligomeric compound comprises an oligonucleotide having a nucleobase sequence complementary to more than one RNA, wherein only one RNA is the target RNA of the oligomeric compound. In some embodiments, the target RNA is RNA present in the species to which the oligomeric compound is applied.

[0114] As used herein, "therapeutic index" refers to the comparison between the amount of a compound that causes a therapeutic effect and the amount that causes toxicity. Compounds with a high therapeutic index are potent and have low toxicity. In some embodiments, increasing the therapeutic index of a compound increases the amount of the compound that can be safely administered.

[0115] As used in this article, “treatment” means administering a compound or pharmaceutical composition to an animal in order to alter or improve a disease, symptom, or ailment.

[0116] As used herein, a “translation repressive element” means any sequence and / or secondary structure in the 5'-UTR of a target transcript that reduces, blocks, and / or inhibits the translation of the target transcript. In some embodiments, the translation repressive element comprises a uORF. In some embodiments, the translation repressive element does not comprise a uORF. In some embodiments, the translation repressive element comprises one or more stem-loops. In some embodiments, the translation repressive element comprises a GC content greater than 60%, greater than 70%, or greater than 80%. In some embodiments, the translation repressive element is a uORF. In some embodiments, the translation repressive element is a stem-loop.

[0117] Some implementation schemes

[0118] This disclosure provides the following non-restrictive implementation methods:

[0119] Implementation Scheme 1. An oligomeric compound comprising a modified oligonucleotide composed of linking nucleosides connected by internucleotide linking groups, wherein at least one of the internucleotide linking groups has the formula VIII:

[0120]

[0121] For each nucleoside linker of formula VIII in the modified oligonucleotide, independently:

[0122] R1 is selected from H, C1-C6 alkyl groups, and substituted C1-C6 alkyl groups; and

[0123] T is selected from SO2R2, C(=O)R3 and P(=O)R4R5, where:

[0124] R2 is selected from aryl, substituted aryl, heterocyclic, substituted heterocyclic, aromatic heterocyclic, substituted aromatic heterocyclic, diazole, substituted diazole, amine, substituted amine, C1-C6 alkoxy, C1-C6 alkyl and substituted C1-C6 alkyl.

[0125] R3 is selected from aryl, substituted aryl, CH3, N(CH3)2 and OCH3;

[0126] R4 is selected from OCH3, OH, C1-C6 alkyl, and substituted C1-C6 alkyl; and

[0127] R5 is selected from OCH3, OH, C1-C6 alkyl, and substituted C1-C6 alkyl.

[0128] Implementation Scheme 2. An oligomeric compound comprising a modified oligonucleotide consisting of linked nucleosides connected by internucleotide linking groups, wherein at least one of the internucleotide linking groups has the formula VIII:

[0129]

[0130] For each nucleoside linker of formula VIII in the modified oligonucleotide, independently:

[0131] R1 is selected from H, C1-C6 alkyl groups, and substituted C1-C6 alkyl groups; and

[0132] T is selected from SO2R2, C(=O)R3 and P(=O)R4R5, where:

[0133] R2 is selected from aryl, substituted aryl, heterocyclic, substituted heterocyclic, aromatic heterocyclic, substituted aromatic heterocyclic, diazole, substituted diazole, C1-C6 alkoxy, C1-C6 alkyl and substituted C1-C6 alkyl.

[0134] R3 is selected from aryl, substituted aryl, CH3, N(CH3)2 and OCH3;

[0135] R4 is selected from OCH3, OH, C1-C6 alkyl, and substituted C1-C6 alkyl; and

[0136] R5 is selected from OCH3, OH, C1-C6 alkyl, and substituted C1-C6 alkyl;

[0137] The condition is that if R1 is H, then T is not:

[0138]

[0139] Implementation scheme 3. The oligomeric compound of implementation scheme 1 or 2, wherein R1 is H.

[0140] Implementation Scheme 4. The oligomeric compound of Implementation Scheme 1 or 2, wherein R1 is a C1-C6 alkyl group.

[0141] Implementation Scheme 5. The oligomeric compound of Implementation Scheme 4, wherein R1 is methyl.

[0142] Implementation Scheme 6. The oligomeric compound of Implementation Scheme 1 or 2, wherein R1 is a substituted C1-C6 alkyl group;

[0143] Implementation Scheme 7. An oligomeric compound of any one of Implementation Schemes 1-6, wherein T is SO2R2.

[0144] Implementation scheme 8. The oligomeric compound of implementation scheme 7, wherein R2 is an aryl group.

[0145] Implementation Scheme 9. The oligomeric compound of Implementation Scheme 7, wherein R2 is a substituted aryl group.

[0146] Implementation Scheme 10. The oligomeric compound of Implementation Scheme 7, wherein R2 is a heterocyclic ring.

[0147] Implementation Scheme 11. The oligomeric compound of Implementation Scheme 7, wherein R2 is a substituted heterocycle.

[0148] Implementation Scheme 12. The oligomeric compound of Implementation Scheme 7, wherein R2 is an aromatic heterocycle.

[0149] Implementation Scheme 13. The oligomeric compound of Implementation Scheme 7, wherein R2 is a substituted aromatic heterocycle.

[0150] Implementation Scheme 14. The oligomeric compound of Implementation Scheme 7, wherein R2 is a diazole.

[0151] Implementation Scheme 15. The oligomeric compound of Implementation Scheme 7, wherein R2 is a substituted diazole.

[0152] Implementation scheme 16. The oligomeric compound of implementation scheme 7, wherein R2 is an amine.

[0153] Implementation Scheme 17. The oligomeric compound of Implementation Scheme 7, wherein R2 is a substituted amine.

[0154] Implementation Scheme 18. The oligomeric compound of Implementation Scheme 7, wherein R2 is a C1-C6 alkoxy group.

[0155] Implementation Scheme 19. The oligomeric compound of Implementation Scheme 7, wherein R2 is a C1-C6 alkyl group.

[0156] Implementation Scheme 20. The oligomeric compound of Implementation Scheme 7, wherein R2 is a substituted C1-C6 alkyl group.

[0157] Implementation Scheme 21. The oligomeric compound of Implementation Scheme 7, wherein T is:

[0158]

[0159] Implementation Scheme 22. The oligomeric compound of Implementation Scheme 7, wherein T is:

[0160]

[0161] Implementation Scheme 23. The oligomeric compound of Implementation Scheme 7, wherein T is:

[0162]

[0163] Implementation Scheme 24. The oligomeric compound of Implementation Scheme 7, wherein T is:

[0164]

[0165] Implementation Scheme 25. The oligomeric compound of Implementation Scheme 7, wherein T is:

[0166]

[0167] Implementation Scheme 26. The oligomeric compound of Implementation Scheme 7, wherein T is:

[0168]

[0169] Implementation Scheme 27. The oligomeric compound of Implementation Scheme 7, wherein T is:

[0170]

[0171] Implementation Scheme 28. The oligomeric compound of Implementation Scheme 7, wherein T is:

[0172]

[0173] Implementation Scheme 29. The oligomeric compound of Implementation Scheme 7, wherein T is:

[0174]

[0175] Implementation scheme 30. An oligomeric compound of any one of implementation schemes 1-6, wherein T is C(=O)R3.

[0176] Implementation Scheme 31. The oligomeric compound of Implementation Scheme 30, wherein R3 is an aryl group.

[0177] Implementation Scheme 32. The oligomeric compound of Implementation Scheme 30, wherein R3 is a substituted aryl group.

[0178] Implementation scheme 33. The oligomeric compound of implementation scheme 30, wherein R3 is CH3.

[0179] Implementation scheme 34. The oligomeric compound of implementation scheme 30, wherein R3 is N(CH3)2.

[0180] Implementation Scheme 35. The oligomeric compound of Implementation Scheme 30, wherein R3 is OCH3.

[0181] Implementation Scheme 36. The oligomeric compound of Implementation Scheme 30, wherein T is:

[0182]

[0183] Implementation Scheme 37. The oligomeric compound of Implementation Scheme 30, wherein T is:

[0184]

[0185] Implementation Scheme 38. The oligomeric compound of Implementation Scheme 30, wherein T is:

[0186]

[0187] Implementation Scheme 39. The oligomeric compound of Implementation Scheme 30, wherein T is:

[0188]

[0189] Implementation Scheme 40. An oligomeric compound of any one of Implementation Schemes 1-6, wherein T is P(=O)R4R5

[0190] Implementation Scheme 41. The oligomeric compound of Implementation Scheme 40, wherein R4 is OCH3.

[0191] Implementation Scheme 42. The oligomeric compound of Implementation Scheme 40, wherein R4 is OH.

[0192] Implementation Scheme 43. The oligomeric compound of Implementation Scheme 40, wherein R4 is a C1-C6 alkyl group.

[0193] Implementation Scheme 44. The oligomeric compound of Implementation Scheme 40, wherein R4 is a substituted C1-C6 alkyl group.

[0194] Implementation Scheme 45. An oligomeric compound of any one of Implementation Schemes 40-42, wherein R5 is OCH3.

[0195] Implementation Scheme 46. An oligomeric compound of any one of Implementation Schemes 40-42, wherein R5 is OH.

[0196] Implementation Scheme 47. An oligomeric compound of any one of Implementation Schemes 40-42, wherein R5 is a C1-C6 alkyl group.

[0197] Implementation Scheme 48. An oligomeric compound of any one of Implementation Schemes 40-42, wherein R5 is a substituted C1-C6 alkyl group.

[0198] Implementation Scheme 49. The oligomeric compound of Implementation Scheme 40, wherein T is:

[0199]

[0200] Implementation Scheme 50. The oligomeric compound of Implementation Scheme 40, wherein T is:

[0201]

[0202] Implementation Scheme 51. An oligomeric compound of any one of Implementation Schemes 1-50, wherein at least one internucleotide linking group of the modified oligonucleotide is not a linking group of Formula VIII.

[0203] Implementation Scheme 52. An oligomeric compound of any one of Implementation Schemes 1-50, wherein exactly one of the internucleotide linkage groups of the modified oligonucleotide is an internucleotide linkage group of any one of Implementation Schemes 1-50.

[0204] Implementation Scheme 53. An oligomeric compound of any one of Implementation Schemes 1-50, wherein exactly two nucleoside linking groups of the modified oligonucleotide are nucleoside linking groups of any one of Implementation Schemes 1-50.

[0205] Implementation Scheme 54. An oligomeric compound of any one of Implementation Schemes 1-50, wherein exactly three internucleotide linking groups of the modified oligonucleotide are internucleotide linking groups of any one of Implementation Schemes 1-50.

[0206] Implementation Scheme 55. An oligomeric compound of any one of Implementation Schemes 1-50, wherein exactly four internucleotide linking groups of the modified oligonucleotide are internucleotide linking groups of any one of Implementation Schemes 1-50.

[0207] Implementation Scheme 56. An oligomeric compound of any one of Implementation Schemes 1-50, wherein exactly five nucleoside linking groups of the modified oligonucleotide are nucleoside linking groups of any one of Implementation Schemes 1-50.

[0208] Implementation Scheme 57. An oligomeric compound of any one of Implementation Schemes 1-50, wherein at least six internucleotide linking groups of the modified oligonucleotide are internucleotide linking groups of any one of Implementation Schemes 1-50.

[0209] Implementation Scheme 58. An oligomeric compound of any one of Implementation Schemes 1-51 or 53-57, having at least two linking groups of any one of Implementation Schemes 1-50, wherein the linking groups of at least two Implementation Schemes 1-50 are identical to each other.

[0210] Implementation Scheme 59. An oligomeric compound of any one of Implementation Schemes 1-58, wherein each nucleoside linker of the modified oligonucleotide that is not a nucleoside linker of any one of Implementation Schemes 1-50 is a phosphate diester nucleoside linker or a thiophosphate nucleoside linker.

[0211] Implementation Scheme 60. An oligomeric compound of any one of Implementation Schemes 1-58, wherein each nucleoside linker of the modified oligonucleotide is a nucleoside linker of any one of Implementation Schemes 1-50.

[0212] Implementation Scheme 61. An oligomeric compound of any one of Implementation Schemes 1-60, wherein at least one nucleoside of the modified oligonucleotide is a modified nucleoside.

[0213] Implementation Scheme 62. The oligomeric compound of Implementation Scheme 61, wherein at least one nucleoside of the modified oligonucleotide is a modified nucleoside selected from bicyclic nucleosides and non-bicyclic substituted nucleosides.

[0214] Implementation Scheme 63. An oligomeric compound of any one of Implementation Schemes 1-62, wherein at least one nucleoside of the modified oligonucleotide is selected from: β-D-LNA nucleoside, α-L-LNA nucleoside, ENA nucleoside, cEt nucleoside, 2'-MOE nucleoside, 2'-OMe nucleoside, 2'-F nucleoside, 2'-NMA nucleoside, 5'-Me nucleoside, DNA nucleoside, and RNA nucleoside.

[0215] Implementation Scheme 64. An oligomeric compound of any one of Implementation Schemes 1-62, wherein each nucleoside of the modified oligonucleotide is selected from: β-D-LNA nucleoside, α-L-LNA nucleoside, ENA nucleoside, cEt nucleoside, 2'-MOE nucleoside, 2'-OMe nucleoside, 2'-F nucleoside, 2'-NMA nucleoside, 5'-Me nucleoside, DNA nucleoside, and RNA nucleoside.

[0216] Implementation Scheme 65. An oligomeric compound of any one of Implementation Schemes 1-62, wherein at least one nucleoside of the modified oligonucleotide is selected from: 2'-OMe nucleoside, 2'-F nucleoside and RNA nucleoside.

[0217] Implementation Scheme 66. An oligomeric compound of any one of Implementation Schemes 1-62, wherein at least one nucleoside of the modified oligonucleotide is a 2'-OMe nucleoside, and at least one nucleoside of the modified oligonucleotide is an RNA nucleoside.

[0218] Implementation Scheme 67. An oligomeric compound of any one of Implementation Schemes 61-66, wherein the modified oligonucleotide has a region of alternating nucleoside types having a motif ABABA, wherein each A is a stereostandard nucleoside of a first type and each B is a stereostandard nucleoside of a second type, wherein the first type and the second type are different from each other.

[0219] Implementation Scheme 68. The oligomeric compound of Implementation Scheme 67, wherein A and B are selected from 2'-F substituted nucleosides, 2'-OMe substituted nucleosides and stereostandard RNA nucleosides.

[0220] Implementation Scheme 69. An oligomeric compound of any one of Implementation Schemes 1-68, wherein the 5' end of the modified oligonucleotide comprises a stable phosphate ester group.

[0221] Implementation Scheme 70. An oligomeric compound of any one of Implementation Schemes 1-69, wherein the modified oligonucleotide is composed of 12-30 linked nucleosides.

[0222] Implementation Scheme 71. An oligomeric compound of any one of Implementation Schemes 1-69, wherein the modified oligonucleotide is composed of 16-24 linked nucleosides.

[0223] Implementation Scheme 72. An oligomeric compound of any one of Implementation Schemes 1-69, wherein the modified oligonucleotide is composed of 18-22 linked nucleosides.

[0224] Implementation Scheme 73. An oligomeric compound of any one of Implementation Schemes 1-69, wherein the modified oligonucleotide is composed of 16 linked nucleosides.

[0225] Implementation Scheme 74. An oligomeric compound of any one of Implementation Schemes 1-69, wherein the modified oligonucleotide is composed of 17 linked nucleosides.

[0226] Implementation Scheme 75. An oligomeric compound of any one of Implementation Schemes 1-69, wherein the modified oligonucleotide is composed of 18 linked nucleosides.

[0227] Implementation Scheme 76. An oligomeric compound of any one of Implementation Schemes 1-69, wherein the modified oligonucleotide is composed of 19 linked nucleosides.

[0228] Implementation Scheme 77. An oligomeric compound of any one of Implementation Schemes 1-69, wherein the modified oligonucleotide is composed of 20 linked nucleosides.

[0229] Implementation Scheme 78. An oligomeric compound of any one of Implementation Schemes 1-69, wherein the modified oligonucleotide is composed of 21 linked nucleosides.

[0230] Implementation Scheme 79. An oligomeric compound of any one of Implementation Schemes 1-69, wherein the modified oligonucleotide is composed of 22 linked nucleosides.

[0231] Implementation Scheme 80. An oligomeric compound of any one of Implementation Schemes 1-69, wherein the modified oligonucleotide is composed of 23 linked nucleosides.

[0232] Implementation Scheme 81. An oligomeric compound of any one of Implementation Schemes 1-80, wherein the oligomeric compound is an RNAi compound.

[0233] Implementation Scheme 82. The oligomeric compound of Implementation Scheme 81, wherein the RNAi compound is a single-stranded RNAi compound comprising an RNAi antisense modified oligonucleotide, wherein the RNAi antisense modified compound is an oligonucleotide modified by any one of Implementation Schemes 1-78.

[0234] Implementation Scheme 83. The oligomeric compound of Implementation Scheme 81, wherein the RNAi compound is a double-stranded RNAi compound comprising an RNAi antisense modified oligonucleotide and an RNAi sense modified oligonucleotide, wherein the RNAi antisense modified oligonucleotide and / or the RNAi sense modified oligonucleotide are oligonucleotides modified in any of Implementation Schemes 1-78.

[0235] Implementation Scheme 84. The oligomeric compound of Implementation Scheme 82 or 83, wherein at least one nucleoside linker of the RNAi antisense modified oligonucleotide is a nucleoside linker of any one of Implementation Schemes 1-50.

[0236] Implementation Scheme 85. The oligomeric compound of Implementation Scheme 82 or 83, wherein at least two internucleotide linking groups of the RNAi antisense modified oligonucleotide are independently selected internucleotide linking groups of any one of Implementation Schemes 1-50.

[0237] Implementation Scheme 86. An oligomeric compound of any one of Implementation Schemes 82-85, wherein at least one of the five 3' internucleotide linking groups of the RNAi antisense modified oligonucleotide is an internucleotide linking group of any one of Implementation Schemes 1-50.

[0238] Implementation Scheme 87. An oligomeric compound of any one of Implementation Schemes 82-86, wherein at least two of the five 3' internucleotide linking groups of the RNAi antisense modified oligonucleotide are internucleotide linking groups of any one of Implementation Schemes 1-50.

[0239] Implementation Scheme 88. An oligomeric compound of any one of Implementation Schemes 82-87, wherein at least one internucleotide linker in the seed region of the RNAi antisense modified oligonucleotide is an internucleotide linker of any one of Implementation Schemes 1-50.

[0240] Implementation Scheme 89. The oligomeric compound of Implementation Schemes 83-88, wherein at least one nucleoside linker of the RNAi positively modified oligonucleotide is a nucleoside linker of any one of Implementation Schemes 1-50.

[0241] Implementation Scheme 90. The oligomeric compound of Implementation Scheme 89, wherein at least one of the first five internucleotide linking groups from the 5' end of the RNAi positively modified oligonucleotide is an internucleotide linking group of any one of Implementation Schemes 1-50.

[0242] Implementation Scheme 91. An oligomeric compound of any one of Implementation Schemes 89-90, wherein at least one of the five 3' internucleotide linking groups of the RNAi positively modified oligonucleotide is an internucleotide linking group of any one of Implementation Schemes 1-50.

[0243] Implementation Scheme 92. An oligomeric compound of any one of Implementation Schemes 89-91, wherein at least one of the first five internucleotide linking groups from the 5' end of the RNAi positively modified oligonucleotide and at least one of the five 3' linking groups of the RNAi positively modified oligonucleotide are internucleotide linking groups of any one of Implementation Schemes 1-50.

[0244] Implementation Scheme 93. An oligomeric compound of any one of Implementation Schemes 1-92, wherein at least one nucleoside of the modified oligonucleotide is a stereononstandard nucleoside.

[0245] Implementation Scheme 94. The oligomeric compound of Implementation Scheme 93, wherein the internucleotide linking group connecting at least one stereonon-standard nucleoside to an adjacent nucleoside is any one of the internucleotide linking groups of Implementation Schemes 1-50.

[0246] Implementation Scheme 95. The oligomeric compound of Implementation Scheme 93 or 94, wherein at least two nucleosides of the modified oligonucleotide are stereononstandard nucleosides.

[0247] Implementation Scheme 96. The oligomeric compound of Implementation Scheme 95, wherein at least two stereonon-standard nucleosides of the modified oligonucleotide are adjacent to each other.

[0248] Implementation Scheme 97. The oligomeric compound of Implementation Scheme 96, wherein at least two stereonon-standard nucleosides of the modified oligonucleotide are linked to each other by an inter-nucleoside linking group of any one of Implementation Schemes 1-50.

[0249] Implementation Scheme 98. An oligomeric compound of any one of Implementation Schemes 95-97, wherein at least one stereononstandard nucleoside of the modified oligonucleotide is a stereononstandard DNA nucleoside.

[0250] Implementation Scheme 99. An oligomeric compound of any one of Implementation Schemes 95-97, wherein at least one stereononstandard nucleoside of the modified oligonucleotide is a substituted stereononstandard nucleoside or a stereononstandard RNA nucleoside.

[0251] Implementation Scheme 100. The oligomeric compound of Implementation Scheme 99, wherein the 2'-substituent of at least one substituted stereonon-standard nucleoside of the modified oligonucleotide is selected from: 2'-MOE, 2'-OMe, 2'-F or 2'-OH.

[0252] Implementation Scheme 101. An oligomeric compound of any one of Implementation Schemes 1-100, wherein the modified oligonucleotide comprises a deoxygenated region consisting of 6-11 linked nucleosides, wherein each nucleoside of the deoxygenated region is a modified nucleoside or a stereostandard DNA nucleoside, and wherein at least 3 consecutive nucleosides of the deoxygenated region are stereostandard DNA nucleosides, and no more than 3 nucleosides of the deoxygenated region are modified nucleosides.

[0253] Implementation scheme 102. The oligomeric compound of implementation scheme 101, wherein at least four consecutive nucleosides in the deoxygenated region are stereostandard DNA nucleosides.

[0254] Implementation scheme 103. The oligomeric compound of implementation scheme 101, wherein at least five consecutive nucleosides in the deoxygenated region are stereostandard DNA nucleosides.

[0255] Implementation scheme 104. The oligomeric compound of implementation scheme 101, wherein at least 6 consecutive nucleosides in the deoxygenated region are stereostandard DNA nucleosides.

[0256] Implementation scheme 105. The oligomeric compound of implementation scheme 101, wherein at least 7 consecutive nucleosides in the deoxygenated region are stereostandard DNA nucleosides.

[0257] Implementation Scheme 106. The oligomeric compound of Implementation Scheme 101, wherein at least eight consecutive nucleosides in the deoxygenated region are stereostandard DNA nucleosides.

[0258] Implementation scheme 107. An oligomeric compound of any one of implementation schemes 101-106, wherein the deoxygenated region is composed of 8-10 linked nucleosides.

[0259] Implementation scheme 108. An oligomeric compound of any one of implementation schemes 101-106, wherein the deoxygenated region is composed of 9 linked nucleosides.

[0260] Implementation scheme 109. An oligomeric compound of any one of implementation schemes 101-106, wherein the deoxygenated region is composed of 10 linked nucleosides.

[0261] Implementation scheme 110. An oligomeric compound of any one of implementation schemes 101-106, wherein the deoxygenated region is composed of 11 linked nucleosides.

[0262] Implementation scheme 111. An oligomeric compound of any one of implementation schemes 101-110, wherein at least 6 nucleotides of the deoxygenated region are stereostandard DNA nucleotides.

[0263] Implementation Scheme 112. An oligomeric compound of any one of Implementation Schemes 101-110, wherein at least 7 nucleotides of the deoxygenated region are stereostandard DNA nucleotides.

[0264] Implementation scheme 113. An oligomeric compound of any one of implementation schemes 101-110, wherein at least 8 nucleotides of the deoxygenated region are stereostandard DNA nucleotides.

[0265] Implementation Scheme 114. An oligomeric compound of any one of Implementation Schemes 101-110, wherein at least nine nucleosides in the deoxygenated region are stereostandard DNA nucleosides.

[0266] Implementation Scheme 115. An oligomeric compound of any one of Implementation Schemes 101-114, wherein the two nucleosides of the deoxygenated region are modified nucleosides.

[0267] Implementation Scheme 116. An oligomeric compound of any one of Implementation Schemes 101-114, wherein one of the nucleosides in the deoxygenated region is a modified nucleoside.

[0268] Implementation Scheme 117. An oligomeric compound of any one of Implementation Schemes 101-116, wherein at least one modified nucleoside in the deoxygenated region is a stereostandard modified nucleoside or bicyclic nucleoside selected from β-D-LNA nucleoside, α-L-LNA nucleoside, ENA nucleoside, cEt nucleoside, 2'-MOE nucleoside, 2'-OMe nucleoside, 2'-F nucleoside and 5'-alkyl nucleoside.

[0269] Implementation Scheme 118. An oligomeric compound of any one of Implementation Schemes 101-117, wherein at least one modified nucleoside of the deoxygenated region is a stereonon-standard nucleoside.

[0270] Implementation Scheme 119. The oligomeric compound of Implementation Scheme 118, wherein at least one stereononstandard isomeric nucleoside of the deoxygenated region is a stereononstandard DNA nucleoside.

[0271] Implementation Scheme 120. The oligomeric compound of Implementation Scheme 119, wherein the stereononstandard DNA nucleoside is selected from stereononstandard DNA nucleosides having formula I, formula II, formula III, formula IV, formula V, formula VI and formula VII.

[0272] Implementation Scheme 121. The oligomeric compound of Implementation Scheme 120, wherein the stereononstandard DNA nucleoside is selected from stereononstandard DNA nucleosides having Formula V and Formula II.

[0273] Implementation Scheme 122. An oligomeric compound of any one of Implementation Schemes 118-121, wherein at least one stereonon-standard nucleoside in the deoxygenated region is a substituted stereonon-standard nucleoside.

[0274] Implementation Scheme 123. The oligomeric compound of Implementation Scheme 122, wherein at least one substituted stereonon-standard nucleoside has a 2'-substituent selected from 2'-MOE, 2'-OMe, 2'-F or 2'-OH.

[0275] Implementation scheme 124. An oligomeric compound of any one of implementation schemes 101-123, wherein the second nucleoside from the 5' end of the deoxygenated region is a modified nucleoside.

[0276] Implementation Scheme 125. An oligomeric compound of any one of Implementation Schemes 101-124, wherein the third nucleoside from the 5' end of the deoxygenated region is a modified nucleoside.

[0277] Implementation Scheme 126. An oligomeric compound of any one of Implementation Schemes 101-125, wherein the fourth nucleoside from the 5' end of the deoxygenated region is a modified nucleoside.

[0278] Implementation scheme 127. An oligomeric compound of any one of implementation schemes 101-126, wherein each nucleoside of the deoxygenated region is a stereostandard DNA nucleoside.

[0279] Implementation Scheme 128. An oligomeric compound of any one of Implementation Schemes 101-127, wherein at least one internucleotide linking group in the deoxygenated region is an internucleotide linking group of any one of Implementation Schemes 1-50.

[0280] Implementation Scheme 129. An oligomeric compound of any one of Implementation Schemes 101-128, wherein the internucleotide linking group connecting the first and second nucleosides of the deoxygenated region, counted from the 5' end of the deoxygenated region, is an internucleotide linking group of any one of Implementation Schemes 1-50.

[0281] Implementation Scheme 130. An oligomeric compound of any one of Implementation Schemes 101-129, wherein the internucleotide linking group connecting the second and third nucleosides of the deoxygenated region, counted from the 5' end of the deoxygenated region, is an internucleotide linking group of any one of Implementation Schemes 1-50.

[0282] Implementation Scheme 131. An oligomeric compound of any one of Implementation Schemes 101-130, wherein the internucleotide linking group connecting the third and fourth nucleosides of the deoxygenated region, counted from the 5' end of the deoxygenated region, is an internucleotide linking group of any one of Implementation Schemes 1-50.

[0283] Implementation Scheme 132. An oligomeric compound of any one of Implementation Schemes 101-131, wherein the internucleotide linking group connecting the fourth and fifth nucleosides of the deoxygenated region, counted from the 5' end of the deoxygenated region, is an internucleotide linking group of any one of Implementation Schemes 1-50.

[0284] Implementation Scheme 133. An oligomeric compound of any one of Implementation Schemes 101-132, wherein one of the internucleotide linking groups in the deoxygenated region is a linking group of any one of Implementation Schemes 1-50, and the other internucleotide linking groups in the deoxygenated region are each phosphate diester or thiophosphate internucleotide linking groups.

[0285] Implementation Scheme 134. An oligomeric compound of any one of Implementation Schemes 101-133, wherein the two internucleotide linking groups in the deoxygenated region are linking groups of any one of Implementation Schemes 1-50, and the other internucleotide linking groups in the deoxygenated region are each phosphate diester or thiophosphate internucleotide linking groups.

[0286] Implementation Scheme 135. An oligomeric compound of any one of Implementation Schemes 101-134, wherein the three internucleotide linking groups in the deoxygenated region are linking groups of any one of Implementation Schemes 1-50, and the other internucleotide linking groups in the deoxygenated region are each phosphate diester or thiophosphate internucleotide linking groups.

[0287] Implementation Scheme 136. An oligomeric compound of any one of Implementation Schemes 101-135, wherein the deoxygenated region is side-attached on the 5' side by a 5' region consisting of 1-6 linked 5' region nucleosides, and on the 3' side by a 3' region consisting of 1-6 linked 3' region nucleosides; wherein

[0288] The 3' nucleotide in the 5' region is a modified nucleotide; and

[0289] The 5' nucleotide in the 3' region is a modified nucleotide.

[0290] Implementation scheme 137. The oligomeric compound of implementation scheme 136, wherein at least one 5' region nucleoside is a stereostandard DNA nucleoside.

[0291] Implementation scheme 138. The oligomeric compound of implementation scheme 136, wherein each 5' region nucleoside is a modified nucleoside.

[0292] Implementation scheme 139. An oligomeric compound of any one of implementation schemes 136, wherein at least one 5'-block nucleoside is a 2'-substituted nucleoside.

[0293] Implementation scheme 140. An oligomeric compound of any one of implementation schemes 136 or 138-139, wherein each 5' block nucleoside is a 2'-substituted nucleoside.

[0294] Implementation Scheme 141. An oligomeric compound of any one of Implementation Schemes 139-140, wherein the 2'-substituent is selected from 2'-F, 2'-OCH3 and 2'-MOE.

[0295] Implementation scheme 142. An oligomeric compound of any one of implementation schemes 136-139 or 141, wherein at least one 5' nucleoside is a bicyclic nucleoside.

[0296] Implementation scheme 143. The oligomeric compound of implementation scheme 142, wherein each 5' nucleoside is a bicyclic nucleoside.

[0297] Implementation Scheme 144. An oligomeric compound of any one of Implementation Schemes 142-143, wherein the bicyclic 5' region nucleoside is selected from β-D-LNA nucleoside, α-L-LNA nucleoside, ENA nucleoside and cEt nucleoside.

[0298] Implementation scheme 145. An oligomeric compound of any one of implementation schemes 136-144, wherein at least one 3' region nucleoside is a stereostandard DNA nucleoside.

[0299] Implementation scheme 146. An oligomeric compound of any one of implementation schemes 136-144, wherein each 3' nucleoside is a modified nucleoside.

[0300] Implementation scheme 147. An oligomeric compound of any one of implementation schemes 136-146, wherein at least one 3' block nucleoside is a 2'-substituted nucleoside.

[0301] Implementation scheme 148. An oligomeric compound of any one of implementation schemes 136-144 or 146-147, wherein each 3' block nucleoside is a 2'-substituted nucleoside.

[0302] Implementation Scheme 149. The oligomeric compound of Implementation Scheme 147 or 148, wherein the 2'-substituent is selected from 2'-F, 2'-OCH3 and 2'-MOE.

[0303] Implementation scheme 150. An oligomeric compound of any one of implementation schemes 136-147 or 149, wherein at least one 3' nucleoside is a bicyclic nucleoside.

[0304] Implementation scheme 151. The oligomeric compound of implementation scheme 150, wherein each 3' nucleoside is a bicyclic nucleoside.

[0305] Implementation Scheme 152. An oligomeric compound of any one of Implementation Schemes 150-151, wherein the bicyclic 3' region nucleoside is selected from β-D-LNA nucleoside, α-L-LNA nucleoside, ENA nucleoside and cEt nucleoside.

[0306] Implementation Scheme 153. An oligomeric compound of any one of Implementation Schemes 101-152, wherein the modified oligonucleotide is a nicked polymer.

[0307] Implementation Scheme 154. An oligomeric compound of any one of Implementation Schemes 1-80, wherein each nucleoside of the modified oligonucleotide is a modified nucleoside, and each modified nucleoside of the modified oligonucleotide contains the same modification.

[0308] Implementation Scheme 155. An oligomeric compound of any one of Implementation Schemes 1-153, wherein the nucleobase sequence of the modified oligonucleotide is complementary to the target nucleic acid.

[0309] Implementation Scheme 156. The oligomeric compound of Implementation Scheme 155, wherein the nucleobase sequence of the modified oligonucleotide is at least 80% complementary to the target nucleic acid.

[0310] Implementation Scheme 157. The oligomeric compound of Implementation Scheme 155, wherein the nucleobase sequence of the modified oligonucleotide is at least 85% complementary to the target nucleic acid.

[0311] Implementation Scheme 158. The oligomeric compound of Implementation Scheme 155, wherein the nucleobase sequence of the modified oligonucleotide is at least 90% complementary to the target nucleic acid.

[0312] Implementation Scheme 159. The oligomeric compound of Implementation Scheme 155, wherein the nucleobase sequence of the modified oligonucleotide is at least 95% complementary to the target nucleic acid.

[0313] Implementation Scheme 160. The oligomeric compound of Implementation Scheme 155, wherein the nucleobase sequence of the modified oligonucleotide is 100% complementary to the target nucleic acid.

[0314] Implementation scheme 161. An oligomeric compound of any one of implementation schemes 155-160, wherein the target nucleic acid is a target RNA.

[0315] Implementation Scheme 162. The oligomeric compound of Implementation Scheme 161, wherein the target RNA is selected from: mRNA, premRNA, microRNA and noncoding RNA.

[0316] Implementation scheme 163. The oligomeric compound of implementation scheme 161, wherein the target RNA is not a microRNA.

[0317] Implementation Scheme 164. An oligomeric compound of any one of Implementation Schemes 1-162, wherein the modified oligonucleotide is not complementary to miR-21.

[0318] Implementation Scheme 165. An oligomeric compound of any one of Implementation Schemes 1-163, comprising a conjugation group.

[0319] Implementation Scheme 166. The oligomeric compound of Implementation Scheme 164, wherein the conjugation group comprises at least one GalNAc.

[0320] Implementation scheme 167. The oligomeric compound of implementation scheme 164 or 165, wherein the conjugate group comprises 1-5 linker nucleosides.

[0321] Implementation scheme 168. An oligomeric compound of any one of implementation schemes 1-80, wherein the oligomeric compound is a CRISPR compound.

[0322] Implementation scheme 169. The oligomeric compound of implementation scheme 168, wherein the CRISPR compound consists of 20-50 linked nucleosides.

[0323] Implementation scheme 170. The oligomeric compound of implementation scheme 168, wherein the CRISPR compound consists of 29-32 linked nucleosides.

[0324] Implementation Scheme 171. A pharmaceutical composition comprising a CRISPR compound of Implementation Schemes 169-170 and a pharmaceutically acceptable carrier or diluent.

[0325] Implementation Scheme 172. A method comprising contacting cells with a CRISPR compound or composition of any one of Implementation Schemes 169-170.

[0326] Implementation Scheme 173. The method of Implementation Scheme 172, which includes contacting the cell with a plasmid encoding Cas9 or Cpf1.

[0327] Implementation scheme 174. The methods of implementation schemes 172-173, wherein the plasmid encodes tracrRNA.

[0328] Implementation Scheme 175. The method of Implementation Scheme 174, which includes contacting the cell with mRNA encoding Cas9 or Cpf1.

[0329] Implementation Scheme 176. The method of any one of Implementation Schemes 172-175, comprising contacting the cell with a plasmid encoding tracrRNA.

[0330] Implementation scheme 177. The method of any one of implementation schemes 172-176, wherein the target gene is edited.

[0331] Implementation scheme 178. An oligomeric compound of any one of implementation schemes 1-80, wherein the oligomeric compound is an artificial mRNA compound.

[0332] Implementation Scheme 179. The artificial mRNA compound of Implementation Scheme 178, wherein the artificial mRNA oligonucleotide is composed of 17-3000 linked nucleosides.

[0333] Implementation scheme 180. The artificial mRNA compound of implementation scheme 178 or 179, wherein the artificial mRNA oligonucleotide encodes a protein.

[0334] Implementation Scheme 181. A pharmaceutical composition comprising an artificial mRNA compound of any one of Implementation Schemes 178-180 and a pharmaceutically acceptable carrier or diluent.

[0335] Implementation Scheme 182. A method comprising contacting cells with an artificial mRNA compound or composition of any one of Implementation Schemes 178-181.

[0336] Implementation Scheme 183. A pharmaceutical composition comprising an oligomeric compound of any one of Implementation Schemes 1-182 and a pharmaceutically acceptable carrier or diluent.

[0337] Implementation Scheme 184. A method comprising contacting cells with an oligomeric compound or pharmaceutical composition of any one of Implementation Schemes 1-167 or 183.

[0338] Implementation Scheme 185. A method for regulating 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 one of Implementation Schemes 1-167 or 183, thereby regulating the amount or activity of the target nucleic acid.

[0339] Implementation Scheme 186. A method for regulating 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 one of Implementation Schemes 1-167 or 183.

[0340] Implementation scheme 187. The method of implementation scheme 186, wherein the amount or activity of the target nucleic acid is reduced.

[0341] Implementation Scheme 188. Use of any oligomeric compound or composition of any one of Implementation Schemes 1-171, 178-181 or 183 for the treatment of diseases or ailments.

[0342] Implementation Scheme 189. Use of any oligomeric compound or composition of any one of Implementation Schemes 1-171, 178-181 or 183 for the preparation of a medicament for treating a disease or ailment.

[0343] Implementation Scheme 190. An oligomeric compound comprising a modified oligonucleotide consisting of 12-23 linked nucleosides, wherein the modified oligonucleotide comprises a 5' region, a central region, and a 3' region, wherein:

[0344] The 5' region is composed of 1-5 linked nucleosides; wherein at least one 5' region nucleoside is modified.

[0345] The 3' region is composed of 1-5 linking nucleosides; wherein at least one 3' region nucleoside is modified; and

[0346] The central region consists of 7-11 linked nucleosides and has the following formula:

[0347] (N d1 ) L1 (N d2 ) L2 (N d3 ) L3 (N d4 ) L4 [(N d ) L5 ] q ;

[0348] Where N d1 N d2 N d3 N d4 Independently selected from stereostandard DNA nucleosides, stereononstandard DNA nucleosides, or 2'-substituted nucleosides; condition: N d1 Nd2 N d3 or N d4 No more than one of them is a 2'-substituted nucleoside;

[0349] Each N d Independently selected from stereostandard DNA nucleosides and stereonon-standard DNA nucleosides;

[0350] q is 3-8;

[0351] Each of L1, L2, L3, L4 and each of L5 are nucleotide inter-bonds;

[0352] Where at least two of L1, L2, L3, and L4 are nucleoside internucleotides having formula VIII:

[0353]

[0354] For each nucleoside linker of formula VIII in the modified oligonucleotide, independently:

[0355] R1 is selected from H, C1-C6 alkyl groups, and substituted C1-C6 alkyl groups; and

[0356] T is selected from SO2R2, C(=O)R3 and P(=O)R4R5, where:

[0357] R2 is selected from aryl, substituted aryl, heterocyclic, substituted heterocyclic, aromatic heterocyclic, substituted aromatic heterocyclic, diazole, substituted diazole, amine, substituted amine, C1-C6 alkoxy, C1-C6 alkyl and substituted C1-C6 alkyl.

[0358] R3 is selected from aryl, substituted aryl, CH3, N(CH3)2 and OCH3;

[0359] R4 is selected from OCH3, OH, C1-C6 alkyl, and substituted C1-C6 alkyl; and

[0360] R5 is selected from OCH3, OH, C1-C6 alkyl, and substituted C1-C6 alkyl.

[0361] Implementation Scheme 191. The oligomeric compound of Implementation Scheme 190, wherein N d1 N d2 N d3 or N d4 One of them is a 2'-substituted nucleoside.

[0362] Implementation Scheme 192. The oligomeric compound of Implementation Scheme 191, wherein the 2'-substituted nucleoside is 2'-OMe nucleoside.

[0363] Implementation scheme 193. The oligomeric compound of implementation scheme 191, wherein the 2'-OMe nucleoside is a stereostandard 2'-OMe nucleoside.

[0364] Implementation Scheme 194. An oligomeric compound of any one of Implementation Schemes 191-193, wherein the 2'-substituted nucleoside is N d2 .

[0365] Implementation Scheme 195. The oligomeric compound of Implementation Scheme 190, wherein N d1 N d2 N d3 N d4 Each and each N in d It is a DNA nucleoside.

[0366] Implementation scheme 196. The oligomeric compound of implementation scheme 195, wherein each DNA nucleoside is a stereostandard DNA nucleoside.

[0367] Implementation Scheme 197. An oligomeric compound of any one of Implementation Schemes 190-196, wherein L1 and L2 are nucleoside inter-bonds having formula VIII.

[0368] Implementation scheme 198. An oligomeric compound of any one of implementation schemes 190-196, wherein L2 and L3 are nucleoside inter-bonds having formula VIII.

[0369] Implementation Scheme 199. An oligomeric compound of any one of Implementation Schemes 190-196, wherein L3 and L4 are nucleoside inter-bonds having formula VIII.

[0370] Implementation scheme 200. An oligomeric compound of any one of implementation schemes 190-196, wherein L1, L2 and L3 are nucleoside inter-bonds having formula VIII.

[0371] Implementation Scheme 201. An oligomeric compound of any one of Implementation Schemes 190-196, wherein L2, L3 and L4 are nucleoside inter-bonds having formula VIII.

[0372] Implementation Scheme 202. An oligomeric compound of any one of Implementation Schemes 190-196, wherein L1, L2, L3 and L4 are nucleoside inter-bonds having formula VIII.

[0373] Implementation scheme 203. An oligomeric compound of any one of implementation schemes 190-202, wherein R1 is H.

[0374] Implementation scheme 204. An oligomeric compound of any one of implementation schemes 190-202, wherein R1 is a C1-C6 alkyl group.

[0375] Implementation scheme 205. The oligomeric compound of implementation scheme 204, wherein R1 is methyl.

[0376] Implementation Scheme 206. An oligomeric compound of any one of Implementation Schemes 190-202, wherein R1 is a substituted C1-C6 alkyl group;

[0377] Implementation scheme 207. An oligomeric compound of any one of implementation schemes 190-206, wherein T is SO2R2.

[0378] Implementation scheme 208. The oligomeric compound of implementation scheme 207, wherein R2 is an aryl group.

[0379] Implementation scheme 209. The oligomeric compound of implementation scheme 207, wherein R2 is a substituted aryl group.

[0380] Implementation scheme 210. The oligomeric compound of implementation scheme 207, wherein R2 is a heterocyclic ring.

[0381] Implementation scheme 211. The oligomeric compound of implementation scheme 207, wherein R2 is a substituted heterocycle.

[0382] Implementation scheme 212. The oligomeric compound of implementation scheme 207, wherein R2 is an aromatic heterocycle.

[0383] Implementation scheme 213. The oligomeric compound of implementation scheme 207, wherein R2 is a substituted aromatic heterocycle.

[0384] Implementation scheme 214. The oligomeric compound of implementation scheme 207, wherein R2 is a diazole.

[0385] Implementation scheme 215. The oligomeric compound of implementation scheme 207, wherein R2 is a substituted diazole.

[0386] The oligomeric compound of implementation scheme 216. Implementation scheme 207, wherein R2 is an amine.

[0387] Implementation scheme 217. The oligomeric compound of implementation scheme 207, wherein R2 is a substituted amine.

[0388] Implementation scheme 218. The oligomeric compound of implementation scheme 207, wherein R2 is a C1-C6 alkoxy group.

[0389] Implementation scheme 219. The oligomeric compound of implementation scheme 207, wherein R2 is a C1-C6 alkyl group.

[0390] Implementation Scheme 220. The oligomeric compound of Implementation Scheme 207, wherein R2 is a substituted C1-C6 alkyl group.

[0391] Implementation Scheme 221. The oligomeric compound of Implementation Scheme 207, wherein T is:

[0392]

[0393] Implementation Scheme 222. The oligomeric compound of Implementation Scheme 207, wherein T is:

[0394]

[0395] Implementation scheme 223. The oligomeric compound of implementation scheme 207, wherein T is:

[0396]

[0397] Implementation scheme 224. The oligomeric compound of implementation scheme 207, wherein T is:

[0398]

[0399] Implementation scheme 225. The oligomeric compound of implementation scheme 207, wherein T is:

[0400]

[0401] The oligomeric compound of implementation scheme 226. Implementation scheme 207, wherein T is:

[0402]

[0403] Implementation Scheme 227. The oligomeric compound of Implementation Scheme 207, wherein T is:

[0404]

[0405] Implementation scheme 228. The oligomeric compound of implementation scheme 207, wherein T is:

[0406]

[0407] Implementation Scheme 229. The oligomeric compound of Implementation Scheme 207, wherein T is:

[0408]

[0409] Implementation scheme 230. An oligomeric compound of any one of implementation schemes 190-206, wherein T is C(=O)R3.

[0410] Implementation scheme 231. The oligomeric compound of implementation scheme 230, wherein R3 is an aryl group.

[0411] Implementation Scheme 232. The oligomeric compound of Implementation Scheme 230, wherein R3 is a substituted aryl group.

[0412] Implementation scheme 233. The oligomeric compound of implementation scheme 230, wherein R3 is CH3.

[0413] Implementation scheme 234. The oligomeric compound of implementation scheme 230, wherein R3 is N(CH3)2.

[0414] Implementation scheme 235. The oligomeric compound of implementation scheme 230, wherein R3 is OCH3.

[0415] Implementation Scheme 236. The oligomeric compound of Implementation Scheme 230, wherein T is:

[0416]

[0417] Implementation Scheme 237. The oligomeric compound of Implementation Scheme 230, wherein T is:

[0418]

[0419] Implementation Scheme 238. The oligomeric compound of Implementation Scheme 230, wherein T is:

[0420]

[0421] Implementation Scheme 239. The oligomeric compound of Implementation Scheme 230, wherein T is:

[0422]

[0423] Implementation scheme 240. An oligomeric compound of any one of implementation schemes 190-206, wherein T is P(=O)R4R5.

[0424] Implementation Scheme 241. The oligomeric compound of Implementation Scheme 240, wherein R4 is OCH3.

[0425] Implementation scheme 242. The oligomeric compound of implementation scheme 240, wherein R4 is OH.

[0426] Implementation Scheme 243. The oligomeric compound of Implementation Scheme 240, wherein R4 is a C1-C6 alkyl group.

[0427] Implementation Scheme 244. The oligomeric compound of Implementation Scheme 240, wherein R4 is a substituted C1-C6 alkyl group.

[0428] Implementation Scheme 245. An oligomeric compound of any one of Implementation Schemes 240-242, wherein R5 is OCH3.

[0429] Implementation scheme 246. An oligomeric compound of any one of implementation schemes 240-242, wherein R5 is OH.

[0430] Implementation Scheme 247. An oligomeric compound of any one of Implementation Schemes 240-242, wherein R5 is a C1-C6 alkyl group.

[0431] Implementation Scheme 248. An oligomeric compound of any one of Implementation Schemes 240-242, wherein R5 is a substituted C1-C6 alkyl group.

[0432] Implementation Scheme 249. The oligomeric compound of Implementation Scheme 240, wherein T is:

[0433]

[0434] Implementation scheme 250. The oligomeric compound of implementation scheme 240, wherein T is:

[0435]

[0436] Implementation Scheme 251. An oligomeric compound of any one of Implementation Schemes 190-250, wherein at least one internucleotide linking group of the modified oligonucleotide is not a linking group of Formula VIII.

[0437] Implementation Scheme 252. An oligomeric compound of any one of Implementation Schemes 190-250, wherein the two internucleotide linking groups of the modified oligonucleotide are any internucleotide linking groups of Formula VIII.

[0438] Implementation Scheme 253. An oligomeric compound of any one of Implementation Schemes 190-250, wherein exactly three internucleotide linking groups of the modified oligonucleotide are internucleotide linking groups of any formula VIII.

[0439] Implementation Scheme 254. An oligomeric compound of any one of Implementation Schemes 190-250, wherein exactly four internucleotide linking groups of the modified oligonucleotide are internucleotide linking groups of any formula VIII.

[0440] Implementation Scheme 255. An oligomeric compound of any one of Implementation Schemes 190-250, having at least two linking groups of Formula VIII, wherein at least two of the linking groups of Formula VIII are identical to each other.

[0441] Implementation Scheme 256. An oligomeric compound of any one of Implementation Schemes 190-255, wherein each of the nucleoside linking groups of the modified oligonucleotide that is not of Formula VIII is a phosphate diester nucleoside linking group or a thiophosphate nucleoside linking group.

[0442] Implementation scheme 257. An oligomeric compound of any one of implementation schemes 190-256, wherein the 5' region is composed of 2-5 linked nucleosides.

[0443] Implementation scheme 258. The oligomeric compound of implementation scheme 257, wherein the 5' region is composed of 3 linked nucleosides.

[0444] Implementation scheme 259. The oligomeric compound of implementation scheme 257, wherein the 5' region is composed of 5 linked nucleosides.

[0445] Implementation scheme 260. An oligomeric compound of any one of implementation schemes 190-259, wherein each nucleoside in the 5' region is a modified nucleoside.

[0446] Implementation Scheme 261. An oligomeric compound of any one of Implementation Schemes 190-259, wherein each nucleoside in the 5' region is a modified nucleoside containing a modified sugar.

[0447] Implementation Scheme 262. An oligomeric compound of any one of Implementation Schemes 190-261, wherein each nucleoside in the 5' region comprises a 2'-substituted furanyl sugar moiety.

[0448] Implementation Scheme 263. An oligomeric compound of any one of Implementation Schemes 190-261, wherein at least one nucleoside in the 5' region comprises a bicyclic furanyl sugar moiety.

[0449] Implementation scheme 264. An oligomeric compound of any one of implementation schemes 190-261, wherein each nucleoside in the 5' region comprises a bicyclic furanyl sugar moiety.

[0450] Implementation scheme 265. The oligomeric compound of implementation scheme 263, wherein each bicyclic sugar moiety in the 5' region is selected from cEt, LNA and ENA.

[0451] Implementation scheme 266. The oligomeric compound of implementation scheme 263, wherein each bicyclic sugar moiety of the 5' region is a cEt sugar moiety.

[0452] Implementation Scheme 267. The oligomeric compound of Implementation Scheme 262, wherein each 2'-substituted furanose sugar moiety of the 5' region is a ribosyl sugar moiety and has a 2'-substituent selected from 2'-MOE, 2'-OMe and 2'-NMA.

[0453] Implementation scheme 268. An oligomeric compound of any one of implementation schemes 190-267, wherein each nucleobase in the 5' region is independently selected from thymine, uracil, guanine, cytosine, 5-methylcytosine, and adenine.

[0454] Implementation scheme 269. An oligomeric compound of any one of implementation schemes 190-268, wherein the 3' region is composed of 2-5 linked nucleosides.

[0455] The oligomeric compound of implementation scheme 270 and implementation scheme 269, wherein the 3' region is composed of 3 linked nucleosides.

[0456] Implementation scheme 271. The oligomeric compound of implementation scheme 269, wherein the 3' region is composed of 5 linked nucleosides.

[0457] Implementation Scheme 272. An oligomeric compound of any one of Implementation Schemes 190-271, wherein each nucleoside in the 3' region is a modified nucleoside.

[0458] Implementation Scheme 273. An oligomeric compound of any one of Implementation Schemes 190-272, wherein each nucleoside in the 3' region is a modified nucleoside containing a modified sugar.

[0459] Implementation Scheme 274. An oligomeric compound of any one of Implementation Schemes 190-273, wherein each nucleoside in the 3' region comprises a 2'-substituted furanyl sugar moiety.

[0460] Implementation Scheme 275. An oligomeric compound of any one of Implementation Schemes 190-273, wherein at least one nucleoside in the 3' region comprises a bicyclic furanyl sugar moiety.

[0461] Implementation scheme 276. An oligomeric compound of any one of implementation schemes 190-273, wherein each nucleoside in the 3' region comprises a bicyclic furanyl sugar moiety.

[0462] Implementation scheme 277. The oligomeric compound of implementation scheme 276, wherein each bicyclic sugar moiety in the 3' region is selected from cEt, LNA and ENA.

[0463] Implementation scheme 278. The oligomeric compound of implementation scheme 276, wherein each bicyclic sugar moiety of the 3' region is a cEt sugar moiety.

[0464] Implementation Scheme 279. The oligomeric compound of Implementation Scheme 274, wherein each 2'-substituted furanose sugar moiety of the 5' region is a ribosyl sugar moiety and has a 2'-substituent selected from 2'-MOE, 2'-OMe and 2'-NMA.

[0465] Implementation scheme 280. An oligomeric compound of any one of implementation schemes 190-279, wherein each nucleobase in the 5' region is independently selected from thymine, uracil, guanine, cytosine, 5-methylcytosine, and adenine.

[0466] Implementation Scheme 281. An oligomeric compound of any one of Implementation Schemes 1-80, wherein each nucleoside of the modified oligonucleotide is a modified nucleoside comprising a modified sugar moiety.

[0467] Implementation Scheme 282. The oligomeric compound of Implementation Scheme 281, wherein each modified sugar moiety is independently selected from a bicyclic sugar moiety and a 2'-substituted furanyl sugar moiety.

[0468] Implementation Scheme 283. The oligomeric compound of Implementation Scheme 282, wherein the three most 3' nucleotides comprise a bicyclic sugar moiety, and the remaining nucleotide comprises a 2'-substituted furanyl sugar moiety.

[0469] Implementation Scheme 284. The oligomeric compound of Implementation Scheme 282, wherein four of the 3'-most nucleotides comprise a bicyclic sugar moiety, and the remaining nucleotides comprise a 2'-substituted furanyl sugar moiety.

[0470] Implementation Scheme 285. The oligomeric compound of Implementation Scheme 282, wherein five of the 3'-most nucleosides comprise a bicyclic sugar moiety, and the remaining nucleosides comprise a 2'-substituted furanyl sugar moiety.

[0471] Implementation Scheme 286. The oligomeric compound of Implementation Scheme 282, wherein six of the 3'-most nucleosides comprise a bicyclic sugar moiety, and the remaining nucleosides comprise a 2'-substituted furanyl sugar moiety.

[0472] Implementation scheme 287. An oligomeric compound of any one of implementation schemes 282-286, wherein each bicyclic sugar moiety is selected from cEt, LNA and ENA.

[0473] Implementation scheme 288. The oligomeric compound of implementation scheme 287, wherein the bicyclic sugar moiety is cEt.

[0474] Implementation Scheme 289. An oligomeric compound of any one of Implementation Schemes 282-289, wherein the 2'-substituted furanyl sugar moiety is selected from 2'-OMe, 2'-MOE and 2'-F.

[0475] Implementation Scheme 290. An oligomeric compound of any one of Implementation Schemes 281-289, wherein at least one of the first 10 internucleotide linking groups from the 5' end of the modified oligonucleotide is an internucleotide linking group of any one of Implementation Schemes 1-50.

[0476] Implementation Scheme 291. The oligomeric compound of Implementation Scheme 289, wherein at least two of the first 10 internucleotide linking groups from the 5' end of the modified oligonucleotide are internucleotide linking groups of any one of Implementation Schemes 1-50.

[0477] Implementation Scheme 292. The oligomeric compound of Implementation Scheme 289, wherein at least 3 of the first 10 internucleotide linking groups from the 5' end of the modified oligonucleotide are internucleotide linking groups of any one of Implementation Schemes 1-50.

[0478] Implementation Scheme 293. The oligomeric compound of Implementation Scheme 289, wherein at least 4 of the first 10 internucleotide linking groups from the 5' end of the modified oligonucleotide are internucleotide linking groups of any one of Implementation Schemes 1-50.

[0479] Implementation Scheme 294. The oligomeric compound of Implementation Scheme 289, wherein at least 5 of the first 10 internucleotide linking groups from the 5' end of the modified oligonucleotide are internucleotide linking groups of any one of Implementation Schemes 1-50.

[0480] Implementation Scheme 295. The oligomeric compound of Implementation Scheme 289, wherein at least 6 of the first 10 internucleotide linking groups from the 5' end of the modified oligonucleotide are internucleotide linking groups of any one of Implementation Schemes 1-50.

[0481] Implementation Scheme 296. The oligomeric compound of Implementation Scheme 289, wherein the first two internucleotide linking groups from the 5' end of the modified oligonucleotide are any one of the internucleotide linking groups of Implementation Schemes 1-50.

[0482] Implementation Scheme 297. The oligomeric compound of Implementation Scheme 289, wherein the first three internucleotide linking groups from the 5' end of the modified oligonucleotide are any one of the internucleotide linking groups of Implementation Schemes 1-50.

[0483] The oligomeric compound of embodiment 298 and embodiment 289, wherein the first four internucleotide linking groups from the 5' end of the modified oligonucleotide are any one of the internucleotide linking groups of embodiments 1-50.

[0484] Implementation Scheme 299. The oligomeric compound of Implementation Scheme 289, wherein the first 5 nucleoside linking groups from the 5' end of the modified oligonucleotide are any of the nucleoside linking groups of Implementation Schemes 1-50.

[0485] The oligomeric compound of embodiment 300 and embodiment 289, wherein the first 6 internucleotide linking groups from the 5' end of the modified oligonucleotide are any of the internucleotide linking groups of embodiments 1-50.

[0486] Implementation Scheme 301. A method for increasing the translation of target proteins in cells, comprising contacting said cells with an oligomeric compound of any one of Implementation Schemes 281-300.

[0487] Implementation Scheme 302. The method of Implementation Scheme 301, wherein the target protein is encoded by a target nucleic acid comprising at least one translation repressor element, and wherein the modified oligonucleotide is complementary to a target site within the translation repressor element region of the target nucleic acid.

[0488] Implementation scheme 303. The method of implementation scheme 302, wherein the translation inhibition element region comprises at least one stem-loop structure.

[0489] Implementation Scheme 304. A pharmaceutical composition comprising an oligomeric compound of any one of Implementation Schemes 190-300 and a pharmaceutically acceptable carrier or diluent.

[0490] Implementation Scheme 305. A method comprising contacting cells with an oligomeric compound or pharmaceutical composition of any one of Implementation Schemes 190-300.

[0491] Implementation Scheme 306. A method for regulating 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 one of Implementation Schemes 190-300, thereby regulating the amount or activity of the target nucleic acid.

[0492] Implementation scheme 307. The method of implementation scheme 306, wherein the amount or activity of the target nucleic acid is reduced.

[0493] Implementation scheme 308. The method of implementation scheme 306, wherein the amount or activity of the target nucleic acid is increased.

[0494] Implementation Scheme 309. Use of any oligomeric compound or composition of any of Implementation Schemes 190-300 for the treatment of diseases or ailments.

[0495] Implementation Scheme 310. Use of any oligomeric compound or composition of any of Implementation Schemes 190-300 for the preparation of a medicament for treating a disease or ailment.

[0496] Implementation Scheme 311. An antisense agent comprising a modified oligonucleotide composed of linking nucleosides connected by internucleotide linking groups, wherein at least one of the internucleotide linking groups has the formula XVII:

[0497]

[0498] For each nucleoside linker of formula XVII in the modified oligonucleotide, independently:

[0499] X is selected from O or S;

[0500] R1 is selected from H, C1-C6 alkyl groups, and substituted C1-C6 alkyl groups; and

[0501] T is selected from SO2R2, C(=O)R3 and P(=O)R4R5, where:

[0502] 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 conjugate groups.

[0503] R3 is selected from aryl, substituted aryl, CH3, N(CH3)2, OCH3 and conjugate groups;

[0504] R4 is selected from OCH3, OH, C1-C6 alkyl, substituted C1-C6 alkyl, and conjugate groups; and

[0505] R5 is selected from OCH3, OH, C1-C6 alkyl, and substituted C1-C6 alkyl.

[0506] Implementation Scheme 312. An antisense agent comprising a modified oligonucleotide consisting of linking nucleosides connected by internucleotide linking groups, wherein at least one of the internucleotide linking groups has the formula XVII:

[0507]

[0508] For each nucleoside linker of formula XVII in the modified oligonucleotide, independently:

[0509] X is selected from O or S;

[0510] R1 is selected from H, C1-C6 alkyl groups, and substituted C1-C6 alkyl groups; and

[0511] T is selected from SO2R2, C(=O)R3 and P(=O)R4R5, where:

[0512] 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 conjugate groups.

[0513] R3 is selected from aryl, substituted aryl, CH3, N(CH3)2, OCH3 and conjugate groups;

[0514] R4 is selected from OCH3, OH, C1-C6 alkyl, substituted C1-C6 alkyl, and conjugate groups; and

[0515] R5 is selected from OCH3, OH, C1-C6 alkyl, and substituted C1-C6 alkyl;

[0516] The condition is that if X is O and R1 is H, then T is not:

[0517]

[0518] Implementation scheme 313. The modified oligonucleotide of implementation scheme 311 or 312, wherein X is O for at least one nucleoside linker of formula XVII.

[0519] Implementation scheme 314. The modified oligonucleotide of implementation scheme 311 or 312, wherein X is S for at least one nucleoside linker of formula XVII.

[0520] Implementation scheme 315. The modified oligonucleotide of implementation scheme 311 or 312, wherein R1 is H for at least one nucleoside linker of formula XVII.

[0521] Implementation Scheme 316. The modified oligonucleotide of Implementation Scheme 311 or 312, wherein for at least one nucleoside linker of Formula XVII, R1 is a C1-C6 alkyl, C1-C6 alkenyl or C1-C6 alkynyl.

[0522] Implementation scheme 317. The modified oligonucleotide of implementation scheme 6, wherein R1 is a methyl group.

[0523] Implementation Scheme 318. The modified oligonucleotide of Implementation Scheme 311 or 312, wherein R1 is a substituted C1-C6 alkyl group for at least one nucleoside linker of Formula XVII.

[0524] Implementation scheme 319. The modified oligonucleotide of any one of implementation schemes 311-318, wherein T comprises a conjugate group for at least one nucleoside linker of formula XVII.

[0525] Implementation scheme 320. The modified oligonucleotide of implementation scheme 319, wherein the conjugate group comprises a carbohydrate or a carbohydrate cluster.

[0526] Implementation scheme 321. The modified oligonucleotide of implementation scheme 319 or 320, wherein the conjugation group comprises at least one GalNAc.

[0527] Implementation Scheme 322. The modified oligonucleotide of Implementation Scheme 319, wherein the conjugate group comprises C 10 -C 20 Alkyl chain.

[0528] Implementation Scheme 323. The modified oligonucleotide of Implementation Scheme 322, wherein the conjugation group comprises C 16 alkyl.

[0529] Implementation scheme 324. The modified oligonucleotide of any one of implementation schemes 311-318, wherein T does not contain a conjugation group for at least one nucleoside linker of formula XVII.

[0530] Implementation scheme 325. An oligonucleotide modified by any of Implementation schemes 311-324, wherein T is SO2R2 for at least one nucleoside linker of formula XVII.

[0531] Implementation scheme 326. The modified oligonucleotide of implementation scheme 325, wherein R2 is an aryl group.

[0532] Implementation scheme 327. The modified oligonucleotide of implementation scheme 325, wherein R2 is a substituted aryl group.

[0533] Implementation scheme 328. The modified oligonucleotide of implementation scheme 325, wherein R2 is a heterocycle.

[0534] Implementation scheme 329. The modified oligonucleotide of implementation scheme 325, wherein R2 is a substituted heterocycle.

[0535] Implementation scheme 330. Modified oligonucleotide of implementation scheme 325, wherein R2 is an aromatic heterocycle.

[0536] Implementation scheme 331. The modified oligonucleotide of implementation scheme 325, wherein R2 is a substituted aromatic heterocycle.

[0537] Implementation scheme 332. Modified oligonucleotide of implementation scheme 325, wherein R2 is a diazole.

[0538] Implementation scheme 333. The modified oligonucleotide of implementation scheme 325, wherein R2 is a substituted diazole.

[0539] Implementation scheme 334. Modified oligonucleotide of implementation scheme 325, wherein R2 is an amine.

[0540] Implementation scheme 335. Modified oligonucleotide of implementation scheme 325, wherein R2 is a substituted amine.

[0541] Implementation Scheme 336. The modified oligonucleotide of Implementation Scheme 325, wherein R2 is a C1-C6 alkoxy or a C1-C6 alkenyl or a C1-C6 alkynyl.

[0542] Implementation Scheme 337. The modified oligonucleotide of Implementation Scheme 325, wherein R2 is C1-C 20 C1-C6, C2-C 20 C2-C6 or C 10 -C 20 alkyl.

[0543] Implementation Scheme 338. The modified oligonucleotide of Implementation Scheme 325, wherein R2 is a substituted C1-C 20 C1-C6, C2-C 20 C2-C6 or C 10 -C 20 alkyl.

[0544] Implementation scheme 339. The modified oligonucleotide of implementation scheme 325, wherein R2 comprises a carbohydrate or a cluster of carbohydrates.

[0545] Implementation scheme 340. The modified oligonucleotide of implementation scheme 325, wherein R2 contains at least one GalNAc.

[0546] Implementation scheme 341. The modified oligonucleotide of implementation scheme 325, wherein T is:

[0547]

[0548] Implementation scheme 342. The modified oligonucleotide of implementation scheme 325, wherein T is:

[0549]

[0550] Implementation scheme 343. The modified oligonucleotide of implementation scheme 325, wherein T is:

[0551]

[0552] Implementation scheme 344. The modified oligonucleotide of implementation scheme 325, wherein T is:

[0553]

[0554] Implementation scheme 345. The modified oligonucleotide of implementation scheme 325, wherein T is:

[0555]

[0556] Implementation scheme 346. The modified oligonucleotide of implementation scheme 325, wherein T is:

[0557]

[0558] Implementation scheme 347. The modified oligonucleotide of implementation scheme 325, wherein T is:

[0559]

[0560] Implementation scheme 348. The modified oligonucleotide of implementation scheme 325, wherein T is:

[0561]

[0562] Implementation scheme 349. The modified oligonucleotide of implementation scheme 325, wherein T is:

[0563]

[0564] Implementation scheme 350. The modified oligonucleotide of implementation scheme 325, wherein T is:

[0565] Where n is between 2 and 20.

[0566] Implementation scheme 351. The modified oligonucleotide of implementation scheme 350, wherein n is 15.

[0567] Implementation scheme 352. An oligonucleotide modified by any of Implementation schemes 311-324, wherein for at least one nucleoside linker of formula XVII, T is C(=O)R3.

[0568] Implementation scheme 353. Modified oligonucleotide of implementation scheme 352, wherein R3 is aryl.

[0569] Implementation scheme 354. Modified oligonucleotide of implementation scheme 352, wherein R3 is a substituted aryl group.

[0570] Implementation scheme 355. Modified oligonucleotide of implementation scheme 352, wherein R3 is CH3.

[0571] Implementation scheme 356. The modified oligonucleotide of implementation scheme 352, wherein R3 is N(CH3)2.

[0572] Implementation scheme 357. The modified oligonucleotide of implementation scheme 352, wherein R3 is OCH3.

[0573] Implementation scheme 358. The modified oligonucleotide of implementation scheme 352, wherein R3 is a C1-C6 alkoxy group.

[0574] Implementation Scheme 359. The modified oligonucleotide of Implementation Scheme 352, wherein R3 is C1-C 20 C1-C6, C2-C 20 C2-C6 or C 10 -C 20 alkyl.

[0575] Implementation scheme 360. Implementation scheme 352 modified oligonucleotides, wherein R3 is a substituted C1-C 20 C1-C6, C2-C 20 C2-C6 or C 10 -C 20 alkyl.

[0576] Implementation scheme 361. Modified oligonucleotide of implementation scheme 352, wherein R3 comprises a carbohydrate or a cluster of carbohydrates.

[0577] Implementation scheme 362. Modified oligonucleotide of implementation scheme 352, wherein R 23It contains at least one GalNAc.

[0578] Implementation scheme 363. The modified oligonucleotide of implementation scheme 352, wherein T is:

[0579]

[0580] Implementation scheme 364. The modified oligonucleotide of implementation scheme 352, wherein T is:

[0581]

[0582] Implementation scheme 365. The modified oligonucleotide of implementation scheme 352, wherein T is:

[0583]

[0584] Implementation scheme 366. The modified oligonucleotide of implementation scheme 352, wherein T is:

[0585]

[0586] Implementation scheme 367. The modified oligonucleotide of implementation scheme 352, wherein T is:

[0587] Where n is between 2 and 20.

[0588] Implementation scheme 368. Modified oligonucleotide of implementation scheme 367, wherein n is 15.

[0589] Implementation scheme 369. An oligonucleotide modified by any one of implementation schemes 1-14, wherein for at least one nucleoside linker of formula XVII, T is P(=O)R4R5.

[0590] Implementation scheme 370. Modified oligonucleotides of implementation scheme 369, wherein R4 is OCH3.

[0591] Implementation scheme 371. Modified oligonucleotide of implementation scheme 369, wherein R4 is OH.

[0592] Implementation scheme 372. The modified oligonucleotide of implementation scheme 369, wherein R4 is a C1-C6 alkyl group.

[0593] Implementation scheme 373. The modified oligonucleotide of implementation scheme 369, wherein R4 is a substituted C1-C6 alkyl group.

[0594] Implementation scheme 374. Modified oligonucleotides of implementation scheme 369, wherein R4 is C1-C 20 C1-C6, C2-C 20 C2-C6 or C 10-C 20 alkyl.

[0595] Implementation Scheme 375. Modified oligonucleotides of Implementation Scheme 369, wherein R4 is a substituted C1-C 20 C1-C6, C2-C 20 C2-C6 or C 10 -C 20 alkyl.

[0596] Implementation scheme 376. Implementation scheme 369 modified oligonucleotide, wherein R4 contains a carbohydrate or a carbohydrate cluster.

[0597] Implementation scheme 377. The modified oligonucleotide of implementation scheme 369, wherein R4 contains at least one GalNAc.

[0598] Implementation scheme 378. An oligonucleotide modified by any of implementation schemes 369-67, wherein R5 is OCH3.

[0599] Implementation scheme 379. An oligonucleotide modified by any of implementation schemes 369-67, wherein R5 is OH.

[0600] Implementation scheme 380. The modified oligonucleotide of any one of implementation schemes 369-67, wherein R5 is a C1-C6 alkyl group.

[0601] Implementation Scheme 381. The modified oligonucleotide of any one of Implementation Schemes 369-67, wherein R5 is a substituted C1-C6 alkyl group.

[0602] Implementation scheme 382. The modified oligonucleotide of implementation scheme 369, wherein T is:

[0603]

[0604] Implementation scheme 383. The modified oligonucleotide of implementation scheme 369, wherein T is:

[0605]

[0606] Implementation scheme 384. Modified oligonucleotides of implementation scheme 369, wherein T is:

[0607] Where n is between 2 and 20.

[0608] Implementation scheme 385. Modified oligonucleotide of implementation scheme 384, wherein n is 15.

[0609] Implementation scheme 386. The modified oligonucleotide of any one of implementation schemes 311-385, wherein at least one nucleoside linker of the modified oligonucleotide is not a linker of formula XVII.

[0610] Implementation scheme 387. The modified oligonucleotide of any one of implementation schemes 311-385, wherein exactly one of the nucleoside linking groups of the modified oligonucleotide is a nucleoside linking group of formula XVII.

[0611] Implementation scheme 388. The modified oligonucleotide of any one of implementation schemes 311-385, wherein the two internucleotide linking groups of the modified oligonucleotide are internucleotide linking groups of formula XVII.

[0612] Implementation scheme 389. The modified oligonucleotide of any one of implementation schemes 311-385, wherein exactly three nucleoside linking groups of the modified oligonucleotide are nucleoside linking groups of formula XVII.

[0613] Implementation scheme 390. The modified oligonucleotide of any one of implementation schemes 311-385, wherein exactly four nucleoside linking groups of the modified oligonucleotide are nucleoside linking groups of formula XVII.

[0614] Implementation scheme 391. The modified oligonucleotide of any one of implementation schemes 311-385, wherein exactly five nucleoside linking groups of the modified oligonucleotide are nucleoside linking groups of formula XVII.

[0615] Implementation scheme 392. The modified oligonucleotide of any one of implementation schemes 311-385, wherein at least six nucleoside linking groups of the modified oligonucleotide are nucleoside linking groups of formula XVII.

[0616] Implementation scheme 393. An oligonucleotide modified according to any one of implementation schemes 311-386 or 388-392, having at least two linking groups of formula XVII, wherein at least two of the linking groups of formula XVII are identical to each other.

[0617] Implementation scheme 394. The modified oligonucleotide of any one of implementation schemes 311-393, wherein each nucleoside linker of the modified oligonucleotide that is not a nucleoside linker of formula XVII is a phosphate diester nucleoside linker or a thiophosphate nucleoside linker.

[0618] Implementation scheme 395. The modified oligonucleotide of any one of implementation schemes 311-386 or 393-394, wherein each nucleoside linker of the modified oligonucleotide is a nucleoside linker of formula XVII.

[0619] Implementation Scheme 396. An antisense agent comprising a modified oligonucleotide, wherein at least one region of the modified oligonucleotide has structure A:

[0620]

[0621]

[0622] in:

[0623] Each Bx is a heterocyclic base moiety;

[0624] X is selected from O or S;

[0625] Each of Y1 and Y2 is independently selected from OH or SH;

[0626] Z 1 Z 2 and Z 3 Each of them is independently selected from -(CH2). p -X Z -(CH2) q -, where p is 0 or 1, q is 0 or 1, and X Z It is O, S, or N (E1);

[0627] R1 is selected from H, C1-C6 alkyl groups, and substituted C1-C6 alkyl groups; and

[0628] T is selected from SO2R2, C(=O)R3 and P(=O)R4R5, where:

[0629] R2 is selected from aryl, substituted aryl, heterocyclic, substituted heterocyclic, aromatic heterocyclic, substituted aromatic heterocyclic, 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 conjugate groups.

[0630] R3 is selected from aryl, substituted aryl, CH3, N(CH3)2, OCH3 and conjugate groups;

[0631] R4 is selected from OCH3, OH, C1-C6 alkyl, substituted C1-C6 alkyl and conjugate groups;

[0632] R5 is selected from OCH3, OH, C1-C6 alkyl, and substituted C1-C6 alkyl;

[0633] Either J R1 and G 1 Formation J R1 To G 1 Bridge, or J R1 It is H, and G 1Selected from H, OH, halogens, or O-[C(R6)(R7)] n -[(C=O) m -X G ] j -R8;

[0634] Either J R2 and G 2 Formation J R2 and G 2 Bridge, or J R2 It is H, and G 2 Selected from H, OH, halogens, or O-[C(R6)(R7)] n -[(C=O) m -X G ] j -R8;

[0635] Either J R3 and G 3 Formation J R3 and G 3 Bridge, or J R3 It is H, and G 3 Selected from H, OH, halogens, or O-[C(R6)(R7)] n -[(C=O) m -X G ] j -R8;

[0636] Each J R The G bridge has independent selections from -CH(CH3)-O- or -(CH2). k -O-, where k is 1 to 3;

[0637] Each R6 and R7 is independently H, halogen, C1-C6 alkyl, or substituted C1-C6 alkyl;

[0638] Each X G It is O, S, or N (E1);

[0639] R8 is H, halogen, C1-C6 alkyl, substituted C1-C6 alkyl, C2-C6 alkenyl, substituted C2-C6 alkenyl, C2-C6 ynyl, substituted C2-C6 ynyl or N(E2)(E3).

[0640] E1, E2 and E3 are each independently H, C1-C6 alkyl or substituted C1-C6 alkyl;

[0641] n is 1 to 6;

[0642] m is 0 or 1;

[0643] j is 0 or 1;

[0644] Each substituted group contains one or more optional protected substituent groups independently selected from halogen, OJ1, N(J1)(J2), =NJ1, SJ1, N3, CN, OC(=X2)J1, OC(=X2)N(J1)(J2) and C(=Q2)N(J1)(J2);

[0645] Q2 is O, S, or NJ3;

[0646] Each of J1, J2 and J3 is independently H or C1-C6 alkyl.

[0647] Implementation Scheme 397. An antisense agent comprising a modified oligonucleotide, wherein at least one region of said modified oligonucleotide has structure B:

[0648]

[0649] in:

[0650] Each Bx is a heterocyclic base moiety;

[0651] X is selected from O or S;

[0652] Each of Y1 and Y2 is independently selected from OH or SH;

[0653] Z 1 and Z 2 Each of them is independently selected from -(CH2). p -X Z -(CH2) q -, where p is 0 or 1, q is 0 or 1, and X Z It is O, S, or N (E1);

[0654] R1 is selected from H, C1-C6 alkyl groups, and substituted C1-C6 alkyl groups; and

[0655] T is selected from SO2R2, C(=O)R3 and P(=O)R4R5, where:

[0656] R2 is selected from aryl, substituted aryl, heterocyclic, substituted heterocyclic, aromatic heterocyclic, substituted aromatic heterocyclic, 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 conjugate groups.

[0657] R3 is selected from aryl, substituted aryl, CH3, N(CH3)2, OCH3 and conjugate groups;

[0658] R4 is selected from OCH3, OH, C1-C6 alkyl, substituted C1-C6 alkyl and conjugate groups;

[0659] R5 is selected from OCH3, OH, C1-C6 alkyl, and substituted C1-C6 alkyl;

[0660] Either J R1 and G 1 Formation J R1 To G 1 Bridge, or J R1 It is H, and G 1 Selected from H, OH, halogens, or O-[C(R6)(R7)] n -[(C=O) m -X G ] j -R8;

[0661] Either J R2 and G 2 Formation J R2 and G 2 Bridge, or J R2 It is H, and G 2 Selected from H, OH, halogens, or O-[C(R6)(R7)] n -[(C=O) m -X G ] j -R8;

[0662] Each J R The G bridge has independent selections from -CH(CH3)-O- or -(CH2). k -O-, where k is 1 to 3;

[0663] Each R6 and R7 is independently H, halogen, C1-C6 alkyl, or substituted C1-C6 alkyl;

[0664] Each X G It is O, S, or N (E1);

[0665] R8 is H, halogen, C1-C6 alkyl, substituted C1-C6 alkyl, C2-C6 alkenyl, substituted C2-C6 alkenyl, C2-C6 ynyl, substituted C2-C6 ynyl or N(E2)(E3).

[0666] E1, E2 and E3 are each independently H, C1-C6 alkyl or substituted C1-C6 alkyl;

[0667] n is 1 to 6;

[0668] m is 0 or 1;

[0669] j is 0 or 1;

[0670] Each substituted group contains one or more optional protected substituent groups independently selected from halogen, OJ1, N(J1)(J2), =NJ1, SJ1, N3, CN, OC(=X2)J1, OC(=X2)N(J1)(J2) and C(=Q2)N(J1)(J2);

[0671] Q2 is O, S, or NJ3;

[0672] Each of J1, J2 and J3 is independently H or C1-C6 alkyl.

[0673] Implementation Scheme 398. An antisense agent comprising a modified oligonucleotide, wherein at least one region of the modified oligonucleotide has a structural C:

[0674]

[0675] in:

[0676] Each Bx is a heterocyclic base moiety;

[0677] X is selected from O or S;

[0678] Each of Y1 and Y2 is independently selected from OH or SH;

[0679] Z 2 and Z 3 Each of them is independently selected from -(CH2). p -X Z -(CH2) q -, where p is 0 or 1, q is 0 or 1, and X Z It is O, S, or N (E1);

[0680] R1 is selected from H, C1-C6 alkyl groups, and substituted C1-C6 alkyl groups; and

[0681] T is selected from SO2R2, C(=O)R3 and P(=O)R4R5, where:

[0682] R2 is selected from aryl, substituted aryl, heterocyclic, substituted heterocyclic, aromatic heterocyclic, substituted aromatic heterocyclic, 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 conjugate groups.

[0683] R3 is selected from aryl, substituted aryl, CH3, N(CH3)2, OCH3 and conjugate groups;

[0684] R4 is selected from OCH3, OH, C1-C6 alkyl, substituted C1-C6 alkyl and conjugate groups;

[0685] R5 is selected from OCH3, OH, C1-C6 alkyl, and substituted C1-C6 alkyl;

[0686] Either J R2 and G 2 Formation J R2 and G 2 Bridge, or J R2 It is H, and G 2 Selected from H, OH, halogens, or O-[C(R6)(R7)] n -[(C=O) m -X G ] j -R8;

[0687] Either J R3 and G 3 Formation J R3 and G 3 Bridge, or J R3 It is H, and G 3 Selected from H, OH, halogens, or O-[C(R6)(R7)] n -[(C=O) m -X G ] j -R8;

[0688] Each J R The G bridge has independent selections from -CH(CH3)-O- or -(CH2). k -O-, where k is 1 to 3;

[0689] Each R6 and R7 is independently H, halogen, C1-C6 alkyl, or substituted C1-C6 alkyl;

[0690] Each X G It is O, S, or N (E1);

[0691] R8 is H, halogen, C1-C6 alkyl, substituted C1-C6 alkyl, C2-C6 alkenyl, substituted C2-C6 alkenyl, C2-C6 ynyl, substituted C2-C6 ynyl or N(E2)(E3).

[0692] E1, E2 and E3 are each independently H, C1-C6 alkyl or substituted C1-C6 alkyl;

[0693] n is 1 to 6;

[0694] m is 0 or 1;

[0695] j is 0 or 1;

[0696] Each substituted group contains one or more optional protected substituent groups independently selected from halogen, OJ1, N(J1)(J2), =NJ1, SJ1, N3, CN, OC(=X2)J1, OC(=X2)N(J1)(J2) and C(=Q2)N(J1)(J2);

[0697] Q2 is O, S, or NJ3;

[0698] Each of J1, J2 and J3 is independently H or C1-C6 alkyl.

[0699] Implementation Scheme 399. An antisense agent comprising a modified oligonucleotide, wherein at least one region of said modified oligonucleotide has a structure D:

[0700]

[0701] in:

[0702] Each Bx is a heterocyclic base moiety;

[0703] X is selected from O or S;

[0704] Each of Y1 and Y2 is independently selected from OH or SH;

[0705] Z 2 and Z 3 Each of them is independently selected from -(CH2). p -X Z -(CH2) q -, where p is 0 or 1, q is 0 or 1, and X Z It is O, S, or N (E1);

[0706] R1 is selected from H, C1-C6 alkyl groups, and substituted C1-C6 alkyl groups; and

[0707] T is selected from SO2R2, C(=O)R3 and P(=O)R4R5, where:

[0708] R2 is selected from aryl, substituted aryl, heterocyclic, substituted heterocyclic, aromatic heterocyclic, substituted aromatic heterocyclic, 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 conjugate groups.

[0709] R3 is selected from aryl, substituted aryl, CH3, N(CH3)2, OCH3 and conjugate groups;

[0710] R4 is selected from OCH3, OH, C1-C6 alkyl, substituted C1-C6 alkyl and conjugate groups;

[0711] R5 is selected from OCH3, OH, C1-C6 alkyl, and substituted C1-C6 alkyl;

[0712] Either J R1 and G 1 Formation J R1 To G 1 Bridge, or J R1 It is H, and G 1 Selected from H, OH, halogens, or O-[C(R6)(R7)] n -[(C=O) m -X G ] j -R8;

[0713] Either J R2 and G 2 Formation J R2 and G 2 Bridge, or J R2 It is H, and G 2 Selected from H, OH, halogens, or O-[C(R6)(R7)] n -[(C=O) m -X G ] j -R8;

[0714] Either J R3 and G 3 Formation J R3 and G 3 Bridge, or J R3 It is H, and G 3 Selected from H, OH, halogens, or O-[C(R6)(R7)] n -[(C=O) m -X G ] j -R8;

[0715] Each J R The G bridge has independent selections from -CH(CH3)-O- or -(CH2). k -O-, where k is 1 to 3;

[0716] Each R6 and R7 is independently H, halogen, C1-C6 alkyl, or substituted C1-C6 alkyl;

[0717] Each X G It is O, S, or N (E1);

[0718] R8 is H, halogen, C1-C6 alkyl, substituted C1-C6 alkyl, C2-C6 alkenyl, substituted C2-C6 alkenyl, C2-C6 ynyl, substituted C2-C6 ynyl or N(E2)(E3).

[0719] E1, E2 and E3 are each independently H, C1-C6 alkyl or substituted C1-C6 alkyl;

[0720] n is 1 to 6;

[0721] m is 0 or 1;

[0722] j is 0 or 1;

[0723] Each substituted group contains one or more optional protected substituent groups independently selected from halogen, OJ1, N(J1)(J2), =NJ1, SJ1, N3, CN, OC(=X2)J1, OC(=X2)N(J1)(J2) and C(=Q2)N(J1)(J2);

[0724] Q2 is O, S, or NJ3;

[0725] Each of J1, J2 and J3 is independently H or C1-C6 alkyl.

[0726] Implementation Scheme 400. An antisense agent comprising a modified oligonucleotide, wherein at least one region of said modified oligonucleotide has structure E:

[0727]

[0728] in:

[0729] Each Bx is a heterocyclic base moiety;

[0730] X is selected from O or S;

[0731] Each of Y1 and Y2 is independently selected from OH or SH;

[0732] Z 2 and Z 3 Each of them is independently selected from -(CH2). p -X Z -(CH2) q -, where p is 0 or 1, q is 0 or 1, and X Z It is O, S, or N (E1);

[0733] R1 is selected from H, C1-C6 alkyl groups, and substituted C1-C6 alkyl groups; and

[0734] T is selected from SO2R2, C(=O)R3 and P(=O)R4R5, where:

[0735] R2 is selected from aryl, substituted aryl, heterocyclic, substituted heterocyclic, aromatic heterocyclic, substituted aromatic heterocyclic, 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 conjugate groups.

[0736] R3 is selected from aryl, substituted aryl, CH3, N(CH3)2, OCH3 and conjugate groups;

[0737] R4 is selected from OCH3, OH, C1-C6 alkyl, substituted C1-C6 alkyl and conjugate groups;

[0738] R5 is selected from OCH3, OH, C1-C6 alkyl, and substituted C1-C6 alkyl;

[0739] Either J R1 and G 1 Formation J R1 To G 1 Bridge, or J R1 It is H, and G 1 Selected from H, OH, halogens, or O-[C(R6)(R7)] n -[(C=O) m -X G ] j -R8;

[0740] Either J R2 and G 2 Formation J R2 and G 2 Bridge, or J R2 It is H, and G 2 Selected from H, OH, halogens, or O-[C(R6)(R7)] n -[(C=O) m -X G ] j -R8;

[0741] Either J R3 and G 3 Formation J R3 and G 3 Bridge, or J R3 It is H, and G 3 Selected from H, OH, halogens, or O-[C(R6)(R7)] n -[(C=O) m -X G ] j -R8;

[0742] Each J RThe G bridge has independent selections from -CH(CH3)-O- or -(CH2). k -O-, where k is 1 to 3;

[0743] Each R6 and R7 is independently H, halogen, C1-C6 alkyl, or substituted C1-C6 alkyl;

[0744] Each X G It is O, S, or N (E1);

[0745] R8 is H, halogen, C1-C6 alkyl, substituted C1-C6 alkyl, C2-C6 alkenyl, substituted C2-C6 alkenyl, C2-C6 ynyl, substituted C2-C6 ynyl or N(E2)(E3).

[0746] E1, E2 and E3 are each independently H, C1-C6 alkyl or substituted C1-C6 alkyl;

[0747] n is 1 to 6;

[0748] m is 0 or 1;

[0749] j is 0 or 1;

[0750] Each substituted group contains one or more optional protected substituent groups independently selected from halogen, OJ1, N(J1)(J2), =NJ1, SJ1, N3, CN, OC(=X2)J1, OC(=X2)N(J1)(J2) and C(=Q2)N(J1)(J2);

[0751] Q2 is O, S, or NJ3;

[0752] Each of J1, J2 and J3 is independently H or C1-C6 alkyl.

[0753] Implementation scheme 401. An oligonucleotide modified by any of the implementation schemes 396-400, wherein each Z is O.

[0754] Implementation Scheme 402. An oligonucleotide modified according to any one of Implementation Schemes 396-401, wherein at least one G is selected from H, OH, halogen, C1-C6 alkoxy, -O(CH2)2OCH3 or -OCH2(C=O)NHCH3.

[0755] Implementation Scheme 403. An oligonucleotide modified according to any one of Implementation Schemes 396-401, wherein each G is selected from H, OH, halogen, C1-C6 alkoxy, -O(CH2)2OCH3 or -OCH2(C=O)NHCH3.

[0756] Implementation scheme 404. An oligonucleotide modified according to any one of implementation schemes 396-402, wherein at least one J R Forming a bridge with at least one G, wherein the J R The G bridge has a component selected from 4CH(CH3)-O- or -(CH2). k -O', where k is from 1 to 3.

[0757] Implementation scheme 405. Oligonucleotides modified according to any one of implementation schemes 396-402, wherein each J R And G form a bridge, wherein J R The bridge to G has a component selected from -CH(CH3)-O- or -(CH2). k -O-, where k is from 1 to 3.

[0758] Implementation Scheme 406. An oligonucleotide modified according to any one of Implementation Schemes 404 or 405, wherein at least one Z is O, and the corresponding J R The bridge to G has the formula (CH2). k -O-, where k is 1.

[0759] Implementation scheme 407. An oligonucleotide modified according to any one of implementation schemes 396-406, wherein each nucleoside of structure A, B, C, D or E is a stereostandard nucleoside.

[0760] Implementation scheme 408. An oligonucleotide modified according to any one of implementation schemes 396-406, wherein at least one nucleoside of structure A, B, C, D or E is a stereononstandard nucleoside.

[0761] Implementation Scheme 409. An oligonucleotide modified according to any one of Implementation Schemes 404-406 or 408, wherein at least one has J R The nucleosides to the G-bridge are in the α-L-ribosyl configuration.

[0762] Implementation Scheme 410. The modified oligonucleotide of any one of Implementation Schemes 396-409, wherein the modified oligonucleotide comprises at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or at least 10 regions having structure A, B, C, D or E.

[0763] Implementation Scheme 411. The modified oligonucleotide of any one of Implementation Schemes 396-410, wherein at least one region having structure A, B, C, D or E is located at the 5' end of the modified oligonucleotide.

[0764] Implementation Scheme 412. The modified oligonucleotide of any one of Implementation Schemes 396-410, wherein at least one region having structure A, B, C, D or E is located at the 3' end of the modified oligonucleotide.

[0765] Implementation Scheme 413. The modified oligonucleotide of any one of Implementation Schemes 396-410, wherein at least one region having structure A, B, C, D or E is inside the modified oligonucleotide.

[0766] Implementation Scheme 414. An antisense agent comprising a modified oligonucleotide consisting of 10-30 linked nucleosides, wherein the region of said modified oligonucleotide has the formula (N g1 ) L1 (N g2 ) L2 (N g3 ) L3 , where each N g Each L is a nucleoside, and each L is an inter-nucleoside linking group; wherein each of L1 and L2 is a phosphate diester inter-nucleoside linking group, a thiophosphate inter-nucleoside linking group, or an inter-nucleoside linking group of formula XVII:

[0767]

[0768] L3 is absent or is either a phosphate diester nucleoside linker, a thiophosphate nucleoside linker, or a nucleoside linker of formula XVII.

[0769] At least one of L1, L2, and L3 is a nucleoside linking group of formula XVII; and at least one of L1, L2, and L3 is a thiophosphate or phosphate diester nucleoside linking group.

[0770] For each nucleoside linker of formula XVII in the modified oligonucleotide, independently:

[0771] X is selected from O or S;

[0772] R1 is selected from H, C1-C6 alkyl groups, and substituted C1-C6 alkyl groups; and

[0773] T is selected from SO2R2, C(=O)R3 and P(=O)R4R5, where:

[0774] R2 is selected from aryl, substituted aryl, heterocyclic, substituted heterocyclic, aromatic heterocyclic, substituted aromatic heterocyclic, 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 conjugate groups.

[0775] R3 is selected from aryl, substituted aryl, CH3, N(CH3)2, OCH3 and conjugates;

[0776] R4 is selected from OCH3, OH, C1-C6 alkyl, substituted C1-C6 alkyl, and conjugates; and

[0777] R5 is selected from OCH3, OH, C1-C6 alkyl, and substituted C1-C6 alkyl.

[0778] Implementation Scheme 415. The modified oligonucleotide of Implementation Scheme 414, wherein the modified oligonucleotide comprises at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 oligonucleotides having the formula (N g1 ) L1 (N g2 ) L2 (N g3 ) L3 The district.

[0779] Implementation Scheme 416. The modified oligonucleotide of Implementation Scheme 414, wherein at least one has the formula (N g1 ) L1 (N g2 ) L2 (N g3 ) L3 The region at the 5' end of the oligonucleotide.

[0780] Implementation Scheme 417. The modified oligonucleotide of Implementation Scheme 414, wherein at least one has the formula (N g1 ) L1 (N g2 ) L2 (N g3 ) L3 The region is located inside the oligonucleotide.

[0781] Implementation Scheme 418. The modified oligonucleotide of Implementation Scheme 414, wherein at least one has the formula (N g1 ) L1 (N g2 ) L2 (N g3 ) L3 The region is located at the 3' end of the oligonucleotide.

[0782] Implementation Scheme 419. The modified oligonucleotide of any one of Implementation Schemes 311-418, wherein at least one nucleoside of the modified oligonucleotide is a modified nucleoside.

[0783] Implementation Scheme 420. The modified oligonucleotide of Implementation Scheme 419, wherein at least one nucleoside of the modified oligonucleotide is a modified nucleoside selected from bicyclic nucleosides and non-bicyclic substituted nucleosides.

[0784] Implementation Scheme 421. The modified oligonucleotide of any one of Implementation Schemes 311-420, wherein at least one nucleoside of the modified oligonucleotide is selected from: β-D-LNA nucleoside, α-L-LNA nucleoside, ENA nucleoside, cEt nucleoside, 2'-MOE nucleoside, 2'-OMe nucleoside, 2'-F nucleoside, 2'-NMA nucleoside, 5'-Me nucleoside, DNA nucleoside, and RNA nucleoside.

[0785] Implementation Scheme 422. The modified oligonucleotide of any one of Implementation Schemes 311-421, wherein each nucleoside of the modified oligonucleotide is selected from: β-D-LNA nucleoside, α-L-LNA nucleoside, ENA nucleoside, cEt nucleoside, 2'-MOE nucleoside, 2'-OMe nucleoside, 2'-F nucleoside, 2'-NMA nucleoside, 5'-Me nucleoside, DNA nucleoside, and RNA nucleoside.

[0786] Implementation scheme 423. The modified oligonucleotide of any one of implementation schemes 311-422, wherein at least one nucleoside of the modified oligonucleotide is a stereononstandard nucleoside.

[0787] Implementation scheme 424. The modified oligonucleotide of implementation scheme 423, wherein the internucleotide linking group connecting at least one stereononstandard nucleoside to an adjacent nucleoside is an internucleotide linking group of formula XVII.

[0788] Implementation scheme 425. The modified oligonucleotide of implementation scheme 423 or 424, wherein at least two nucleosides of the modified oligonucleotide are stereononstandard nucleosides.

[0789] Implementation Scheme 426. The modified oligonucleotide of Implementation Scheme 425, wherein at least two stereononstandard nucleosides of the modified oligonucleotide are adjacent to each other.

[0790] Implementation Scheme 427. The modified oligonucleotide of Implementation Scheme 426, wherein at least two stereononstandard nucleosides of the modified oligonucleotide are linked to each other by an internucleotide linking group of Formula XVII.

[0791] Implementation scheme 428. The modified oligonucleotide of any one of implementation schemes 423-427, wherein at least one stereononstandard nucleoside of the modified oligonucleotide is a stereononstandard DNA nucleoside.

[0792] Implementation Scheme 429. The modified oligonucleotide of Implementation Scheme 428, wherein the stereononstandard DNA nucleoside is selected from stereononstandard DNA nucleosides having Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI and Formula VII.

[0793] Implementation Scheme 430. The modified oligonucleotide of Implementation Scheme 429, wherein the stereononstandard DNA nucleoside is selected from stereononstandard DNA nucleosides having Formula V and Formula II.

[0794] Implementation Scheme 431. The modified oligonucleotide of any one of Implementation Schemes 423-427, wherein at least one stereononstandard nucleoside of the modified oligonucleotide is a substituted stereononstandard nucleoside or a stereononstandard RNA nucleoside.

[0795] Implementation Scheme 432. The modified oligonucleotide of Implementation Scheme 431, wherein the 2'-substituent of at least one substituted stereonon-standard nucleoside of the modified oligonucleotide is selected from: 2'-MOE, 2'-OMe, 2'-F or 2'-OH.

[0796] Implementation scheme 433. The modified oligonucleotide of any one of implementation schemes 311-432, wherein the modified oligonucleotide is composed of 12-30 linked nucleosides.

[0797] Implementation scheme 434. The modified oligonucleotide of any one of implementation schemes 311-433, wherein the modified oligonucleotide is composed of 16-24 linked nucleosides.

[0798] Implementation Scheme 435. The modified oligonucleotide of any one of Implementation Schemes 311-434, wherein the modified oligonucleotide consists of 18-22 linked nucleosides.

[0799] Implementation scheme 436. The modified oligonucleotide of any one of implementation schemes 311-434, wherein the modified oligonucleotide consists of 16 linked nucleosides.

[0800] Implementation scheme 437. The modified oligonucleotide of any one of implementation schemes 311-434, wherein the modified oligonucleotide consists of 17 linked nucleosides.

[0801] Implementation scheme 438. The modified oligonucleotide of any one of implementation schemes 311-435, wherein the modified oligonucleotide consists of 18 linked nucleosides.

[0802] Implementation scheme 439. The modified oligonucleotide of any one of implementation schemes 311-435, wherein the modified oligonucleotide consists of 19 linked nucleosides.

[0803] Implementation scheme 440. The modified oligonucleotide of any one of implementation schemes 311-435, wherein the modified oligonucleotide consists of 20 linked nucleosides.

[0804] Implementation scheme 441. The modified oligonucleotide of any one of implementation schemes 311-435, wherein the modified oligonucleotide consists of 21 linked nucleosides.

[0805] Implementation scheme 442. The modified oligonucleotide of any one of implementation schemes 311-435, wherein the modified oligonucleotide consists of 22 linked nucleosides.

[0806] Implementation scheme 443. The modified oligonucleotide of any one of implementation schemes 311-434, wherein the modified oligonucleotide is composed of 23 linked nucleosides.

[0807] Implementation Scheme 444. The modified oligonucleotide of any one of Implementation Schemes 311-443, wherein at least one nucleoside of the modified oligonucleotide is selected from: 2'-OMe nucleoside, 2'-F nucleoside and RNA nucleoside.

[0808] Implementation Scheme 445. The modified oligonucleotide of any one of Implementation Schemes 311-444, wherein at least one nucleoside of the modified oligonucleotide is a 2'-OMe nucleoside, and at least one nucleoside of the modified oligonucleotide is an RNA nucleoside.

[0809] Implementation Scheme 446. A modified oligonucleotide of any one of Implementation Schemes 444-445, wherein the modified oligonucleotide has a region having alternating nucleoside types with the motif ABABA, wherein each A is a stereostandard nucleoside of a first type and each B is a stereostandard nucleoside of a second type, wherein the first type and the second type are different from each other.

[0810] Implementation scheme 447. The modified oligonucleotide of implementation scheme 446, wherein A and B are selected from 2'-F substituted nucleosides, 2'-OMe substituted nucleosides and stereostandard RNA nucleosides.

[0811] Implementation scheme 448. The modified oligonucleotide of any one of implementation schemes 311-447, wherein the 5' end of the modified oligonucleotide contains a stable phosphate ester group.

[0812] Implementation Scheme 449. The modified oligonucleotide of Implementation Scheme 448, wherein the stable phosphate ester group is 5'-vinylphosphonate or 5'-cyclopropylphosphonate.

[0813] Implementation Scheme 450. An RNAi agent comprising an oligonucleotide modified according to any one of Implementation Schemes 311-449.

[0814] Implementation Scheme 451. The RNAi agent of Implementation Scheme 450, wherein the RNAi agent is a single-stranded RNAi agent comprising an RNAi antisense modified oligonucleotide, wherein the RNAi antisense modified oligonucleotide is an oligonucleotide modified by any one of Implementation Schemes 311-449.

[0815] Implementation Scheme 452. The RNAi agent of Implementation Scheme 450, wherein the RNAi agent is an oligoduplex comprising an RNAi antisense modified oligonucleotide and an RNAi sense modified oligonucleotide, wherein the RNAi antisense modified oligonucleotide and / or the RNAi sense modified oligonucleotide is a modified oligonucleotide of any one of Implementation Schemes 311-449.

[0816] Implementation Scheme 453. The RNAi agent of Implementation Scheme 451 or 452, wherein at least one nucleoside linker of the RNAi antisense modified oligonucleotide is a nucleoside linker of Formula XVII.

[0817] Implementation Scheme 454. The RNAi agent of Implementation Scheme 451 or 452, wherein at least two internucleotide linking groups of the RNAi antisense modified oligonucleotide are independently selected internucleotide linking groups of any one of Implementation Schemes 311-385.

[0818] Implementation Scheme 455. An RNAi agent of any one of Implementation Schemes 450-454, wherein at least one of the five 3' internucleotide linking groups of the RNAi antisense modified oligonucleotide is an internucleotide linking group of Formula XVII.

[0819] Implementation Scheme 456. An RNAi agent of any one of Implementation Schemes 450-454, wherein at least two of the five 3' internucleotide linking groups of the RNAi antisense modified oligonucleotide are internucleotide linking groups of Formula XVII.

[0820] Implementation Scheme 457. An RNAi agent of any one of Implementation Schemes 450-454, wherein at least one internucleotide linker in the seed region of the RNAi antisense modified oligonucleotide is an internucleotide linker of Formula XVII.

[0821] Implementation Scheme 458. An RNAi agent of any one of Implementation Schemes 450-457, wherein at least one region of the RNAi antisense modified oligonucleotide has a structure A, B, C, D or E.

[0822] Implementation Scheme 459. The RNAi agent of Implementation Scheme 458, wherein at least one region having structure A, B, C, D or E is located within the seed region of the RNAi antisense modified oligonucleotide.

[0823] Implementation scheme 460. The RNAi agent of implementation scheme 458, wherein at least one region having structure A, B, C, D or E is located at the 3' end of the RNAi antisense modified oligonucleotide.

[0824] Implementation Scheme 461. An RNAi agent of any one of Implementation Schemes 450-457, wherein at least one region of the RNAi antisense modified oligonucleotide has the formula (N g1 ) L1 (N g2 ) L2 (N g3 ) L3 , where each N g Each L is a nucleoside, and each L is an inter-nucleoside linking group; wherein each of L1 and L2 is a phosphate diester inter-nucleoside linking group, a thiophosphate inter-nucleoside linking group, or an inter-nucleoside linking group of formula XVII:

[0825]

[0826] L3 is absent or is either a phosphate diester nucleoside linker, a thiophosphate nucleoside linker, or a nucleoside linker of formula XVII.

[0827] At least one of L1, L2, and L3 is a nucleoside linking group of formula XVII; and at least one of L1, L2, and L3 is a thiophosphate or phosphate diester nucleoside linking group.

[0828] For each nucleoside linker of formula XVII in the modified oligonucleotide, independently:

[0829] X is selected from O or S;

[0830] R1 is selected from H, C1-C6 alkyl groups, and substituted C1-C6 alkyl groups; and

[0831] T is selected from SO2R2, C(=O)R3 and P(=O)R4R5, where:

[0832] R2 is selected from aryl, substituted aryl, heterocyclic, substituted heterocyclic, aromatic heterocyclic, substituted aromatic heterocyclic, 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 conjugate groups.

[0833] R3 is selected from aryl, substituted aryl, CH3, N(CH3)2, OCH3 and conjugates;

[0834] R4 is selected from OCH3, OH, C1-C6 alkyl, substituted C1-C6 alkyl, and conjugates; and

[0835] R5 is selected from OCH3, OH, C1-C6 alkyl, and substituted C1-C6 alkyl.

[0836] Implementation Scheme 462. The RNAi agent of Implementation Scheme 461, wherein at least one has the formula (N g1 ) L1 (N g2 ) L2 (N g3 ) L3 The region is located at the 3' end of the RNAi antisense modified oligonucleotide.

[0837] Implementation Scheme 463. The RNAi agent of Implementation Scheme 461, wherein at least one has the formula (N g1 ) L1 (N g2 ) L2 (N g3 ) L3 The region is located within the seed region of the RNAi antisense modified oligonucleotide.

[0838] Implementation Scheme 464. The RNAi agent of Implementation Scheme 450 or 452-463, wherein at least one nucleoside linker of the RNAi positively modified oligonucleotide is a nucleoside linker of Formula XVII.

[0839] Implementation Scheme 465. The RNAi agent of Implementation Scheme 464, wherein at least one of the first five internucleotide linking groups from the 5' end of the positively modified oligonucleotide of said RNAi is an internucleotide linking group of Formula XVII.

[0840] Implementation Scheme 466. An RNAi agent of any one of Implementation Schemes 464-465, wherein at least one of the five 3' internucleotide linking groups of the RNAi positively modified oligonucleotide is an internucleotide linking group of Formula XVII.

[0841] Implementation Scheme 467. An RNAi agent of any one of Implementation Schemes 464-466, wherein at least one of the first five internucleotide linking groups from the 5' end of the RNAi positively modified oligonucleotide and at least one of the five 3' linking groups of the RNAi positively modified oligonucleotide are internucleotide linking groups of Formula XVII.

[0842] Implementation Scheme 468. An RNAi agent of any one of Implementation Schemes 464-467, wherein at least one region of the RNAi positively modified oligonucleotide has a structure A, B, C, D or E.

[0843] Implementation Scheme 469. The RNAi agent of Implementation Scheme 468, wherein at least one region having structure A, B, C, D or E is located at the 3' end of the RNAi positively modified oligonucleotide.

[0844] Implementation Scheme 470. The RNAi agent of Implementation Scheme 468, wherein at least one region having structure A, B, C, D or E is located at the 5' end of the RNAi positively modified oligonucleotide.

[0845] Implementation Scheme 471. An RNAi agent of any one of Implementation Schemes 464-467, wherein at least one region of the RNAi positively modified oligonucleotide has the formula (N g1 ) L1 (N g2 ) L2 (N g3 ) L3 , where each N g Each L is a nucleoside, and each L is an inter-nucleoside linking group; wherein each of L1 and L2 is a phosphate diester inter-nucleoside linking group, a thiophosphate inter-nucleoside linking group, or an inter-nucleoside linking group of formula XVII:

[0846]

[0847] L3 is absent or is either a phosphate diester nucleoside linker, a thiophosphate nucleoside linker, or a nucleoside linker of formula XVII.

[0848] At least one of L1, L2, and L3 is a nucleoside linking group of formula XVII; and at least one of L1, L2, and L3 is a thiophosphate or phosphate diester nucleoside linking group.

[0849] For each nucleoside linker of formula XVII in the modified oligonucleotide, independently:

[0850] X is selected from O or S;

[0851] R1 is selected from H, C1-C6 alkyl groups, and substituted C1-C6 alkyl groups; and

[0852] T is selected from SO2R2, C(=O)R3 and P(=O)R4R5, where:

[0853] R2 is selected from aryl, substituted aryl, heterocyclic, substituted heterocyclic, aromatic heterocyclic, substituted aromatic heterocyclic, 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 conjugate groups.

[0854] R3 is selected from aryl, substituted aryl, CH3, N(CH3)2, OCH3 and conjugates;

[0855] R4 is selected from OCH3, OH, C1-C6 alkyl, substituted C1-C6 alkyl, and conjugates; and

[0856] R5 is selected from OCH3, OH, C1-C6 alkyl, and substituted C1-C6 alkyl.

[0857] Implementation Scheme 472. The RNAi agent of Implementation Scheme 471, wherein at least one has the formula (N g1 ) L1 (N g2 ) L2 (N g3 ) L3 The region is located at the 3' end of the RNAi positively modified oligonucleotide.

[0858] Implementation Scheme 473. The RNAi agent of Implementation Scheme 471, wherein at least one has the formula (N g1 ) L1 (N g2 ) L2 (N g3 ) L3 The region is located at the 5' end of the RNAi positively modified oligonucleotide.

[0859] Implementation Scheme 474. The modified oligonucleotide of any one of Implementation Schemes 311-443, wherein each nucleoside of the modified oligonucleotide is a modified nucleoside containing a modified sugar moiety.

[0860] Implementation Scheme 475. The modified oligonucleotide of Implementation Scheme 474, wherein each modified sugar moiety is independently selected from a bicyclic sugar moiety and a 2'-substituted furanyl sugar moiety.

[0861] Implementation scheme 476. Modified oligonucleotides of implementation scheme 474 or 475, wherein each modified sugar moiety contains the same modification.

[0862] Implementation scheme 477. The modified oligonucleotide of any one of implementation schemes 474-476, wherein each modified sugar moiety is selected from the 2'-OMe sugar moiety, the 2'-MOE sugar moiety and the 2'-NMA sugar moiety.

[0863] Implementation scheme 478. The modified oligonucleotide of implementation scheme 476 or 477, wherein the three most 3' nucleotides contain a bicyclic sugar moiety and the remaining nucleotide contains a 2'-substituted furanyl sugar moiety.

[0864] Implementation scheme 479. The modified oligonucleotide of implementation scheme 476 or 477, wherein the four most 3' nucleotides contain a bicyclic sugar moiety and the remaining nucleotides contain a 2'-substituted furanyl sugar moiety.

[0865] Implementation scheme 480. Implementation scheme 476 or 477 modified oligonucleotides wherein five of the most 3' nucleotides contain a bicyclic sugar moiety and the remaining nucleotides contain a 2'-substituted furanyl sugar moiety.

[0866] Implementation scheme 481. The modified oligonucleotide of implementation scheme 476 or 477, wherein the six most 3' nucleotides contain a bicyclic sugar moiety and the remaining nucleotides contain a 2'-substituted furanyl sugar moiety.

[0867] Implementation scheme 482. An oligonucleotide modified according to any one of implementation schemes 476 or 478-481, wherein each bicyclic sugar moiety is selected from cEt, LNA and ENA.

[0868] Implementation scheme 483. The modified oligonucleotide of implementation scheme 482, wherein the bicyclic sugar moiety is cEt.

[0869] Implementation scheme 484. The modified oligonucleotide of any one of implementation schemes 476 or 478-481, wherein the 2'-substituted furanose glycosyl moiety is selected from 2'-OMe, 2'-MOE and 2'-F.

[0870] Implementation Scheme 485. The modified oligonucleotide of any one of Implementation Schemes 474-484, wherein at least one of the ten 5' linking groups of the modified oligonucleotide is a nucleoside linking group of Formula XVII.

[0871] Implementation Scheme 486. The modified oligonucleotide of Implementation Scheme 485, wherein at least two of the ten 5' linking groups of the modified oligonucleotide are nucleoside linking groups of Formula XVII.

[0872] Implementation Scheme 487. The modified oligonucleotide of Implementation Scheme 485, wherein at least three of the ten 5' linking groups of the modified oligonucleotide are nucleoside linking groups of Formula XVII.

[0873] Implementation Scheme 488. The modified oligonucleotide of Implementation Scheme 485, wherein at least four of the ten 5' linking groups of the modified oligonucleotide are nucleoside linking groups of Formula XVII.

[0874] Implementation Scheme 489. The modified oligonucleotide of Implementation Scheme 485, wherein at least 5 of the ten 5' linking groups of the modified oligonucleotide are nucleoside linking groups of Formula XVII.

[0875] Implementation Scheme 490. The modified oligonucleotide of Implementation Scheme 485, wherein at least 6 of the ten 5' linking groups of the modified oligonucleotide are nucleoside linking groups of Formula XVII.

[0876] Implementation scheme 491. The modified oligonucleotide of implementation scheme 485, wherein the two most 5' internucleotide linking groups are internucleotide linking groups of formula XVII.

[0877] Implementation Scheme 492. The modified oligonucleotide of any one of Implementation Schemes 478-491, wherein at least one of the ten 3' internucleotide linking groups of the modified oligonucleotide is an internucleotide linking group of Formula XVII.

[0878] Implementation Scheme 493. The modified oligonucleotide of Implementation Scheme 492, wherein at least two of the ten 3' internucleotide linking groups of the modified oligonucleotide are internucleotide linking groups of Formula XVII.

[0879] Implementation scheme 494. The modified oligonucleotide of implementation scheme 492, wherein at least three of the ten 3' internucleotide linking groups are internucleotide linking groups of formula XVII.

[0880] Implementation Scheme 495. The modified oligonucleotide of Implementation Scheme 492, wherein at least four of the ten 3' internucleotide linking groups are internucleotide linking groups of Formula XVII.

[0881] Implementation Scheme 496. The modified oligonucleotide of Implementation Scheme 492, wherein at least 5 of the ten 3' internucleotide linking groups are internucleotide linking groups of Formula XVII.

[0882] Implementation Scheme 497. The modified oligonucleotide of Implementation Scheme 492, wherein at least 6 of the ten 3' internucleotide linking groups are internucleotide linking groups of Formula XVII.

[0883] Implementation Scheme 498. The modified oligonucleotide of Implementation Scheme 492, wherein the two 3' internucleotide linking groups of the modified oligonucleotide are internucleotide linking groups of Formula XVII.

[0884] Implementation Scheme 499. The modified oligonucleotide of any one of Implementation Schemes 474-484, wherein the modified oligonucleotide comprises at least one block having at least three consecutive internucleotide linking groups of Formula XVII.

[0885] Implementation scheme 500. The modified oligonucleotide of any one of implementation schemes 474-484, wherein the modified oligonucleotide comprises at least one block having at least four consecutive internucleotide linking groups of formula XVII.

[0886] Implementation scheme 501. The modified oligonucleotide of any one of implementation schemes 474-484, wherein the modified oligonucleotide comprises at least one block having at least 5 consecutive internucleotide linking groups of formula XVII.

[0887] Implementation scheme 502. The modified oligonucleotide of any one of implementation schemes 474-484, wherein the modified oligonucleotide comprises at least one block having at least 6 consecutive internucleotide linking groups of formula XVII.

[0888] Implementation scheme 503. The modified oligonucleotide of any one of implementation schemes 499-502, wherein at least one block of a continuous nucleoside linker of formula XVII is located at the 5' end of the modified oligonucleotide.

[0889] Implementation scheme 504. The modified oligonucleotide of any one of implementation schemes 499-502, wherein a block of at least one consecutive nucleoside linker of formula XVII is located at the 3' end of the modified oligonucleotide.

[0890] Implementation Scheme 505. A modified oligonucleotide of any one of Implementation Schemes 311-443, wherein the modified oligonucleotide comprises a deoxygenated region consisting of 6-11 linked nucleosides, wherein each nucleoside of the deoxygenated region is a modified nucleoside or a stereostandard DNA nucleoside, and wherein at least 3 consecutive nucleosides of the deoxygenated region are stereostandard DNA nucleosides, and no more than 3 nucleosides of the deoxygenated region are modified nucleosides.

[0891] Implementation scheme 506. The modified oligonucleotide of implementation scheme 505, wherein at least four consecutive nucleosides in the deoxygenated region are stereostandard DNA nucleosides.

[0892] Implementation scheme 507. The modified oligonucleotide of implementation scheme 505, wherein at least 5 consecutive nucleosides of the deoxygenated region are stereostandard DNA nucleosides.

[0893] Implementation scheme 508. The modified oligonucleotide of implementation scheme 505, wherein at least 6 consecutive nucleosides in the deoxygenated region are stereostandard DNA nucleosides.

[0894] Implementation scheme 509. The modified oligonucleotide of implementation scheme 505, wherein at least 7 consecutive nucleotides of the deoxygenated region are stereostandard DNA nucleotides.

[0895] Implementation scheme 510. The modified oligonucleotide of implementation scheme 505, wherein at least 8 consecutive nucleosides of the deoxygenated region are stereostandard DNA nucleosides.

[0896] Implementation scheme 511. The modified oligonucleotide of any one of implementation schemes 505-510, wherein the deoxygenated region consists of 8-10 linked nucleosides.

[0897] Implementation scheme 512. The modified oligonucleotide of any one of implementation schemes 505-510, wherein the deoxy region is composed of 9 linked nucleosides.

[0898] Implementation scheme 513. An oligonucleotide modified according to any one of implementation schemes 505-510, wherein the deoxy region is composed of 10 linked nucleosides.

[0899] Implementation scheme 514. The modified oligonucleotide of any one of implementation schemes 505-510, wherein the deoxy region consists of 11 linked nucleosides.

[0900] Implementation scheme 515. The modified oligonucleotide of any one of implementation schemes 505-510, wherein at least 6 nucleotides of the deoxygenated region are stereostandard DNA nucleotides.

[0901] Implementation scheme 516. The modified oligonucleotide of any one of implementation schemes 505-510, wherein at least 7 nucleotides of the deoxygenated region are stereostandard DNA nucleotides.

[0902] Implementation scheme 517. The modified oligonucleotide of any one of implementation schemes 505-510, wherein at least 8 nucleotides of the deoxygenated region are stereostandard DNA nucleotides.

[0903] Implementation scheme 518. The modified oligonucleotide of any one of implementation schemes 505-510, wherein at least nine nucleotides in the deoxygenated region are stereostandard DNA nucleotides.

[0904] Implementation scheme 519. The modified oligonucleotide of any one of implementation schemes 505-518, wherein the two nucleosides of the deoxy region are modified nucleosides.

[0905] Implementation scheme 520. The modified oligonucleotide of any one of implementation schemes 505-518, wherein one of the nucleosides in the deoxy region is a modified nucleoside.

[0906] Implementation Scheme 521. The modified oligonucleotide of any one of Implementation Schemes 505-520, wherein at least one modified nucleoside in the deoxygenated region is a stereostandard modified nucleoside or bicyclic nucleoside selected from β-D-LNA nucleoside, α-L-LNA nucleoside, ENA nucleoside, cEt nucleoside, 2'-MOE nucleoside, 2'-OMe nucleoside, 2'-F nucleoside and 5'-alkyl nucleoside.

[0907] Implementation scheme 522. The modified oligonucleotide of any one of implementation schemes 505-520, wherein at least one modified nucleoside of the deoxy region is a stereonon-standard nucleoside.

[0908] Implementation scheme 523. The modified oligonucleotide of implementation scheme 522, wherein at least one stereonon-standard nucleoside of the deoxygenated region is a stereonon-standard DNA nucleoside.

[0909] Implementation Scheme 524. The modified oligonucleotide of Implementation Scheme 523, wherein the stereononstandard DNA nucleoside is selected from stereononstandard DNA nucleosides having Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI and Formula VII.

[0910] Implementation scheme 525. The modified oligonucleotide of implementation scheme 524, wherein the stereononstandard DNA nucleoside is selected from stereononstandard DNA nucleosides having formula V and formula II.

[0911] Implementation Scheme 526. The modified oligonucleotide of Implementation Scheme 525, wherein at least one stereonon-standard nucleoside of the deoxy region is a substituted stereonon-standard nucleoside.

[0912] Implementation Scheme 527. The modified oligonucleotide of Implementation Scheme 526, wherein at least one substituted stereononstandard nucleoside has a 2'-substituent selected from 2'-MOE, 2'-OMe, 2'-F or 2'-OH.

[0913] Implementation scheme 528. The modified oligonucleotide of any one of implementation schemes 505-527, wherein the second nucleoside from the 5' end of the deoxygenated region is a modified nucleoside.

[0914] Implementation scheme 529. The modified oligonucleotide of any one of implementation schemes 505-527, wherein the third nucleoside from the 5' end of the deoxy region is a modified nucleoside.

[0915] Implementation scheme 530. The modified oligonucleotide of any one of implementation schemes 505-527, wherein the fourth nucleoside from the 5' end of the deoxygenated region is a modified nucleoside.

[0916] Implementation scheme 531. The modified oligonucleotide of any one of implementation schemes 528-530, wherein the modified nucleoside in the deoxygenated region is a 2'-OMe nucleoside.

[0917] Implementation scheme 532. The modified oligonucleotide of any one of implementation schemes 505-518, wherein each nucleoside of the deoxygenated region is a stereostandard DNA nucleoside.

[0918] Implementation scheme 533. The modified oligonucleotide of any one of implementation schemes 505-532, wherein at least one internucleotide linker in the deoxygenated region is an internucleotide linker of formula XVII.

[0919] Implementation scheme 534. An oligonucleotide modified according to any one of implementation schemes 505-532, wherein the internucleotide linking group connecting the first and second nucleosides of the deoxygenated region, counted from the 5' end of the deoxygenated region, is an internucleotide linking group of formula XVII.

[0920] Implementation scheme 535. An oligonucleotide modified according to any one of implementation schemes 505-534, wherein the internucleotide linking group connecting the second and third nucleosides of the deoxygenated region, counted from the 5' end of the deoxygenated region, is an internucleotide linking group of formula XVII.

[0921] Implementation scheme 536. An oligonucleotide modified according to any one of implementation schemes 505-535, wherein the internucleotide linking group connecting the third and fourth nucleosides of the deoxygenated region, counted from the 5' end of the deoxygenated region, is an internucleotide linking group of formula XVII.

[0922] Implementation scheme 537. The modified oligonucleotide of any one of implementation schemes 505-536, wherein the internucleotide linking group connecting the fourth and fifth nucleotides of the deoxygenated region, counted from the 5' end of the deoxygenated region, is an internucleotide linking group of formula XVII.

[0923] Implementation scheme 538. An oligonucleotide modified according to any one of implementation schemes 505-537, wherein one of the internucleotide linking groups in the deoxygenated region is a linking group of formula XVII, and the other internucleotide linking groups in the deoxygenated region are each phosphate diester or thiophosphate internucleotide linking groups.

[0924] Implementation Scheme 539. An oligonucleotide modified according to any one of Implementation Schemes 505-537, wherein the two internucleotide linking groups in the deoxygenated region are linking groups of Formula XVII, and the other internucleotide linking groups in the deoxygenated region are each phosphate diester or thiophosphate internucleotide linking groups.

[0925] Implementation scheme 540. An oligonucleotide modified according to any one of implementation schemes 505-537, wherein the three internucleotide linking groups in the deoxygenated region are linking groups of formula XVII, and the other internucleotide linking groups in the deoxygenated region are each phosphate diester or thiophosphate internucleotide linking groups.

[0926] Implementation Scheme 541. The modified oligonucleotide of any one of Implementation Schemes 505-540, wherein the deoxygenated region comprises at least one region having structure A, B, C, D or E.

[0927] Implementation scheme 542. The modified oligonucleotide of implementation scheme 541, wherein the region having structure A, B, C, D or E is at the 3' end of the deoxygenated region.

[0928] Implementation scheme 543. The modified oligonucleotide of implementation scheme 541, wherein the region having structure A, B, C, D or E is at the 5' end of the deoxygenated region.

[0929] Implementation Scheme 544. The modified oligonucleotide of any one of Implementation Schemes 505-540, wherein the deoxygenated region comprises at least one having the formula (N g1 ) L1 (N g2 ) L2 (N g3 ) L3 The region, where each N g Each L is a nucleoside, and each L is an inter-nucleoside linking group; wherein each of L1 and L2 is a phosphate diester inter-nucleoside linking group, a thiophosphate inter-nucleoside linking group, or an inter-nucleoside linking group of formula XVII:

[0930]

[0931] L3 is absent or is either a phosphate diester nucleoside linker, a thiophosphate nucleoside linker, or a nucleoside linker of formula XVII.

[0932] At least one of L1, L2, and L3 is a nucleoside linking group of formula XVII; and at least one of L1, L2, and L3 is a thiophosphate or phosphate diester nucleoside linking group.

[0933] For each nucleoside linker of formula XVII in the modified oligonucleotide, independently:

[0934] X is selected from O or S;

[0935] R1 is selected from H, C1-C6 alkyl groups, and substituted C1-C6 alkyl groups; and

[0936] T is selected from SO2R2, C(=O)R3 and P(=O)R4R5, where:

[0937] R2 is selected from aryl, substituted aryl, heterocyclic, substituted heterocyclic, aromatic heterocyclic, substituted aromatic heterocyclic, 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 conjugate groups.

[0938] R3 is selected from aryl, substituted aryl, CH3, N(CH3)2, OCH3 and conjugates;

[0939] R4 is selected from OCH3, OH, C1-C6 alkyl, substituted C1-C6 alkyl, and conjugates; and

[0940] R5 is selected from OCH3, OH, C1-C6 alkyl, and substituted C1-C6 alkyl.

[0941] Implementation Scheme 545. The modified oligonucleotide of any one of Implementation Scheme 544, wherein the oligonucleotide having the formula (N g1 ) L1 (N g2 ) L2 (N g3 ) L3 The region is located at the 3' end of the deoxygenation region.

[0942] Implementation Scheme 546. The modified oligonucleotide of any one of Implementation Scheme 544, wherein the oligonucleotide having the formula (N g1 ) L1 (N g2 ) L2 (N g3 ) L3 The region is located at the 5' end of the deoxygenation region.

[0943] Implementation Scheme 547. The oligonucleotide modified according to any one of Implementation Schemes 505-546, wherein the deoxygenated region is side-mounted on the 5' side by a 5' region consisting of 1-6 linked 5' region nucleotides, and on the 3' side by a 3' region consisting of 1-6 linked 3' region nucleotides; wherein

[0944] The 3' nucleotide in the 5' region is a modified nucleotide; and

[0945] The 5' nucleotide in the 3' region is a modified nucleotide.

[0946] Implementation Scheme 548. The modified oligonucleotide of Implementation Scheme 547, wherein the deoxygenated region consists of 7-11 linked nucleosides and has the following formula:

[0947] (N d1 ) L1 (N d2 ) L2 (N d3 ) L3 (N d4 ) L4 [(N d ) L5 ] q ;

[0948] Where N d1 N d2 N d3 N d4Independently selected from stereostandard DNA nucleosides, stereononstandard DNA nucleosides, or 2'-substituted nucleosides; condition: N d1 N d2 N d3 or N d4 No more than one of them is a 2'-substituted nucleoside;

[0949] Each N d Independently selected from stereostandard DNA nucleosides and stereonon-standard DNA nucleosides;

[0950] q is 3-8;

[0951] Each of L1, L2, L3, L4 and each of L5 are nucleotide inter-bonds;

[0952] At least two of L1, L2, L3, and L4 are nucleoside inter-bonds of formula XVII.

[0953] Implementation Scheme 549. Modified oligonucleotides of Implementation Scheme 548, wherein N d1 N d2 N d3 or N d4 One of them is a 2'-substituted nucleoside.

[0954] Implementation scheme 550. The modified oligonucleotide of implementation scheme 549, wherein the 2'-substituted nucleoside is 2'-OMe nucleoside.

[0955] Implementation Scheme 551. The modified oligonucleotide of Implementation Scheme 550, wherein the 2'-OMe nucleoside is a stereostandard 2'-OMe nucleoside.

[0956] Implementation Scheme 552. An oligonucleotide modified according to any one of Implementation Schemes 548-551, wherein the 2'-substituted nucleoside is N d2 .

[0957] Implementation scheme 553. Modified oligonucleotides of implementation scheme 548, wherein N d1 N d2 N d3 N d4 Each and each N in d It is a DNA nucleoside.

[0958] Implementation scheme 554. Modified oligonucleotides of implementation scheme 553, wherein each DNA nucleoside is a stereostandard DNA nucleoside.

[0959] Implementation scheme 555. An oligonucleotide modified by any one of implementation schemes 548-554, wherein L1 and L2 are nucleoside internucleotides of formula XVII.

[0960] Implementation scheme 556. An oligonucleotide modified by any one of implementation schemes 548-554, wherein L2 and L3 are nucleoside internucleotides of formula XVII.

[0961] Implementation scheme 557. An oligonucleotide modified by any one of implementation schemes 548-554, wherein L3 and L4 are nucleoside internucleotides of formula XVII.

[0962] Implementation scheme 558. An oligonucleotide modified by any one of implementation schemes 548-554, wherein L1, L2 and L3 are nucleoside internucleotides of formula XVII.

[0963] Implementation scheme 559. An oligonucleotide modified by any one of implementation schemes 548-554, wherein L2, L3 and L4 are nucleoside internucleotides of formula XVII.

[0964] Implementation scheme 560. An oligonucleotide modified by any one of implementation schemes 548-554, wherein L1, L2, L3 and L4 are nucleoside internucleotides of formula XVII.

[0965] Implementation scheme 561. An oligonucleotide modified according to any one of implementation schemes 547-560, wherein the 5' region consists of 2-5 linked nucleosides.

[0966] Implementation scheme 562. The modified oligonucleotide of implementation scheme 561, wherein the 5' region is composed of 3 linked nucleosides.

[0967] Implementation scheme 563. The modified oligonucleotide of implementation scheme 561, wherein the 5' region is composed of 5 linked nucleosides.

[0968] Implementation scheme 564. The modified oligonucleotide of any one of implementation schemes 547-563, wherein each nucleoside in the 5' region is a modified nucleoside.

[0969] Implementation scheme 565. The modified oligonucleotide of any one of implementation schemes 547-564, wherein each nucleoside in the 5' region is a modified nucleoside containing a modified sugar.

[0970] Implementation scheme 566. The modified oligonucleotide of any one of implementation schemes 547-565, wherein at least one nucleoside in the 5' region comprises a 2'-substituted furanyl sugar moiety.

[0971] Implementation scheme 567. The modified oligonucleotide of any one of implementation schemes 547-566, wherein each nucleoside in the 5' region comprises a 2'-substituted furanyl sugar moiety.

[0972] Implementation scheme 568. The modified oligonucleotide of any one of implementation schemes 547-567, wherein each 2'-substituted furanose glycosyl moiety of the 5' region has a 2'-substituent selected from 2'-MOE, 2'-OMe and 2'-NMA.

[0973] Implementation scheme 569. The modified oligonucleotide of any one of implementation schemes 547-566 or 568, wherein at least one nucleoside in the 5' region comprises a bicyclic furanyl sugar moiety.

[0974] Implementation scheme 570. An oligonucleotide modified according to any one of implementation schemes 547-566 or 568-569, wherein each nucleoside in the 5' region comprises a bicyclic furanyl sugar moiety.

[0975] Implementation scheme 571. Modified oligonucleotides of implementation scheme 569 or 570, wherein each bicyclic sugar moiety in the 5' region is selected from cEt, LNA and ENA.

[0976] Implementation scheme 572. The modified oligonucleotide of implementation scheme 571, wherein each bicyclic sugar moiety of the 5' region is a cEt sugar moiety.

[0977] Implementation scheme 573. The modified oligonucleotide of any one of implementation schemes 547-563, 566 or 569, wherein at least one nucleoside in the 5' region is a stereostandard DNA nucleoside.

[0978] Implementation scheme 574. The modified oligonucleotide of any one of implementation schemes 547-572, wherein at least one nucleoside in the 5' region is a stereononstandard nucleoside.

[0979] Implementation scheme 575. An oligonucleotide modified according to any one of implementation schemes 547-574, wherein each nucleobase in the 5' region is independently selected from thymine, uracil, guanine, cytosine, 5-methylcytosine, and adenine.

[0980] Implementation scheme 576. The modified oligonucleotide of any one of implementation schemes 547-575, wherein the 3' region consists of 2-5 linking nucleosides.

[0981] Implementation scheme 577. Modified oligonucleotide of implementation scheme 576, wherein the 3' region is composed of 3 linking nucleosides.

[0982] Implementation scheme 578. The modified oligonucleotide of implementation scheme 576, wherein the 3' region is composed of 5 linking nucleosides.

[0983] Implementation scheme 579. The modified oligonucleotide of any one of implementation schemes 547-578, wherein each nucleoside in the 3' region is a modified nucleoside.

[0984] Implementation scheme 580. The modified oligonucleotide of any one of implementation schemes 547-578, wherein each nucleoside in the 3' region is a modified nucleoside containing a modified sugar.

[0985] Implementation Scheme 581. The modified oligonucleotide of any one of Implementation Schemes 547-580, wherein at least one nucleoside in the 3' region comprises a 2'-substituted furanyl sugar moiety.

[0986] Implementation scheme 582. The modified oligonucleotide of any one of implementation schemes 547-581, wherein each nucleoside in the 3' region comprises a 2'-substituted furanyl sugar moiety.

[0987] Implementation Scheme 583. The modified oligonucleotide of any one of Implementation Schemes 547-582, wherein each 2'-substituted furanose sugar moiety of the 3' region has a 2'-substituent selected from 2'-MOE, 2'-OMe and 2'-NMA.

[0988] Implementation scheme 584. The modified oligonucleotide of any one of implementation schemes 547-581 or 583, wherein at least one nucleoside in the 3' region comprises a bicyclic furanyl sugar moiety.

[0989] Implementation scheme 585. The modified oligonucleotide of any one of implementation schemes 547-580 or 584, wherein each nucleoside in the 3' region comprises a bicyclic furanyl sugar moiety.

[0990] Implementation scheme 586. The modified oligonucleotide of implementation scheme 584 or 585, wherein each bicyclic sugar moiety in the 3' region is selected from cEt, LNA and ENA.

[0991] Implementation scheme 587. The modified oligonucleotide of implementation scheme 586, wherein each bicyclic sugar moiety of the 3' region is a cEt sugar moiety.

[0992] Implementation scheme 588. The modified oligonucleotide of any one of implementation schemes 547-578, 581 or 584, wherein at least one nucleoside in the 3' region is a stereostandard DNA nucleoside.

[0993] Implementation scheme 589. The modified oligonucleotide of any one of implementation schemes 547-588, wherein at least one nucleoside in the 3' region is a stereononstandard nucleoside.

[0994] Implementation scheme 590. An oligonucleotide modified according to any one of implementation schemes 547-589, wherein each nucleobase in the 3' region is independently selected from thymine, uracil, guanine, cytosine, 5-methylcytosine, and adenine.

[0995] Implementation scheme 591. The modified oligonucleotide of any one of implementation schemes 547-590, wherein the modified oligonucleotide is a nicked polymer.

[0996] Implementation scheme 592. The modified oligonucleotide of any one of implementation schemes 311-432, wherein the modified oligonucleotide is a CRISPR compound.

[0997] Implementation scheme 593. The modified oligonucleotide of implementation scheme 592, wherein the CRISPR compound consists of 20-50 linked nucleosides.

[0998] Implementation scheme 594. The modified oligonucleotide of implementation scheme 592, wherein the CRISPR compound consists of 29-32 linked nucleosides.

[0999] Implementation scheme 595. The modified oligonucleotide of any one of implementation schemes 311-432, wherein the modified oligonucleotide is an artificial mRNA compound.

[1000] Implementation Scheme 596. The artificial mRNA compound of Implementation Scheme 595, wherein the artificial mRNA oligonucleotide is composed of 17-3000 linked nucleosides.

[1001] Implementation scheme 597. The artificial mRNA compound of implementation scheme 595 or 596, wherein the artificial mRNA oligonucleotide encodes a protein.

[1002] Implementation scheme 598. Oligonucleotides modified by any of Implementation schemes 396-597, wherein each X is O.

[1003] Implementation scheme 599. Oligonucleotides modified by any of implementation schemes 396-597, wherein each X is S.

[1004] Implementation scheme 600. An oligonucleotide modified by any of implementation schemes 396-599, wherein at least one R1 is H.

[1005] Implementation Scheme 601. An oligonucleotide modified according to any one of Implementation Schemes 396-599, wherein at least one R1 is a C1-C6 alkyl group.

[1006] Implementation Scheme 602. The modified oligonucleotide of Implementation Scheme 601, wherein at least one R1 is a methyl group.

[1007] Implementation Scheme 603. The modified oligonucleotide of any one of Implementation Schemes 396-602, wherein at least one R1 is a substituted C1-C6 alkyl group.

[1008] Implementation scheme 604. The modified oligonucleotide of any one of implementation schemes 396-603, wherein at least one T contains a conjugate group.

[1009] Implementation Scheme 605. The modified oligonucleotide of Implementation Scheme 604, wherein the conjugate group comprises a carbohydrate or a carbohydrate cluster.

[1010] Implementation Scheme 606. The modified oligonucleotide of Implementation Scheme 604 or 605, wherein the conjugate group comprises at least one GalNAc.

[1011] Implementation Scheme 607. The modified oligonucleotide of Implementation Scheme 604, wherein the conjugate group comprises C 10 -C 20 Alkyl chain.

[1012] Implementation Scheme 608. The modified oligonucleotide of Implementation Scheme 607, wherein the conjugate group comprises C 16 alkyl.

[1013] Implementation scheme 609. An oligonucleotide modified according to any one of implementation schemes 396-603, wherein at least one T does not contain a conjugate group.

[1014] Implementation scheme 610. An oligonucleotide modified according to any one of implementation schemes 396-603, wherein each T does not contain a conjugate group.

[1015] Implementation scheme 611. An oligonucleotide modified by any of the implementation schemes 396-603, wherein at least one T is SO2R2.

[1016] Implementation scheme 612. The modified oligonucleotide of implementation scheme 611, wherein R2 is an aryl group.

[1017] Implementation Scheme 613. The modified oligonucleotide of Implementation Scheme 611, wherein R2 is a substituted aryl group.

[1018] Implementation scheme 614. The modified oligonucleotide of implementation scheme 611, wherein R2 is a heterocycle.

[1019] Implementation Scheme 615. The modified oligonucleotide of Implementation Scheme 611, wherein R2 is a substituted heterocycle.

[1020] Implementation scheme 616. Modified oligonucleotide of implementation scheme 611, wherein R2 is an aromatic heterocycle.

[1021] Implementation Scheme 617. The modified oligonucleotide of Implementation Scheme 611, wherein R2 is a substituted aromatic heterocycle.

[1022] Implementation scheme 618. The modified oligonucleotide of implementation scheme 611, wherein R2 is a diazole.

[1023] Implementation Scheme 619. The modified oligonucleotide of Implementation Scheme 611, wherein R2 is a substituted diazole.

[1024] Implementation scheme 620. Modified oligonucleotide of implementation scheme 611, wherein R2 is an amine.

[1025] Implementation Scheme 621. The modified oligonucleotide of Implementation Scheme 611, wherein R2 is a substituted amine.

[1026] Implementation Scheme 622. The modified oligonucleotide of Implementation Scheme 611, wherein R2 is a C1-C6 alkoxy, C1-C6 alkenyl or C1-C6 alkynyl.

[1027] Implementation Scheme 623. The modified oligonucleotide of Implementation Scheme 611, wherein R2 is C1-C 20 C1-C6, C2-C 20 C2-C6 or C 10 -C 20 alkyl.

[1028] Implementation Scheme 624. The modified oligonucleotide of Implementation Scheme 611, wherein R2 is a substituted C1-C 20 C1-C6, C2-C 20 C2-C6 or C 10 -C 20 alkyl.

[1029] Implementation scheme 625. The modified oligonucleotide of implementation scheme 611, wherein R2 comprises a carbohydrate or a cluster of carbohydrates.

[1030] Implementation scheme 626. The modified oligonucleotide of implementation scheme 611, wherein R2 contains at least one GalNAc.

[1031] Implementation Scheme 627. The modified oligonucleotide of Implementation Scheme 611, wherein T is:

[1032]

[1033] Implementation scheme 628. The modified oligonucleotide of implementation scheme 611, wherein T is:

[1034]

[1035] Implementation scheme 629. The modified oligonucleotide of implementation scheme 611, wherein T is:

[1036]

[1037] Implementation scheme 630. The modified oligonucleotide of implementation scheme 611, wherein T is:

[1038]

[1039] Implementation Scheme 631. The modified oligonucleotide of Implementation Scheme 611, wherein T is:

[1040]

[1041] Implementation Scheme 632. The modified oligonucleotide of Implementation Scheme 611, wherein T is:

[1042]

[1043] Implementation Scheme 633. The modified oligonucleotide of Implementation Scheme 611, wherein T is:

[1044]

[1045] Implementation Scheme 634. The modified oligonucleotide of Implementation Scheme 611, wherein T is:

[1046]

[1047] Implementation scheme 635. The modified oligonucleotide of implementation scheme 611, wherein T is:

[1048]

[1049] Implementation scheme 636. The modified oligonucleotide of implementation scheme 611, wherein T is:

[1050] Where n is between 2 and 20.

[1051] Implementation scheme 637. Modified oligonucleotide of implementation scheme 636, wherein n is 15.

[1052] Implementation scheme 638. An oligonucleotide modified by any of the implementation schemes 396-603, wherein at least one T is C(=O)R3.

[1053] Implementation scheme 639. Modified oligonucleotide of implementation scheme 638, wherein R3 is aryl.

[1054] Implementation scheme 640. Modified oligonucleotide of implementation scheme 638, wherein R3 is a substituted aryl group.

[1055] Implementation scheme 641. The modified oligonucleotide of implementation scheme 638, wherein R3 is CH3.

[1056] Implementation scheme 642. Modified oligonucleotide of implementation scheme 638, wherein R3 is N(CH3)2.

[1057] Implementation scheme 643. Modified oligonucleotide of implementation scheme 638, wherein R3 is OCH3.

[1058] Implementation Scheme 644. The modified oligonucleotide of Implementation Scheme 638, wherein R3 is a C1-C6 alkoxy group.

[1059] Implementation Scheme 645. Modified oligonucleotide of Implementation Scheme 638, wherein R3 is C1-C 20 C1-C6, C2-C 20 C2-C6 or C 10 -C 20 alkyl.

[1060] Implementation Scheme 646. Modified oligonucleotide of Implementation Scheme 638, wherein R3 is a substituted C1-C 20 C1-C6, C2-C 20 C2-C6 or C 10 -C 20 alkyl.

[1061] Implementation scheme 647. The modified oligonucleotide of implementation scheme 638, wherein R3 contains a carbohydrate or a cluster of carbohydrates.

[1062] Implementation Scheme 648. The modified oligonucleotide of Implementation Scheme 638, wherein R 23 It contains at least one GalNAc.

[1063] Implementation scheme 649. The modified oligonucleotide of implementation scheme 638, wherein T is:

[1064]

[1065] Implementation scheme 650. The modified oligonucleotide of implementation scheme 638, wherein T is:

[1066]

[1067] Implementation Scheme 651. The modified oligonucleotide of Implementation Scheme 638, wherein T is:

[1068]

[1069] Implementation scheme 652. The modified oligonucleotide of implementation scheme 638, wherein T is:

[1070]

[1071] Implementation scheme 653. The modified oligonucleotide of implementation scheme 638, wherein T is:

[1072] Where n is between 2 and 20.

[1073] Implementation scheme 654. Modified oligonucleotide of implementation scheme 653, wherein n is 15.

[1074] Implementation scheme 655. An oligonucleotide modified by any of the implementation schemes 396-603, wherein at least one T is P(=O)R4R5.

[1075] Implementation scheme 656. Modified oligonucleotide of implementation scheme 655, wherein R4 is OCH3.

[1076] Implementation scheme 657. Modified oligonucleotide of implementation scheme 655, wherein R4 is OH.

[1077] Implementation Scheme 658. The modified oligonucleotide of Implementation Scheme 655, wherein R4 is a C1-C6 alkyl group.

[1078] Implementation Scheme 659. The modified oligonucleotide of Implementation Scheme 655, wherein R4 is a substituted C1-C6 alkyl group.

[1079] Implementation scheme 660. Modified oligonucleotides of implementation scheme 655, wherein R4 is C1-C 20 C1-C6, C2-C 20 C2-C6 or C 10 -C 20 alkyl.

[1080] Implementation Scheme 661. The modified oligonucleotide of Implementation Scheme 655, wherein R4 is a substituted C1-C 20 C1-C6, C2-C 20 C2-C6 or C 10 -C 20 alkyl.

[1081] Implementation scheme 662. The modified oligonucleotide of implementation scheme 655, wherein R4 comprises a carbohydrate or a carbohydrate cluster.

[1082] Implementation scheme 663. The modified oligonucleotide of implementation scheme 655, wherein R4 contains at least one GalNAc.

[1083] Implementation scheme 664. An oligonucleotide modified by any one of implementation schemes 655-663, wherein R5 is OCH3.

[1084] Implementation scheme 665. An oligonucleotide modified by any of implementation schemes 655-663, wherein R5 is OH.

[1085] Implementation Scheme 666. An oligonucleotide modified according to any one of Implementation Schemes 655-663, wherein R5 is a C1-C6 alkyl group.

[1086] Implementation Scheme 667. The modified oligonucleotide of any one of Implementation Schemes 655-663, wherein R5 is a substituted C1-C6 alkyl group.

[1087] Implementation scheme 668. The modified oligonucleotide of implementation scheme 655, wherein T is:

[1088]

[1089] Implementation scheme 669. The modified oligonucleotide of implementation scheme 655, wherein T is:

[1090]

[1091] Implementation scheme 670. Modified oligonucleotide of implementation scheme 655, wherein T is:

[1092] Where n is between 2 and 20.

[1093] Implementation scheme 671. The modified oligonucleotide of implementation scheme 670, wherein n is 15.

[1094] Implementation Scheme 672. A chiral enriched cluster of modified oligonucleotides according to any one of Implementation Schemes 311-671, wherein the cluster is enriched with modified oligonucleotides comprising at least one specific internucleotide linker having a specific stereochemical configuration.

[1095] Implementation Scheme 673. The chiral rich cluster of modified oligonucleotides of Implementation Scheme 672, wherein the specific internucleotide linker having a specific stereochemical configuration is an internucleotide linker of Formula XVIII, as shown in Formulas XVIIIa and XVIIIb below:

[1096]

[1097] Implementation Scheme 674. The chiral rich cluster of modified oligonucleotides of Implementation Scheme 672, wherein the specific internucleotide linking group having a specific stereochemical configuration is a thiophosphate internucleotide linking group.

[1098] Implementation scheme 675. A chiral enriched cluster of any one of implementation schemes 672-674, wherein the cluster is enriched with oligonucleotides containing at least one modified nucleotide internucleotide bond having a (Sp) configuration.

[1099] Implementation scheme 676. A chiral enriched cluster of any one of implementation schemes 672-675, wherein the cluster is enriched with oligonucleotides containing at least one modified nucleotide inter-bond having a specific (Rp) configuration.

[1100] Implementation scheme 677. The chiral enrichment cluster of implementation scheme 672, wherein the cluster is enriched with modified oligonucleotides having a specific, independently selected stereochemical configuration at each chiral nucleotide inter-bond.

[1101] Implementation scheme 678. A chiral enriched cluster of any one of implementation schemes 672-677, wherein the cluster is enriched with oligonucleotides modified with a (Sp) configuration at each chiral nucleotide inter-bond.

[1102] Implementation scheme 679. A chiral enriched cluster of any one of implementation schemes 672-677, wherein the cluster is enriched with oligonucleotides modified to have an (Rp) configuration at each chiral nucleotide inter-bond.

[1103] Implementation scheme 680. Chiral enrichment clusters of any one of implementation schemes 672-677, wherein the clusters are enriched with modified oligonucleotides having an (Rp) configuration at a particular chiral nucleotide inter-bond and an (Sp) configuration at each of the remaining chiral nucleotide inter-bonds.

[1104] Implementation scheme 681. Implementation scheme 673: chiral rich clusters, wherein the internucleotide bonds of each thiophosphate are stereo-random.

[1105] Implementation scheme 682. The modified oligonucleotide of any one of implementation schemes 311-681, wherein the nucleobase sequence of the modified oligonucleotide is complementary to the target nucleic acid.

[1106] Implementation Scheme 683. The modified oligonucleotide of Implementation Scheme 682, wherein the nucleobase sequence of the modified oligonucleotide is at least 80% complementary to the target nucleic acid.

[1107] Implementation Scheme 684. The modified oligonucleotide of Implementation Scheme 682, wherein the nucleobase sequence of the modified oligonucleotide is at least 85% complementary to the target nucleic acid.

[1108] Implementation Scheme 685. The modified oligonucleotide of Implementation Scheme 682, wherein the nucleobase sequence of the modified oligonucleotide is at least 90% complementary to the target nucleic acid.

[1109] Implementation Scheme 686. The modified oligonucleotide of Implementation Scheme 682, wherein the nucleobase sequence of the modified oligonucleotide is at least 95% complementary to the target nucleic acid.

[1110] Implementation Scheme 687. The modified oligonucleotide of Implementation Scheme 682, wherein the nucleobase sequence of the modified oligonucleotide is 100% complementary to the target nucleic acid.

[1111] Implementation scheme 688. An oligonucleotide modified by any of implementation schemes 682-687, wherein the target nucleic acid is a target RNA.

[1112] Implementation Scheme 689. The modified oligonucleotide of Implementation Scheme 688, wherein the target RNA is selected from: mRNA, premRNA, microRNA and noncoding RNA.

[1113] Implementation scheme 690. Modified oligonucleotides of implementation scheme 688, wherein the target RNA is not a microRNA.

[1114] Implementation Scheme 691. The modified oligonucleotide of any one of Implementation Schemes 311-690, wherein the modified oligonucleotide is not complementary to miR-21.

[1115] Implementation scheme 692. An oligonucleotide modified according to any one of implementation schemes 311-691, comprising a conjugate group.

[1116] Implementation Scheme 693. The modified oligonucleotide of Implementation Scheme 692, wherein the conjugate group comprises at least one GalNAc.

[1117] Implementation Scheme 694. The modified oligonucleotide of Implementation Scheme 692 or 693, wherein the conjugate group comprises 1-5 linker nucleosides.

[1118] Implementation Scheme 695. A pharmaceutical composition comprising a modified oligonucleotide of any one of Implementation Schemes 311-694 and a pharmaceutically acceptable carrier or diluent.

[1119] Implementation Scheme 696. A method comprising contacting cells with a modified oligonucleotide or pharmaceutical composition of any one of Implementation Schemes 311-695.

[1120] Implementation Scheme 697. A method for regulating the amount or activity of a target nucleic acid in a cell, comprising contacting the cell with a modified oligonucleotide or pharmaceutical composition of any one of Implementation Schemes 311-695, thereby regulating the amount or activity of the target nucleic acid.

[1121] Implementation Scheme 698. A method for regulating the amount or activity of a target nucleic acid in a cell, comprising contacting the cell with a modified oligonucleotide or pharmaceutical composition of any one of Implementation Schemes 311-695.

[1122] Implementation scheme 699. Methods of implementation schemes 696-698, wherein the amount or activity of the target nucleic acid is reduced.

[1123] Implementation scheme 700. Implementation schemes 696-698, wherein the amount or activity of the target nucleic acid is increased.

[1124] Implementation Scheme 701. The method of Implementation Scheme 700, wherein the target protein is encoded by a target nucleic acid comprising at least one translation repressor element, and wherein the modified oligonucleotide is complementary to a target site within the translation repressor element region of the target nucleic acid.

[1125] Implementation Scheme 702. The method of Implementation Scheme 701, wherein the translation inhibition element region comprises at least one stem-loop structure.

[1126] Implementation Scheme 703. Use of the modified oligonucleotide or composition of any of Implementation Schemes 311-695 for the treatment of diseases or ailments.

[1127] Implementation Scheme 704. Use of any of the modified oligonucleotides or compositions of Implementation Schemes 311-695 for the preparation of a medicament for treating a disease or ailment.

[1128] Implementation Scheme 705. An antisense agent comprising a modified oligonucleotide consisting of 12-70 linked nucleosides connected by internucleotide linking groups, wherein at least one nucleoside comprises a modified sugar moiety, and wherein at least one of the internucleotide linking groups has the formula XVII:

[1129]

[1130] For each nucleoside linker of formula XVII in the modified oligonucleotide, independently:

[1131] X is selected from O or S;

[1132] R1 is selected from H, C1-C6 alkyl groups, and substituted C1-C6 alkyl groups; and

[1133] T is selected from SO2R2, C(=O)R3 and P(=O)R4R5, where:

[1134] 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 conjugate groups.

[1135] R3 is selected from aryl, substituted aryl, CH3, N(CH3)2, OCH3 and conjugate groups;

[1136] R4 is selected from OCH3, OH, C1-C6 alkyl, substituted C1-C6 alkyl, and conjugate groups; and

[1137] R5 is selected from OCH3, OH, C1-C6 alkyl, and substituted C1-C6 alkyl.

[1138] Implementation Scheme 706. An antisense agent comprising a modified oligonucleotide consisting of 12-70 linked nucleosides connected by internucleotide linking groups, wherein at least one nucleoside comprises a modified sugar moiety, and wherein at least one of the internucleotide linking groups has the formula XVII:

[1139]

[1140] For each nucleoside linker of formula XVII in the modified oligonucleotide, independently:

[1141] X is selected from O or S;

[1142] R1 is selected from H, C1-C6 alkyl groups, and substituted C1-C6 alkyl groups; and

[1143] T is selected from SO2R2, C(=O)R3 and P(=O)R4R5, where:

[1144] 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 conjugate groups.

[1145] R3 is selected from aryl, substituted aryl, CH3, N(CH3)2, OCH3 and conjugate groups;

[1146] R4 is selected from OCH3, OH, C1-C6 alkyl, substituted C1-C6 alkyl, and conjugate groups; and

[1147] R5 is selected from OCH3, OH, C1-C6 alkyl, and substituted C1-C6 alkyl.

[1148] The condition is that if X is O and if R1 is H, then T is not:

[1149]

[1150] Implementation scheme 707. The antisense agent of implementation scheme 705 or implementation scheme 706, wherein at least one nucleoside linking group is a phosphate diester or thiophosphate nucleoside linking group.

[1151] Implementation scheme 708. An antisense agent of any one of implementation schemes 705-707, wherein at least one nucleoside comprises a 2'-β-D-deoxyribosyl sugar moiety.

[1152] Implementation Scheme 709. An oligonucleotide modified by any one of Implementation Schemes 705-708, wherein X is O for at least one nucleoside linker of Formula XVII.

[1153] Implementation Scheme 710. An oligonucleotide modified according to any one of Implementation Schemes 705-709, wherein X is S for at least one nucleoside linker of Formula XVII.

[1154] Implementation Scheme 711. The modified oligonucleotide of Implementation Scheme 705 or 706, wherein R1 is H for at least one nucleoside linker of Formula XVII.

[1155] Implementation Scheme 712. The modified oligonucleotide of Implementation Scheme 705 or 706, wherein for at least one nucleoside linker of Formula XVII, R1 is a C1-C6 alkyl group.

[1156] Implementation Scheme 713. The modified oligonucleotide of Implementation Scheme 710, wherein R1 is a methyl group.

[1157] Implementation Scheme 714. The modified oligonucleotide of Implementation Scheme 705 or 706, wherein for at least one nucleoside linker of Formula XVII, R1 is a substituted C1-C6 alkyl group.

[1158] Implementation Scheme 715. The modified oligonucleotide of any one of Implementation Schemes 705-714, wherein T comprises a conjugate group for at least one nucleoside linker of Formula XVII.

[1159] Implementation Scheme 716. The modified oligonucleotide of Implementation Scheme 715, wherein the conjugate group comprises a cell-targeting moiety.

[1160] Implementation Scheme 717. The modified oligonucleotide of Implementation Scheme 715, wherein the conjugate group comprises a carbohydrate or a carbohydrate cluster.

[1161] Implementation Scheme 718. The modified oligonucleotide of any one of Implementation Schemes 715-717, wherein the conjugate group comprises at least one GalNAc.

[1162] Implementation Scheme 719. The modified oligonucleotide of Implementation Scheme 715, wherein the conjugate group comprises C 10 -C 20 Alkyl chain.

[1163] Implementation Scheme 720. Modified oligonucleotide of Implementation Scheme 719, wherein the conjugate group comprises C 16 alkyl.

[1164] Implementation Scheme 721. The modified oligonucleotide of any of Implementation Schemes 705-714, wherein T does not contain a conjugation group for at least one nucleoside linker of Formula XVII.

[1165] Implementation scheme 722. The modified oligonucleotide of any one of implementation schemes 705-714, wherein for at least one nucleoside linker group of formula XVII, T does not contain a cell-targeting portion.

[1166] Implementation scheme 723. An oligonucleotide modified by any of Implementation schemes 705-722, wherein T is SO2R2 for at least one nucleoside linker of formula XVII.

[1167] Implementation scheme 724. Modified oligonucleotide of implementation scheme 723, wherein R2 is aryl.

[1168] Implementation scheme 725. Modified oligonucleotide of implementation scheme 723, wherein R2 is a substituted aryl group.

[1169] Implementation scheme 726. Modified oligonucleotide of implementation scheme 723, wherein R2 is a heterocycle.

[1170] Implementation scheme 727. Modified oligonucleotide of implementation scheme 723, wherein R2 is a substituted heterocycle.

[1171] Implementation scheme 728. Modified oligonucleotide of implementation scheme 723, wherein R2 is an aromatic heterocycle.

[1172] Implementation scheme 729. Modified oligonucleotide of implementation scheme 723, wherein R2 is a substituted aromatic heterocycle.

[1173] Implementation scheme 730. Modified oligonucleotide of implementation scheme 723, wherein R2 is a diazole.

[1174] Implementation scheme 731. Modified oligonucleotide of implementation scheme 723, wherein R2 is a substituted diazole.

[1175] Implementation scheme 732. The modified oligonucleotide of implementation scheme 723, wherein R2 is an amine.

[1176] Implementation scheme 733. The modified oligonucleotide of implementation scheme 723, wherein R2 is a substituted amine.

[1177] Implementation Scheme 734. The modified oligonucleotide of Implementation Scheme 723, wherein R2 is C1-C6 alkoxy, C1-C6 alkenyl or C1-C6 alkynyl.

[1178] Implementation Scheme 735. Modified oligonucleotide of Implementation Scheme 723, wherein R2 is C1-C 20 C1-C6, C2-C 20 C2-C6 or C 10 -C 20 alkyl.

[1179] Implementation Scheme 736. Modified oligonucleotide of Implementation Scheme 723, wherein R2 is a substituted C1-C 20 C1-C6, C2-C 20 C2-C6 or C 10 -C 20 alkyl.

[1180] Implementation scheme 737. The modified oligonucleotide of implementation scheme 723, wherein R2 contains a carbohydrate or a cluster of carbohydrates.

[1181] Implementation scheme 738. The modified oligonucleotide of implementation scheme 723, wherein R2 contains at least one GalNAc.

[1182] Implementation scheme 739. The modified oligonucleotide of implementation scheme 723, wherein T is:

[1183]

[1184] Implementation scheme 740. The modified oligonucleotide of implementation scheme 723, wherein T is:

[1185]

[1186] Implementation scheme 741. The modified oligonucleotide of implementation scheme 723, wherein T is:

[1187]

[1188] Implementation scheme 742. The modified oligonucleotide of implementation scheme 723, wherein T is:

[1189]

[1190] Implementation scheme 743. The modified oligonucleotide of implementation scheme 723, wherein T is:

[1191]

[1192] Implementation scheme 744. The modified oligonucleotide of implementation scheme 723, wherein T is:

[1193]

[1194] Implementation scheme 745. The modified oligonucleotide of implementation scheme 723, wherein T is:

[1195]

[1196] Implementation scheme 746. The modified oligonucleotide of implementation scheme 723, wherein T is:

[1197]

[1198] Implementation scheme 747. The modified oligonucleotide of implementation scheme 723, wherein T is:

[1199]

[1200] Implementation scheme 748. The modified oligonucleotide of implementation scheme 723, wherein T is:

[1201] Where n is between 2 and 20.

[1202] Implementation scheme 749. Modified oligonucleotide of implementation scheme 748, wherein n is 15.

[1203] Implementation scheme 750. The modified oligonucleotide of any one of implementation schemes 705-722, wherein for at least one nucleoside linker of formula XVII, T is C(=O)R3.

[1204] Implementation scheme 751. The modified oligonucleotide of implementation scheme 750, wherein R3 is an aryl group.

[1205] Implementation scheme 752. The modified oligonucleotide of implementation scheme 750, wherein R3 is a substituted aryl group.

[1206] Implementation scheme 753. The modified oligonucleotide of implementation scheme 750, wherein R3 is CH3.

[1207] Implementation scheme 754. Modified oligonucleotide of implementation scheme 750, wherein R3 is N(CH3)2.

[1208] Implementation scheme 755. Modified oligonucleotide of implementation scheme 750, wherein R3 is OCH3.

[1209] Implementation Scheme 756. The modified oligonucleotide of Implementation Scheme 750, wherein R3 is a C1-C6 alkoxy group.

[1210] Implementation Scheme 757. Modified oligonucleotide of Implementation Scheme 750, wherein R3 is C1-C 20 C1-C6, C2-C 20 C2-C6 or C 10 -C 20alkyl.

[1211] Implementation Scheme 758. The modified oligonucleotide of Implementation Scheme 750, wherein R3 is a substituted C1-C 20 C1-C6, C2-C 20 C2-C6 or C 10 -C 20 alkyl.

[1212] Implementation scheme 759. The modified oligonucleotide of implementation scheme 750, wherein R3 contains a carbohydrate or a cluster of carbohydrates.

[1213] Implementation scheme 760. Modified oligonucleotides of implementation scheme 750, wherein R 23 It contains at least one GalNAc.

[1214] Implementation Scheme 761. The modified oligonucleotide of Implementation Scheme 750, wherein T is:

[1215]

[1216] Implementation scheme 762. The modified oligonucleotide of implementation scheme 750, wherein T is:

[1217]

[1218] Implementation scheme 763. The modified oligonucleotide of implementation scheme 750, wherein T is:

[1219]

[1220] Implementation scheme 764. The modified oligonucleotide of implementation scheme 750, wherein T is:

[1221]

[1222] Implementation scheme 765. Modified oligonucleotide of implementation scheme 750, wherein T is:

[1223] Where n is between 2 and 20.

[1224] Implementation scheme 766. Modified oligonucleotide of implementation scheme 765, wherein n is 15.

[1225] Implementation scheme 767. The modified oligonucleotide of any one of implementation schemes 705-722, wherein for at least one nucleoside linker of formula XVII, T is P(=O)R4R5.

[1226] Implementation scheme 768. Modified oligonucleotide of implementation scheme 767, wherein R4 is OCH3.

[1227] Implementation scheme 769. Modified oligonucleotide of implementation scheme 767, wherein R4 is OH.

[1228] Implementation scheme 770. The modified oligonucleotide of implementation scheme 767, wherein R4 is a C1-C6 alkyl group.

[1229] Implementation Scheme 771. Modified oligonucleotide of Implementation Scheme 767, wherein R4 is a substituted C1-C6 alkyl group.

[1230] Implementation Scheme 772. Modified oligonucleotides of Implementation Scheme 767, wherein R4 is C1-C 20 C1-C6, C2-C 20 C2-C6 or C 10 -C 20 alkyl.

[1231] Implementation Scheme 773. Modified oligonucleotides of Implementation Scheme 767, wherein R4 is a substituted C1-C 20 C1-C6, C2-C 20 C2-C6 or C 10 -C 20 alkyl.

[1232] Implementation scheme 774. Implementation scheme 767 modified oligonucleotide, wherein R4 contains a carbohydrate or a cluster of carbohydrates.

[1233] Implementation scheme 775. Implementation scheme 767 of the modified oligonucleotide, wherein R4 contains at least one GalNAc.

[1234] Implementation scheme 776. An oligonucleotide modified by any of Implementation schemes 767-775, wherein R5 is OCH3.

[1235] Implementation scheme 777. An oligonucleotide modified by any of Implementation schemes 767-775, wherein R5 is OH.

[1236] Implementation scheme 778. An oligonucleotide modified according to any one of implementation schemes 767-775, wherein R5 is a C1-C6 alkyl group.

[1237] Implementation Scheme 779. The modified oligonucleotide of any one of Implementation Schemes 767-775, wherein R5 is a substituted C1-C6 alkyl group.

[1238] The modified oligonucleotides of implementation schemes 780 and 767, wherein T is:

[1239]

[1240] Implementation scheme 781. The modified oligonucleotide of implementation scheme 767, wherein T is:

[1241]

[1242] Implementation scheme 782. The modified oligonucleotide of implementation scheme 767, wherein T is:

[1243] Where n is between 2 and 20.

[1244] Implementation scheme 783. Modified oligonucleotide of implementation scheme 782, wherein n is 15.

[1245] Implementation Scheme 784. The modified oligonucleotide of any one of Implementation Schemes 705-783, wherein at least one nucleoside linker of the modified oligonucleotide is not a linker of Formula XVII.

[1246] Implementation Scheme 785. The modified oligonucleotide of any one of Implementation Schemes 705-784, wherein exactly one of the nucleoside linking groups of the modified oligonucleotide is a nucleoside linking group of Formula XVII.

[1247] Implementation Scheme 786. The modified oligonucleotide of any one of Implementation Schemes 705-784, wherein the two internucleotide linking groups of the modified oligonucleotide are internucleotide linking groups of Formula XVII.

[1248] Implementation Scheme 787. The modified oligonucleotide of any one of Implementation Schemes 705-784, wherein exactly three internucleotide linking groups of the modified oligonucleotide are internucleotide linking groups of Formula XVII.

[1249] Implementation scheme 788. The modified oligonucleotide of any one of implementation schemes 705-784, wherein exactly four nucleoside linking groups of the modified oligonucleotide are nucleoside linking groups of formula XVII.

[1250] Implementation Scheme 789. The modified oligonucleotide of any one of Implementation Schemes 705-784, wherein exactly five nucleoside linking groups of the modified oligonucleotide are nucleoside linking groups of Formula XVII.

[1251] Implementation Scheme 790. The modified oligonucleotide of any one of Implementation Schemes 705-784, wherein at least six internucleotide linking groups of the modified oligonucleotide are internucleotide linking groups of Formula XVII.

[1252] Implementation Scheme 791. An oligonucleotide modified according to any one of Implementation Schemes 705-783 or 785-787, having at least two linking groups of Formula XVII, wherein at least two of the linking groups of Formula XVII are identical to each other.

[1253] Implementation Scheme 792. The modified oligonucleotide of any one of Implementation Schemes 705-791, wherein each nucleoside linker of the modified oligonucleotide that is not a nucleoside linker of Formula XVII is a phosphate diester nucleoside linker or a thiophosphate nucleoside linker.

[1254] Implementation Scheme 793. The modified oligonucleotide of any one of Implementation Schemes 705-784 or 790, wherein each nucleoside linker of the modified oligonucleotide is a nucleoside linker of Formula XVII.

[1255] Implementation Scheme 794. An antisense agent comprising a modified oligonucleotide, wherein at least one region of said modified oligonucleotide has structure A:

[1256]

[1257] in:

[1258] Each Bx is a heterocyclic base moiety;

[1259] X is selected from O or S;

[1260] Each of Y1 and Y2 is independently selected from OH or SH;

[1261] Z 1 Z 2 and Z 3 Each of them is independently selected from -(CH2). p -X Z -(CH2) q -, where p is 0 or 1, q is 0 or 1, and X Z It is O, S, or N (E1);

[1262] R1 is selected from H, C1-C6 alkyl groups, and substituted C1-C6 alkyl groups; and

[1263] T is selected from SO2R2, C(=O)R3 and P(=O)R4R5, where:

[1264] 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 conjugate groups.

[1265] R3 is selected from aryl, substituted aryl, CH3, N(CH3)2, OCH3 and conjugate groups;

[1266] R4 is selected from OCH3, OH, C1-C6 alkyl, substituted C1-C6 alkyl and conjugate groups;

[1267] R5 is selected from OCH3, OH, C1-C6 alkyl, and substituted C1-C6 alkyl;

[1268] Either J R1 and G 1 Formation J R1 To G 1 Bridge, or J R1 It is H, and G 1 Selected from H, OH, halogens, or O-[C(R6)(R7)] n -[(C=O) m -X G ] j -R8;

[1269] Either J R2 and G 2 Formation J R2 and G 2 Bridge, or J R2 It is H, and G 2 Selected from H, OH, halogens, or O-[C(R6)(R7)] n -[(C=O) m -X G ] j -R8;

[1270] Either J R3 and G 3 Formation J R3 and G 3 Bridge, or J R3 It is H, and G 3 Selected from H, OH, halogens, or O-[C(R6)(R7)] n -[(C=O) m -X G ] j -R8;

[1271] Each J R The G bridge has independent selections from -CH(CH3)-O- or -(CH2). k -O-, where k is 1 to 3;

[1272] Each R6 and R7 is independently H, halogen, C1-C6 alkyl, or substituted C1-C6 alkyl;

[1273] Each X G It is O, S, or N (E1);

[1274] R8 is H, halogen, C1-C6 alkyl, substituted C1-C6 alkyl, C2-C6 alkenyl, substituted C2-C6 alkenyl, C2-C6 ynyl, substituted C2-C6 ynyl or N(E2)(E3).

[1275] E1, E2 and E3 are each independently H, C1-C6 alkyl or substituted C1-C6 alkyl;

[1276] n is 1 to 6;

[1277] m is 0 or 1;

[1278] j is 0 or 1;

[1279] Each substituted group contains one or more optional protected substituent groups independently selected from halogen, OJ1, N(J1)(J2), =NJ1, SJ1, N3, CN, OC(=X2)J1, OC(=X2)N(J1)(J2) and C(=Q2)N(J1)(J2);

[1280] Q2 is O, S, or NJ3; and

[1281] Each of J1, J2 and J3 is independently H or C1-C6 alkyl.

[1282] Implementation Scheme 795. An antisense agent comprising a modified oligonucleotide, wherein at least one region of said modified oligonucleotide has structure B:

[1283]

[1284] in:

[1285] Each Bx is a heterocyclic base moiety;

[1286] X is selected from O or S;

[1287] Each of Y1 and Y2 is independently selected from OH or SH;

[1288] Z 1 and Z 2 Each of them is independently selected from -(CH2). p -X Z -(CH2) q -, where p is 0 or 1, q is 0 or 1, and X Z It is O, S, or N (E1);

[1289] R1 is selected from H, C1-C6 alkyl groups, and substituted C1-C6 alkyl groups; and

[1290] T is selected from SO2R2, C(=O)R3 and P(=O)R4R5, where:

[1291] 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 conjugate groups.

[1292] R3 is selected from aryl, substituted aryl, CH3, N(CH3)2, OCH3 and conjugate groups;

[1293] R4 is selected from OCH3, OH, C1-C6 alkyl, substituted C1-C6 alkyl and conjugate groups;

[1294] R5 is selected from OCH3, OH, C1-C6 alkyl, and substituted C1-C6 alkyl;

[1295] Either J R1 and G 1 Formation J R1 To G 1 Bridge, or J R1 It is H, and G 1 Selected from H, OH, halogens, or O-[C(R6)(R7)] n -[(C=O) m -X G ] j -R8;

[1296] Either J R2 and G 2 Formation J R2 and G 2 Bridge, or J R2 It is H, and G 2 Selected from H, OH, halogens, or O-[C(R6)(R7)] n -[(C=O) m -X G ] j -R8;

[1297] Each J R The G bridge has independent selections from -CH(CH3)-O- or -(CH2). k -O-, where k is 1 to 3;

[1298] Each R6 and R7 is independently H, halogen, C1-C6 alkyl, or substituted C1-C6 alkyl;

[1299] Each X G It is O, S, or N (E1);

[1300] R8 is H, halogen, C1-C6 alkyl, substituted C1-C6 alkyl, C2-C6 alkenyl, substituted C2-C6 alkenyl, C2-C6 ynyl, substituted C2-C6 ynyl or N(E2)(E3).

[1301] E1, E2 and E3 are each independently H, C1-C6 alkyl or substituted C1-C6 alkyl;

[1302] n is 1 to 6;

[1303] m is 0 or 1;

[1304] j is 0 or 1;

[1305] Each substituted group contains one or more optional protected substituent groups independently selected from halogen, OJ1, N(J1)(J2), =NJ1, SJ1, N3, CN, OC(=X2)J1, OC(=X2)N(J1)(J2) and C(=Q2)N(J1)(J2);

[1306] Q2 is O, S, or NJ3;

[1307] Each of J1, J2 and J3 is independently H or C1-C6 alkyl.

[1308] Implementation Scheme 796. An antisense agent comprising a modified oligonucleotide, wherein at least one region of said modified oligonucleotide has a structural C:

[1309]

[1310] in:

[1311] Each Bx is a heterocyclic base moiety;

[1312] X is selected from O or S;

[1313] Each of Y1 and Y2 is independently selected from OH or SH;

[1314] Z 2 and Z 3 Each of them is independently selected from -(CH2). p -X Z -(CH2) q -, where p is 0 or 1, q is 0 or 1, and X Z It is O, S, or N (E1);

[1315] R1 is selected from H, C1-C6 alkyl groups, and substituted C1-C6 alkyl groups; and

[1316] T is selected from SO2R2, C(=O)R3 and P(=O)R4R5, where:

[1317] 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 conjugate groups.

[1318] R3 is selected from aryl, substituted aryl, CH3, N(CH3)2, OCH3 and conjugate groups;

[1319] R4 is selected from OCH3, OH, C1-C6 alkyl, substituted C1-C6 alkyl and conjugate groups;

[1320] R5 is selected from OCH3, OH, C1-C6 alkyl, and substituted C1-C6 alkyl;

[1321] Either J R2 and G 2 Formation J R2 and G 2 Bridge, or J R2 It is H, and G 2 Selected from H, OH, halogens, or O-[C(R6)(R7)] n -[(C=O) m -X G ] j -R8;

[1322] Either J R3 and G 3 Formation J R3 and G 3 Bridge, or J R3 It is H, and G 3 Selected from H, OH, halogens, or O-[C(R6)(R7)] n -[(C=O) m -X G ] j -R8;

[1323] Each J R The G bridge has independent selections from -CH(CH3)-O- or -(CH2). k -O-, where k is 1 to 3;

[1324] Each R6 and R7 is independently H, halogen, C1-C6 alkyl, or substituted C1-C6 alkyl;

[1325] Each X G It is O, S, or N (E1);

[1326] R8 is H, halogen, C1-C6 alkyl, substituted C1-C6 alkyl, C2-C6 alkenyl, substituted C2-C6 alkenyl, C2-C6 ynyl, substituted C2-C6 ynyl or N(E2)(E3).

[1327] E1, E2 and E3 are each independently H, C1-C6 alkyl or substituted C1-C6 alkyl;

[1328] n is 1 to 6;

[1329] m is 0 or 1;

[1330] j is 0 or 1;

[1331] Each substituted group contains one or more optional protected substituent groups independently selected from halogen, OJ1, N(J1)(J2), =NJ1, SJ1, N3, CN, OC(=X2)J1, OC(=X2)N(J1)(J2) and C(=Q2)N(J1)(J2);

[1332] Q2 is O, S, or NJ3;

[1333] Each of J1, J2 and J3 is independently H or C1-C6 alkyl.

[1334] Implementation Scheme 797. An antisense agent comprising a modified oligonucleotide, wherein at least one region of said modified oligonucleotide has a structure D:

[1335]

[1336] in:

[1337] Each Bx is a heterocyclic base moiety;

[1338] X is selected from O or S;

[1339] Each of Y1 and Y2 is independently selected from OH or SH;

[1340] Z 2 and Z 3 Each of them is independently selected from -(CH2). p -X Z -(CH2) q -, where p is 0 or 1, q is 0 or 1, and X Z It is O, S, or N (E1);

[1341] R1 is selected from H, C1-C6 alkyl groups, and substituted C1-C6 alkyl groups; and

[1342] T is selected from SO2R2, C(=O)R3 and P(=O)R4R5, where:

[1343] 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 conjugate groups.

[1344] R3 is selected from aryl, substituted aryl, CH3, N(CH3)2, OCH3 and conjugate groups;

[1345] R4 is selected from OCH3, OH, C1-C6 alkyl, substituted C1-C6 alkyl and conjugate groups;

[1346] R5 is selected from OCH3, OH, C1-C6 alkyl, and substituted C1-C6 alkyl;

[1347] Either J R1 and G 1 Formation J R1 To G 1 Bridge, or J R1 It is H, and G 1 Selected from H, OH, halogens, or O-[C(R6)(R7)] n -[(C=O) m -X G ] j -R8;

[1348] Either J R2 and G 2 Formation J R2 and G 2 Bridge, or J R2 It is H, and G 2 Selected from H, OH, halogens, or O-[C(R6)(R7)] n -[(C=O) m -X G ] j -R8;

[1349] Either J R3 and G 3 Formation J R3 and G 3 Bridge, or J R3 It is H, and G 3 Selected from H, OH, halogens, or O-[C(R6)(R7)] n -[(C=O) m -X G ] j -R8;

[1350] Each J RThe G bridge has independent selections from -CH(CH3)-O- or -(CH2). k -O-, where k is 1 to 3;

[1351] Each R6 and R7 is independently H, halogen, C1-C6 alkyl, or substituted C1-C6 alkyl;

[1352] Each X G It is O, S, or N (E1);

[1353] R8 is H, halogen, C1-C6 alkyl, substituted C1-C6 alkyl, C2-C6 alkenyl, substituted C2-C6 alkenyl, C2-C6 ynyl, substituted C2-C6 ynyl or N(E2)(E3).

[1354] E1, E2 and E3 are each independently H, C1-C6 alkyl or substituted C1-C6 alkyl;

[1355] n is 1 to 6;

[1356] m is 0 or 1;

[1357] j is 0 or 1;

[1358] Each substituted group contains one or more optional protected substituent groups independently selected from halogen, OJ1, N(J1)(J2), =NJ1, SJ1, N3, CN, OC(=X2)J1, OC(=X2)N(J1)(J2) and C(=Q2)N(J1)(J2);

[1359] Q2 is O, S, or NJ3;

[1360] Each of J1, J2 and J3 is independently H or C1-C6 alkyl.

[1361] Implementation Scheme 798. An antisense agent comprising a modified oligonucleotide, wherein at least one region of said modified oligonucleotide has structure E:

[1362]

[1363] in:

[1364] Each Bx is a heterocyclic base moiety;

[1365] X is selected from O or S;

[1366] Each of Y1 and Y2 is independently selected from OH or SH;

[1367] Z 2 and Z 3 Each of them is independently selected from -(CH2). p -XZ -(CH2) q -, where p is 0 or 1, q is 0 or 1, and X Z It is O, S, or N (E1);

[1368] R1 is selected from H, C1-C6 alkyl groups, and substituted C1-C6 alkyl groups; and

[1369] T is selected from SO2R2, C(=O)R3 and P(=O)R4R5, where:

[1370] 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 conjugate groups.

[1371] R3 is selected from aryl, substituted aryl, CH3, N(CH3)2, OCH3 and conjugate groups;

[1372] R4 is selected from OCH3, OH, C1-C6 alkyl, substituted C1-C6 alkyl and conjugate groups;

[1373] R5 is selected from OCH3, OH, C1-C6 alkyl, and substituted C1-C6 alkyl;

[1374] Either J R1 and G 1 Formation J R1 To G 1 Bridge, or J R1 It is H, and G 1 Selected from H, OH, halogens, or O-[C(R6)(R7)] n -[(C=O) m -X G ] j -R8;

[1375] Either J R2 and G 2 Formation J R2 and G 2 Bridge, or J R2 It is H, and G 2 Selected from H, OH, halogens, or O-[C(R6)(R7)] n -[(C=O) m -X G ] j -R8;

[1376] Either J R3 and G 3 Formation J R3and G 3 Bridge, or J R3 It is H, and G 3 Selected from H, OH, halogens, or O-[C(R6)(R7)] n -[(C=O) m -X G ] j -R8;

[1377] Each J R The G bridge has independent selections from -CH(CH3)-O- or -(CH2). k -O-, where k is 1 to 3;

[1378] Each R6 and R7 is independently H, halogen, C1-C6 alkyl, or substituted C1-C6 alkyl;

[1379] Each X G It is O, S, or N (E1);

[1380] R8 is H, halogen, C1-C6 alkyl, substituted C1-C6 alkyl, C2-C6 alkenyl, substituted C2-C6 alkenyl, C2-C6 ynyl, substituted C2-C6 ynyl or N(E2)(E3).

[1381] E1, E2 and E3 are each independently H, C1-C6 alkyl or substituted C1-C6 alkyl;

[1382] n is 1 to 6;

[1383] m is 0 or 1;

[1384] j is 0 or 1;

[1385] Each substituted group contains one or more optional protected substituent groups independently selected from halogen, OJ1, N(J1)(J2), =NJ1, SJ1, N3, CN, OC(=X2)J1, OC(=X2)N(J1)(J2) and C(=Q2)N(J1)(J2);

[1386] Q2 is O, S, or NJ3;

[1387] Each of J1, J2 and J3 is independently H or C1-C6 alkyl.

[1388] Implementation scheme 799. Oligonucleotides modified by any of Implementation schemes 794-798, wherein each Z is O.

[1389] Implementation scheme 800. An oligonucleotide modified according to any one of implementation schemes 794-799, wherein at least one G is selected from H, OH, halogen, C1-C6 alkoxy, -O(CH2)2OCH3 or -OCH2(C=O)NHCH3.

[1390] Implementation scheme 801. An oligonucleotide modified according to any one of implementation schemes 794-799, wherein each G is selected from H, OH, halogen, C1-C6 alkoxy, -O(CH2)2OCH3 or -OCH2(C=O)NHCH3.

[1391] Implementation scheme 802. An oligonucleotide modified according to any one of implementation schemes 794-801, wherein at least one J R Forming a bridge with at least one G, wherein the J R The bridge to G has a component selected from -CH(CH3)-O- or -(CH2). k -O', where k is from 1 to 3.

[1392] Implementation scheme 803. Oligonucleotides modified according to any one of implementation schemes 794-802, wherein each J R And G form a bridge, wherein J R The bridge to G has a component selected from -CH(CH3)-O- or -(CH2). k -O-, where k is from 1 to 3.

[1393] Implementation Scheme 804. An oligonucleotide modified according to any one of Implementation Schemes 802 or 803, wherein at least one Z is O, and the corresponding J R The bridge to G has the formula (CH2). k -O-, where k is 1.

[1394] Implementation scheme 805. An oligonucleotide modified according to any one of implementation schemes 794-804, wherein each nucleoside of structure A, B, C, D or E is a stereostandard nucleoside.

[1395] Implementation scheme 806. An oligonucleotide modified according to any one of implementation schemes 794-804, wherein at least one nucleoside of structure A, B, C, D or E is a stereononstandard nucleoside.

[1396] Implementation Scheme 807. An oligonucleotide modified according to any one of Implementation Schemes 802-804 or 806, wherein at least one has J R The nucleosides to the G-bridge are in the α-L-ribosyl configuration.

[1397] Implementation scheme 808. The modified oligonucleotide of any one of implementation schemes 794-807, wherein the modified oligonucleotide comprises at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or at least 10 regions having structure A, B, C, D or E.

[1398] Implementation scheme 809. The modified oligonucleotide of any one of implementation schemes 794-807, wherein at least one region having structure A, B, C, D or E is located at the 5' end of the modified oligonucleotide.

[1399] Implementation scheme 810. An oligonucleotide modified according to any one of implementation schemes 794-807, wherein at least one region having structure A, B, C, D or E is located at the 3' end of the modified oligonucleotide.

[1400] Implementation scheme 811. An oligonucleotide modified according to any one of implementation schemes 794-807, wherein at least one region having structure A, B, C, D or E is inside the modified oligonucleotide.

[1401] Implementation Scheme 812. An antisense agent comprising a modified oligonucleotide consisting of 10-30 linked nucleosides, wherein the modified oligonucleotide has a region of formula (N g1 ) L1 (N g2 ) L2 (N g3 ) L3 , where each N g Each L is a nucleoside, and each L is an inter-nucleoside linking group; wherein each of L1 and L2 is a phosphate diester inter-nucleoside linking group, a thiophosphate inter-nucleoside linking group, or an inter-nucleoside linking group of formula XVII:

[1402]

[1403] L3 is absent or is either a phosphate diester nucleoside linker, a thiophosphate nucleoside linker, or a nucleoside linker of formula XVII.

[1404] At least one of L1, L2, and L3 is a nucleoside linking group of formula XVII; and at least one of L1, L2, and L3 is a thiophosphate or phosphate diester nucleoside linking group.

[1405] For each nucleoside linker of formula XVII in the modified oligonucleotide, independently:

[1406] X is selected from O or S;

[1407] R1 is selected from H, C1-C6 alkyl groups, and substituted C1-C6 alkyl groups; and

[1408] T is selected from SO2R2, C(=O)R3 and P(=O)R4R5, where:

[1409] 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 conjugate groups.

[1410] R3 is selected from aryl, substituted aryl, CH3, N(CH3)2, OCH3 and conjugates;

[1411] R4 is selected from OCH3, OH, C1-C6 alkyl, substituted C1-C6 alkyl, and conjugates; and

[1412] R5 is selected from OCH3, OH, C1-C6 alkyl, and substituted C1-C6 alkyl.

[1413] Implementation Scheme 813. The modified oligonucleotide of Implementation Scheme 812, wherein the modified oligonucleotide comprises at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 oligonucleotides having the formula (N g1 ) L1 (N g2 ) L2 (N g3 ) L3 The district.

[1414] Implementation Scheme 814. The modified oligonucleotide of Implementation Scheme 812 or 813, wherein at least one has the formula (N g1 ) L1 (N g2 ) L2 (N g3 ) L3 The region at the 5' end of the oligonucleotide.

[1415] Implementation Scheme 815. The modified oligonucleotide of Implementation Scheme 812 or 813, wherein at least one has the formula (N g1 ) L1 (N g2 ) L2 (N g3 ) L3 The region is located inside the oligonucleotide.

[1416] Implementation Scheme 816. The modified oligonucleotide of Implementation Scheme 812 or 813, wherein at least one has the formula (N g1 ) L1 (Ng2 ) L2 (N g3 ) L3 The region is located at the 3' end of the oligonucleotide.

[1417] Implementation Scheme 817. The modified oligonucleotide of any one of Implementation Schemes 705-816, wherein at least one nucleoside of the modified oligonucleotide is a modified nucleoside selected from bicyclic nucleosides and non-bicyclic substituted nucleosides.

[1418] Implementation Scheme 818. The modified oligonucleotide of any one of Implementation Schemes 705-817, wherein at least one nucleoside of the modified oligonucleotide is selected from: β-D-LNA nucleoside, α-L-LNA nucleoside, ENA nucleoside, cEt nucleoside, 2'-MOE nucleoside, 2'-OMe nucleoside, 2'-F nucleoside, 2'-NMA nucleoside, 5'-Me nucleoside, DNA nucleoside, and RNA nucleoside.

[1419] Implementation Scheme 819. The modified oligonucleotide of any one of Implementation Schemes 705-818, wherein each nucleoside of the modified oligonucleotide is selected from: β-D-LNA nucleoside, α-L-LNA nucleoside, ENA nucleoside, cEt nucleoside, 2'-MOE nucleoside, 2'-OMe nucleoside, 2'-F nucleoside, 2'-NMA nucleoside, 5'-Me nucleoside, DNA nucleoside, and RNA nucleoside.

[1420] Implementation scheme 820. The modified oligonucleotide of any one of implementation schemes 705-819, wherein at least one nucleoside of the modified oligonucleotide is a stereononstandard nucleoside.

[1421] Implementation Scheme 821. The modified oligonucleotide of Implementation Scheme 820, wherein the internucleotide linking group connecting at least one stereononstandard nucleoside to an adjacent nucleoside is an internucleotide linking group of Formula XVII.

[1422] Implementation scheme 822. The modified oligonucleotide of implementation scheme 820 or 821, wherein at least two nucleosides of the modified oligonucleotide are stereononstandard nucleosides.

[1423] Implementation scheme 823. The modified oligonucleotide of implementation scheme 822, wherein at least two stereononstandard nucleosides of the modified oligonucleotide are adjacent to each other.

[1424] Implementation Scheme 824. The modified oligonucleotide of Implementation Scheme 823, wherein at least two stereononstandard nucleosides of the modified oligonucleotide are linked to each other by an internucleotide linking group of Formula XVII.

[1425] Implementation Scheme 825. The modified oligonucleotide of any one of Implementation Schemes 820-824, wherein at least one stereononstandard nucleoside of the modified oligonucleotide is a stereononstandard DNA nucleoside.

[1426] Implementation Scheme 826. The modified oligonucleotide of Implementation Scheme 825, wherein the stereononstandard DNA nucleoside is selected from stereononstandard DNA nucleosides having Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI and Formula VII.

[1427] Implementation scheme 827. The modified oligonucleotide of implementation scheme 826, wherein the stereonon-standard DNA nucleoside is selected from stereonon-standard DNA nucleosides having formula V and formula II.

[1428] Implementation Scheme 828. The modified oligonucleotide of any one of Implementation Schemes 820-827, wherein at least one stereononstandard nucleoside of the modified oligonucleotide is a substituted stereononstandard nucleoside or a stereononstandard RNA nucleoside.

[1429] Implementation Scheme 829. The modified oligonucleotide of Implementation Scheme 828, wherein the 2'-substituent of at least one substituted stereonon-standard nucleoside of the modified oligonucleotide is selected from: 2'-MOE, 2'-OMe, 2'-F or 2'-OH.

[1430] Implementation scheme 830. The oligonucleotide modified by any one of implementation schemes 705-819, wherein each nucleoside is a stereostandard nucleoside.

[1431] Implementation scheme 831. The modified oligonucleotide of any one of implementation schemes 705-829, wherein the modified oligonucleotide consists of 12-30 linked nucleosides.

[1432] Implementation scheme 832. The modified oligonucleotide of any one of implementation schemes 705-829, wherein the modified oligonucleotide consists of 16-24 linked nucleosides.

[1433] Implementation scheme 833. The modified oligonucleotide of any one of implementation schemes 705-829, wherein the modified oligonucleotide is composed of 18-22 linked nucleosides.

[1434] Implementation scheme 834. The modified oligonucleotide of any one of implementation schemes 705-832, wherein the modified oligonucleotide consists of 16 linked nucleosides.

[1435] Implementation scheme 835. The modified oligonucleotide of any one of implementation schemes 705-832, wherein the modified oligonucleotide consists of 17 linked nucleosides.

[1436] Implementation scheme 836. The modified oligonucleotide of any one of implementation schemes 705-833, wherein the modified oligonucleotide consists of 18 linked nucleosides.

[1437] Implementation scheme 837. The modified oligonucleotide of any one of implementation schemes 705-833, wherein the modified oligonucleotide consists of 19 linked nucleosides.

[1438] Implementation scheme 838. The modified oligonucleotide of any one of implementation schemes 705-833, wherein the modified oligonucleotide consists of 20 linked nucleosides.

[1439] Implementation scheme 839. The modified oligonucleotide of any one of implementation schemes 705-833, wherein the modified oligonucleotide consists of 21 linked nucleosides.

[1440] Implementation scheme 840. The modified oligonucleotide of any one of implementation schemes 705-833, wherein the modified oligonucleotide consists of 22 linked nucleosides.

[1441] Implementation scheme 841. The modified oligonucleotide of any one of implementation schemes 705-832, wherein the modified oligonucleotide is composed of 23 linked nucleosides.

[1442] Implementation Scheme 842. The modified oligonucleotide of any one of Implementation Schemes 705-841, wherein at least one nucleoside of the modified oligonucleotide is selected from: 2'-OMe nucleoside, 2'-F nucleoside and RNA nucleoside.

[1443] Implementation Scheme 843. The modified oligonucleotide of any one of Implementation Schemes 705-842, wherein at least one nucleoside of the modified oligonucleotide is 2'-OMe nucleoside, and at least one nucleoside of the modified oligonucleotide is 2'-F nucleoside.

[1444] Implementation Scheme 844. The modified oligonucleotide of Implementation Scheme 843, wherein each nucleoside of the modified oligonucleotide is selected from 2'-OMe nucleoside or 2'-F nucleoside.

[1445] Implementation Scheme 845. The modified oligonucleotide of any one of Implementation Schemes 705-743, wherein at least one nucleoside of the modified oligonucleotide is a 2'-OMe nucleoside, at least one nucleoside of the modified oligonucleotide is a 2'-F nucleoside, and at least one nucleoside of the modified oligonucleotide contains a sugar substitute.

[1446] Implementation Scheme 846. The modified oligonucleotide of Implementation Scheme 845, wherein each nucleoside of the modified oligonucleotide is selected from 2'-OMe nucleoside, 2'-F nucleoside and nucleoside containing a sugar substitute.

[1447] Implementation Scheme 847. The oligonucleotide modified according to any one of Implementation Schemes 845-846, wherein the nucleoside containing the sugar substitute is selected from:

[1448] Bx represents the heterocyclic base moiety.

[1449] Implementation scheme 848. The modified oligonucleotide of implementation scheme 847, wherein the nucleoside containing the sugar substitute is GNA.

[1450] Implementation Scheme 849. A modified oligonucleotide of any one of Implementation Schemes 842-848, wherein the modified oligonucleotide has a region having alternating nucleoside types with the motif ABABA, wherein each A is a stereostandard nucleoside of a first type and each B is a stereostandard nucleoside of a second type, wherein the first type and the second type are different from each other.

[1451] Implementation scheme 850. The modified oligonucleotide of implementation scheme 849, wherein A and B are selected from 2'-F substituted nucleosides, 2'-OMe substituted nucleosides and stereostandard RNA nucleosides.

[1452] Implementation Scheme 851. The modified oligonucleotide of any one of Implementation Schemes 705-850, wherein the 5' end of the modified oligonucleotide comprises a terminal group.

[1453] Implementation scheme 852. The modified oligonucleotide of implementation scheme 851, wherein the terminal group is a stable phosphate ester group.

[1454] Implementation Scheme 853. The modified oligonucleotide of Implementation Scheme 852, wherein the stable phosphate ester group is 5'-vinylphosphonate or 5'-cyclopropylphosphonate.

[1455] Implementation Scheme 854. The modified oligonucleotide of Implementation Scheme 851, wherein the terminal group is selected from...

[1456] Where R A It is an OH, OP(=O)OH, OP(=O)SH or a stable phosphate ester group;

[1457] G A It is H, OH, OMe, MOE or halogen;

[1458] X is OH, SH, or NSO2R2;

[1459] R2 is selected from aryl, substituted aryl, heterocyclic, substituted heterocyclic, aromatic heterocyclic, substituted aromatic heterocyclic, 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 conjugate groups.

[1460] Implementation scheme 855. Modified oligonucleotides of implementation scheme 854, wherein G A X is selected from H or OH, and X is SH.

[1461] Implementation scheme 856. An antisense agent of any one of implementation schemes 705-855, wherein the antisense agent is an RNAi agent.

[1462] Implementation Scheme 857. The RNAi agent of Implementation Scheme 856, wherein the RNAi agent is a single-stranded RNAi agent comprising an RNAi antisense modified oligonucleotide, wherein the RNAi antisense modified oligonucleotide is an oligonucleotide modified by any one of Implementation Schemes 705-855.

[1463] Implementation Scheme 858. The RNAi agent of Implementation Scheme 856, wherein the RNAi agent is an oligonucleotide duplex comprising an RNAi antisense modified oligonucleotide and an RNAi sense modified oligonucleotide, wherein the RNAi antisense modified oligonucleotide and / or the RNAi sense modified oligonucleotide is a modified oligonucleotide of any one of Implementation Schemes 705-855.

[1464] Implementation Scheme 859. The RNAi agent of Implementation Scheme 857 or 858, wherein at least one nucleoside linker of the RNAi antisense modified oligonucleotide is a nucleoside linker of Formula XVII.

[1465] Implementation scheme 860. The RNAi agent of implementation scheme 857 or 858, wherein at least two internucleotide linking groups of the RNAi antisense modified oligonucleotide are independently selected internucleotide linking groups of formula XVII.

[1466] Implementation Scheme 861. An RNAi agent of any one of Implementation Schemes 857-860, wherein at least one of the five 3' internucleotide linking groups of the RNAi antisense modified oligonucleotide is an internucleotide linking group of Formula XVII.

[1467] Implementation scheme 862. An RNAi agent of any one of implementation schemes 857-861, wherein at least two of the five 3' internucleotide linking groups of the RNAi antisense modified oligonucleotide are internucleotide linking groups of formula XVII.

[1468] Implementation scheme 863. An RNAi agent of any one of implementation schemes 857-862, wherein 1-3 of the three 3' internucleotide linking groups are internucleotide linking groups of formula XVII, and each of the three internucleotide linking groups is not a phosphate diester or thiophosphate internucleotide linking group.

[1469] Implementation scheme 864. The RNAi agent of implementation scheme 863, wherein the two 3' internucleotide linking groups are the internucleotide linking groups of formula XVII.

[1470] Implementation scheme 865. An RNAi agent of any of Implementation schemes 857-864, wherein exactly one of the most 5' and the second to last most 5' nucleoside linker groups is a nucleoside linker group of formula XVII.

[1471] Implementation Scheme 866. An RNAi agent of any one of Implementation Schemes 857-865, wherein exactly one of the 5'th and the penultimate 5'th nucleoside linker groups of the RNAi antisense oligonucleotide is a nucleoside linker group of Formula XVII, the other of the 5'th and the penultimate 5'th nucleoside linker groups of the RNAi antisense oligonucleotide is selected from phosphodiester and thiophosphate nucleoside links, the two 3'th nucleoside linker groups of the RNAi antisense oligonucleotide are nucleoside linker groups of Formula XVII, and the remaining nucleoside linker groups of the RNAi antisense oligonucleotide are phosphodiester nucleoside links.

[1472] Implementation scheme 867. An RNAi agent of any one of implementation schemes 857-866, wherein the antisense modified oligonucleotide contains a 3'-overhang.

[1473] Implementation scheme 868. The RNAi agent of implementation scheme 867, wherein the 3'-protrusion is composed of two nucleosides.

[1474] Implementation Scheme 869. An RNAi agent of any one of Implementation Schemes 857-865 or 867-868, wherein at least one internucleotide linker in the seed region of the RNAi antisense modified oligonucleotide is an internucleotide linker of Formula XVII.

[1475] Implementation scheme 870. An RNAi agent of any of Implementation schemes 857-869, wherein for each nucleoside linker of formula XVII, R1 is H and T is SO2Me.

[1476] Implementation Scheme 871. An RNAi agent according to any one of Implementation Schemes 857-870, wherein the RNAi antisense modified oligonucleotide is composed of 23 linked nucleosides, and the internucleotide bond motif is selected from: ooooooooooooooooooooooaa, aaoooooooooooooooooooooo, aaooooooooooooooooooooaa, asooooooooooooooooooooss, saoooooooooooooooooooooo, oooooooooooooooooooooaaa, ​​oooooooooooooooooo aaaoss, oooooooooooooaaaooooss, ooooooooooaaaoooooooss, oooooooaaaooooooooooss, ooooaaaooooooooooooooss, saoooaoooooooaooooss, ssoooaoooooooaooooss or ssooooooooooooooooooaa, where each "a" represents a nucleoside bond in formula XVII, each "s" represents a thiophosphate nucleoside bond, and each "o" represents a phosphodiester nucleoside bond.

[1477] Implementation Scheme 872. The RNAi agent of Implementation Scheme 871, wherein the nucleoside internucleotide motif of the RNAi antisense modified oligonucleotide is selected from oooooooooooooooooooooaa, asooooooooooooooooooooss or saoooooooooooooooooooooo.

[1478] Implementation Scheme 873. The RNAi agent of Implementation Scheme 871 or 872, wherein the glycosylation of the RNAi antisense modified oligonucleotide from 5' to 3' is yfyfyfyfyfyfyfyfyfyfy or yfyyyfyyyyyyyyyyfyfyyyyy, where "y" represents the 2'-OMe sugar moiety and "f" represents the 2'-F sugar moiety.

[1479] Implementation Scheme 874. The RNAi agent of any one of Implementation Schemes 857-870, wherein the RNAi antisense modified oligonucleotide consists of 21 linked nucleosides, and the nucleoside bond motif is selected from: aaososososososssssss, ssaaosososososssssss, ssosaaososososossssss, ssososososososssss, ssososososososssss, ssososososososssss, ssosososososossasss, ssosososososossasss, ssosososososososssaass, ssosososososososssaass, ssosososososososssaa, where each "a" represents a nucleoside bond of formula XVII, each "s" represents a phosphate thioester nucleoside bond, and each "o" represents a phosphodiester nucleoside bond.

[1480] Implementation Scheme 875. The RNAi agent of Implementation Scheme 874, wherein the nucleotide internucleotide motif of the RNAi antisense modified oligonucleotide is selected from aaososososososssssss, ssaaososososososssssss, ssososaaososososssssss, ssosososaaosososssssss, ssososososososssaass or ssosososososossssaa, wherein each "a" represents a nucleotide internucleotide of formula XVII, each "s" represents a thiophosphate nucleotide internucleotide, and each "o" represents a phosphodiester nucleotide internucleotide.

[1481] Implementation Scheme 876. The RNAi agent of Implementation Scheme 874 or 875, wherein the glycosylation of the RNAi antisense modified oligonucleotide from 5' to 3' is yfyfyfyfyfyfyfyfyfyfy, where "y" represents the 2'-OMe sugar moiety and "f" represents the 2'-F sugar moiety.

[1482] Implementation scheme 877. An RNAi agent of any one of implementation schemes 873-876, wherein each "a" is a mesylate phosphoramidate bond.

[1483] Implementation Scheme 878. An RNAi agent of any one of Implementation Schemes 857-878, wherein at least one region of the RNAi antisense modified oligonucleotide has a structure A, B, C, D or E.

[1484] Implementation Scheme 879. The RNAi agent of Implementation Scheme 878, wherein at least one region having structure A, B, C, D or E is located within the seed region of the RNAi antisense modified oligonucleotide.

[1485] Implementation scheme 880. The RNAi agent of implementation scheme 878, wherein at least one region having structure A, B, C, D or E is located at the 3' end of the RNAi antisense modified oligonucleotide.

[1486] Implementation Scheme 881. An RNAi agent of any one of Implementation Schemes 857-880, wherein at least one region of the RNAi antisense modified oligonucleotide has the formula (N g1 ) L1 (N g2 ) L2 (N g3 ) L3 , where each N g Each L is a nucleoside, and each L is an inter-nucleoside linking group; wherein each of L1 and L2 is a phosphate diester inter-nucleoside linking group, a thiophosphate inter-nucleoside linking group, or an inter-nucleoside linking group of formula XVII:

[1487]

[1488] L3 is absent or is either a phosphate diester nucleoside linker, a thiophosphate nucleoside linker, or a nucleoside linker of formula XVII.

[1489] At least one of L1, L2, and L3 is a nucleoside linking group of formula XVII; and at least one of L1, L2, and L3 is a thiophosphate or phosphate diester nucleoside linking group.

[1490] For each nucleoside linker of formula XVII in the modified oligonucleotide, independently:

[1491] X is selected from O or S;

[1492] R1 is selected from H, C1-C6 alkyl groups, and substituted C1-C6 alkyl groups; and

[1493] T is selected from SO2R2, C(=O)R3 and P(=O)R4R5, where:

[1494] R2 is selected from aryl, substituted aryl, heterocyclic, substituted heterocyclic, aromatic heterocyclic, substituted aromatic heterocyclic, diazole, substituted diazole, C1-C6 alkoxy, C1-C6 alkyl, substituted C1-C6 alkyl, and conjugates.

[1495] R3 is selected from aryl, substituted aryl, CH3, N(CH3)2, OCH3 and conjugates;

[1496] R4 is selected from OCH3, OH, C1-C6 alkyl, substituted C1-C6 alkyl, and conjugates; and

[1497] R5 is selected from OCH3, OH, C1-C6 alkyl, and substituted C1-C6 alkyl.

[1498] Implementation scheme 882. The RNAi agent of implementation scheme 881, wherein it has the formula (N g1 ) L1 (N g2 ) L2 (N g3 ) L3 The region includes one or two 3'-protruding nucleosides.

[1499] Implementation Scheme 883. The RNAi agent of Implementation Scheme 881, wherein at least one has the formula (N g1 ) L1 (N g2 ) L2 (N g3 ) L3 The region is located at the 3' end of the RNAi antisense modified oligonucleotide.

[1500] Implementation scheme 884. The RNAi agent of implementation scheme 883, wherein L1 and L2 are each nucleoside inter-bonds of formula XVII, wherein R1 is H and T is SO2Me, and L3 is a phosphodiester nucleoside inter-bond.

[1501] Implementation Scheme 885. The RNAi agent of Implementation Scheme 881, wherein at least one has the formula (N g1 ) L1 (N g2 ) L2 (N g3 ) L3 The region is located at the 5' end of the RNAi antisense modified oligonucleotide.

[1502] Implementation Scheme 886. The RNAi agent of Implementation Scheme 885, wherein one of L1 or L2 is a nucleoside inter-bond of Formula XVII, wherein R1 is H and T is SO2Me, the other of L1 or L2 is a thiophosphate nucleoside inter-bond, and L3 is a phosphodiester nucleoside inter-bond.

[1503] Implementation Scheme 887. The RNAi agent of Implementation Scheme 881, wherein at least one has the formula (N g1 ) L1 (N g2 ) L2 (N g3 ) L3 The region is located within the seed region of the RNAi antisense modified oligonucleotide.

[1504] Implementation scheme 888. An RNAi agent of any one of implementation schemes 857-887, wherein the region of the RNAi antisense oligonucleotide complementary to the target is at least 15 nucleotides.

[1505] Implementation scheme 889. An RNAi agent of any one of implementation schemes 857-888, wherein the region of the RNAi antisense oligonucleotide complementary to the target is at least 17 nucleobases.

[1506] Implementation scheme 890. An RNAi agent of any one of implementation schemes 857-889, wherein the region of the RNAi antisense oligonucleotide complementary to the target is at least 19 nucleotides.

[1507] Implementation scheme 891. An RNAi agent of any one of implementation schemes 857-890, wherein the region of the RNAi antisense oligonucleotide complementary to the target is at least 21 nucleotides.

[1508] Implementation scheme 892. An RNAi agent of any one of implementation schemes 857-890, wherein the region of the RNAi antisense oligonucleotide complementary to the target is exactly 19 nucleobases.

[1509] Implementation scheme 893. An RNAi agent of any one of implementation schemes 857-891, wherein the region of the RNAi antisense oligonucleotide complementary to the target is exactly 21 nucleobases.

[1510] Implementation Scheme 894. An RNAi agent of any one of Implementation Schemes 857-893, wherein at least one nucleoside of the RNAi antisense modified oligonucleotide is selected from: 2'-OMe nucleoside, 2'-F nucleoside and RNA nucleoside.

[1511] Implementation Scheme 895. An RNAi agent of any one of Implementation Schemes 857-894, wherein at least one nucleoside of the modified oligonucleotide is a 2'-OMe nucleoside, and at least one nucleoside of the modified oligonucleotide is an RNA nucleoside.

[1512] Implementation Scheme 896. An RNAi agent of any one of Implementation Schemes 857-894, wherein at least one nucleoside of the RNAi antisense modified oligonucleotide is a 2'-OMe nucleoside, and at least one nucleoside of the RNAi antisense modified oligonucleotide is a 2'-F nucleoside.

[1513] Implementation Scheme 897. The RNAi agent of Implementation Scheme 896, wherein each nucleoside of the RNAi antisense modified oligonucleotide is selected from 2'-OMe nucleoside or 2'-F nucleoside.

[1514] Implementation Scheme 898. An RNAi agent of any one of Implementation Schemes 887-894, wherein at least one nucleoside of the RNAi antisense modified oligonucleotide is a 2'-OMe nucleoside, at least one nucleoside of the RNAi antisense modified oligonucleotide is a 2'-F nucleoside, and at least one nucleoside of the modified oligonucleotide contains a sugar substitute.

[1515] Implementation Scheme 899. The RNAi agent of Implementation Scheme 898, wherein each nucleoside of the RNAi antisense modified oligonucleotide is selected from 2'-OMe nucleoside, 2'-F nucleoside and nucleoside containing sugar substitutes.

[1516] Implementation scheme 900. An RNAi agent of any one of implementation schemes 898-899, wherein the nucleoside containing the sugar substitute is selected from:

[1517] Bx represents the heterocyclic base moiety.

[1518] Implementation Scheme 901. The RNAi agent of Implementation Scheme 900, wherein the nucleoside containing the sugar substitute is GNA.

[1519] Implementation Scheme 902. The RNAi agent of Implementation Scheme 900 or 901, wherein at least one nucleotide containing a sugar substitute is one of the nine most 5' nucleotides of the RNAi antisense modified oligonucleotide.

[1520] Implementation scheme 903. An RNAi agent of any one of implementation schemes 857-902, wherein the modified oligonucleotide has a region having alternating nucleoside types with motifs ABABA, wherein each A is a stereostandard nucleoside of type 1 and each B is a stereostandard nucleoside of type 2, wherein the type 1 and the type 2 are different from each other.

[1521] Implementation scheme 904. The RNAi agent of implementation scheme 903, wherein A and B are selected from 2'-F substituted nucleosides, 2'-OMe substituted nucleosides and stereostandard RNA nucleosides.

[1522] Implementation scheme 905. An RNAi agent of any one of implementation schemes 857-904, wherein the 5' end of the RNAi antisense modified oligonucleotide contains a terminal group.

[1523] Implementation Scheme 906. The RNAi agent of Implementation Scheme 905, wherein the terminal group is a stable phosphate ester group.

[1524] Implementation Scheme 907. The RNAi agent of Implementation Scheme 906, wherein the stable phosphate ester group is 5'-vinylphosphonate or 5'-cyclopropylphosphonate.

[1525] Implementation Scheme 908. The RNAi agent of Implementation Scheme 905, wherein the terminal group is selected from...

[1526] Where R A It is an OH, OP(=O)OH, OP(=O)SH or a stable phosphate ester group;

[1527] G A It is H, OH, OMe, MOE or halogen;

[1528] X is OH, SH, or NSO2R2;

[1529] R2 is selected from aryl, substituted aryl, heterocyclic, substituted heterocyclic, aromatic heterocyclic, substituted aromatic heterocyclic, 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 conjugate groups.

[1530] Implementation scheme 909. RNAi agent of implementation scheme 908, wherein G A X is selected from H or OH, and X is SH.

[1531] Implementation Scheme 910. An RNAi agent of any one of Implementation Schemes 858-909, wherein at least one internucleotide linker of the RNAi positively modified oligonucleotide is an internucleotide linker of Formula XVII.

[1532] Implementation Scheme 911. The RNAi agent of Implementation Scheme 910, wherein at least one of the five 5' internucleotide linking groups of the RNAi positively modified oligonucleotide is an internucleotide linking group of Formula XVII.

[1533] Implementation Scheme 912. The RNAi agent of Implementation Scheme 910, wherein at least two of the five 5' internucleotide linking groups of the RNAi positively modified oligonucleotide are internucleotide linking groups of Formula XVII.

[1534] Implementation Scheme 913. The RNAi agent of Implementation Scheme 910, wherein the two 5' internucleotide linking groups of the RNAi positively modified oligonucleotide are internucleotide linking groups of Formula XVII.

[1535] Implementation Scheme 914. An RNAi agent of any one of Implementation Schemes 910-913, wherein at least one of the five 3' internucleotide linking groups of the RNAi positively modified oligonucleotide is an internucleotide linking group of Formula XVII.

[1536] Implementation Scheme 915. An RNAi agent of any one of Implementation Schemes 910-913, wherein at least two of the five 3' internucleotide linking groups of the RNAi positively modified oligonucleotide are internucleotide linking groups of Formula XVII.

[1537] Implementation scheme 916. An RNAi agent of any one of implementation schemes 910-913, wherein the two 3' internucleotide linking groups are internucleotide linking groups of formula XVII.

[1538] Implementation Scheme 917. The RNAi agent of Implementation Scheme 910, wherein the two 3' and two 5' internucleotide linking groups of the RNAi positive oligonucleotide are internucleotide linking groups of Formula XVII, and the remaining internucleotide linking groups of the RNAi positive oligonucleotide are phosphodiester internucleotide bonds.

[1539] Implementation scheme 918. An RNAi agent of any one of implementation schemes 910-917, wherein for each nucleoside linker of formula XVII, R1 is H and T is SO2Me.

[1540] Implementation Scheme 919. An RNAi agent of any one of Implementation Schemes 910-918, wherein the RNAi positively modified oligonucleotide consists of 21 linked nucleosides, and the nucleoside bond motif is selected from: ooooooooooooooooooooaa, aaooooooooooooooooooaa, ooooooooooooooooooaa or ssooooaoaaaooooooooo, wherein each "a" represents a nucleoside bond of formula XVII, each "s" represents a thiophosphate nucleoside bond, and each "o" represents a phosphodiester nucleoside bond.

[1541] Implementation Scheme 920. The RNAi agent of Implementation Scheme 919, wherein the internucleotide motif of the RNAi positively modified oligonucleotide is selected from ooooooooooooooooooooaa, aaooooooooooooooooooaa or ooooooooooooooooooaa, wherein each "a" represents an internucleotide bond of formula XVII, each "s" represents a thiophosphate internucleotide bond, and each "o" represents a phosphodiester internucleotide bond.

[1542] Implementation Scheme 921. The RNAi agent of Implementation Scheme 919 or 920, wherein the glycosylation of the positively modified oligonucleotide of the RNAi is selected from: yyyyyyfyfffyyyyyyyyyy or fyfyfyfyfyfyfyfyfyfyfyf, where “y” represents the 2'-OMe sugar moiety and “f” represents the 2'-F sugar moiety.

[1543] Implementation Scheme 922. The RNAi agent of Implementation Scheme 921, wherein the positively modified oligonucleotide of the RNAi has a nucleoside inter-bond motif of aaooooooooooooooooooaa and a glycosyl motif of yyyyyyfyfffyyyyyyyyyyy, wherein each “a” represents a nucleoside inter-bond of formula XVII, each “s” represents a thiophosphate nucleoside inter-bond, and each “o” represents a phosphodiester nucleoside inter-bond, wherein “y” represents the 2'-OMe sugar motif, and “f” represents the 2'-F sugar motif.

[1544] Implementation scheme 923. An RNAi agent of any one of implementation schemes 919-922, wherein each "a" is a methanesulfonyl phosphate bond.

[1545] Implementation Scheme 924. An RNAi agent of any one of Implementation Schemes 910-923, wherein at least one region of the RNAi positively modified oligonucleotide has a structure A, B, C, D or E.

[1546] Implementation Scheme 925. The RNAi agent of Implementation Scheme 924, wherein at least one region having structure A, B, C, D or E is located at the 3' end of the RNAi positively modified oligonucleotide.

[1547] Implementation Scheme 926. The RNAi agent of Implementation Scheme 924, wherein at least one region having structure A, B, C, D or E is located at the 5' end of the RNAi positively modified oligonucleotide.

[1548] Implementation Scheme 927. An RNAi agent of any one of Implementation Schemes 910-926, wherein at least one region of the RNAi positively modified oligonucleotide has the formula (N g1 ) L1 (N g2 ) L2 (N g3 ) L3 , where each N g Each L is a nucleoside, and each L is an inter-nucleoside linking group; wherein each of L1 and L2 is a phosphate diester inter-nucleoside linking group, a thiophosphate inter-nucleoside linking group, or an inter-nucleoside linking group of formula XVII:

[1549]

[1550] L3 is absent or is either a phosphate diester nucleoside linker, a thiophosphate nucleoside linker, or a nucleoside linker of formula XVII.

[1551] At least one of L1, L2, and L3 is a nucleoside linking group of formula XVII; and at least one of L1, L2, and L3 is a thiophosphate or phosphate diester nucleoside linking group.

[1552] For each nucleoside linker of formula XVII in the modified oligonucleotide, independently:

[1553] X is selected from O or S;

[1554] R1 is selected from H, C1-C6 alkyl groups, and substituted C1-C6 alkyl groups; and

[1555] T is selected from SO2R2, C(=O)R3 and P(=O)R4R5, where:

[1556] 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 conjugate groups.

[1557] R3 is selected from aryl, substituted aryl, CH3, N(CH3)2, OCH3 and conjugates;

[1558] R4 is selected from OCH3, OH, C1-C6 alkyl, substituted C1-C6 alkyl, and conjugates; and

[1559] R5 is selected from OCH3, OH, C1-C6 alkyl, and substituted C1-C6 alkyl.

[1560] Implementation scheme 928. The RNAi agent of implementation scheme 927, wherein at least one has the formula (N g1 ) L1 (N g2 ) L2 (N g3 ) L3 The region is located at the 3' end of the RNAi positively modified oligonucleotide.

[1561] Implementation Scheme 929. The RNAi agent of Implementation Scheme 928, wherein L1 and L2 are nucleoside linking groups of Formula XVII, wherein R1 is H and T is SO2Me, and L3 is a phosphodiester nucleoside linker.

[1562] Implementation scheme 930. RNAi agent of implementation scheme 927, wherein at least one has the formula (N g1 ) L1 (N g2 ) L2 (N g3 ) L3 The region is located at the 5' end of the RNAi positively modified oligonucleotide.

[1563] Implementation Scheme 931. The RNAi agent of Implementation Scheme 930, wherein L1 is a phosphodiester nucleoside linker, and L2 and L3 are each nucleoside linkers of Formula XVII, wherein R1 is H and T is SO2Me.

[1564] Implementation Scheme 932. An RNAi agent of any one of Implementation Schemes 858-931, wherein the RNAi positively modified oligonucleotide comprises a 3' terminal group and / or a 5' terminal group.

[1565] Implementation scheme 933. An RNAi agent of any one of implementation schemes 858-932, wherein the positive strand of the RNAi contains a conjugate group.

[1566] Implementation scheme 934. The RNAi agent of implementation scheme 933, wherein the conjugate group comprises a cell-targeting portion.

[1567] Implementation Scheme 935. The RNAi agent of Implementation Scheme 933, wherein the conjugate group comprises a carbohydrate or a carbohydrate cluster.

[1568] Implementation Scheme 936. The RNAi agent of Implementation Scheme 933, wherein the conjugate group comprises at least one GalNAc.

[1569] Implementation Scheme 937. The RNAi agent of Implementation Scheme 933, wherein the conjugate group comprises C 10 -C 20 Alkyl chain.

[1570] Implementation Scheme 938. The RNAi agent of Implementation Scheme 933, wherein the conjugate group comprises C 16 alkyl.

[1571] Implementation scheme 939. An RNAi agent of any one of implementation schemes 858-938, wherein the double-stranded region of the oligonucleotide duplex is at least 15 nucleotides.

[1572] Implementation scheme 940. An RNAi agent of any one of implementation schemes 858-938, wherein the double-stranded region of the oligonucleotide duplex is at least 17 nucleotides.

[1573] Implementation scheme 941. An RNAi agent of any one of implementation schemes 858-938, wherein the double-stranded region of the oligonucleotide duplex is at least 19 nucleotides.

[1574] Implementation scheme 942. An RNAi agent of any one of implementation schemes 858-938, wherein the double-stranded region of the oligonucleotide duplex is exactly 19 nucleotides.

[1575] Implementation scheme 943. The modified oligonucleotide of any one of implementation schemes 705-841, wherein each nucleoside of the modified oligonucleotide is a modified nucleoside containing a modified sugar moiety.

[1576] Implementation scheme 944. The modified oligonucleotide of implementation scheme 943, wherein each modified sugar moiety is independently selected from a bicyclic sugar moiety and a 2'-substituted furanyl sugar moiety.

[1577] Implementation scheme 945. Modified oligonucleotides of implementation scheme 943 or 944, wherein each modified sugar moiety contains the same modification.

[1578] Implementation scheme 946. The modified oligonucleotide of any one of implementation schemes 943-945, wherein each modified sugar moiety is selected from the 2'-OMe sugar moiety, the 2'-MOE sugar moiety and the 2'-NMA sugar moiety.

[1579] Implementation scheme 947. The modified oligonucleotide of implementation scheme 943 or 944, wherein the three most 3' nucleotides contain a bicyclic sugar moiety and the remaining nucleotide contains a 2'-substituted furanyl sugar moiety.

[1580] Implementation scheme 948. The modified oligonucleotide of implementation scheme 943 or 944, wherein the four most 3' nucleotides contain a bicyclic sugar moiety and the remaining nucleotides contain a 2'-substituted furanyl sugar moiety.

[1581] Implementation scheme 949. The modified oligonucleotide of implementation scheme 943 or 944, wherein five of the 3' nucleotides contain a bicyclic sugar moiety and the remaining nucleotides contain a 2'-substituted furanyl sugar moiety.

[1582] Implementation scheme 950. Implementation scheme 943 or 944 modified oligonucleotides, wherein the six most 3' nucleotides contain a bicyclic sugar moiety and the remaining nucleotides contain a 2'-substituted furanyl sugar moiety.

[1583] Implementation scheme 951. An oligonucleotide modified according to any one of implementation schemes 947-950, wherein each bicyclic sugar moiety is selected from cEt, LNA and ENA.

[1584] Implementation scheme 952. The modified oligonucleotide of implementation scheme 951, wherein the bicyclic sugar moiety is cEt.

[1585] Implementation scheme 953. The modified oligonucleotide of any one of implementation schemes 947-952, wherein the 2'-substituted furanose glycosyl sugar moiety is selected from 2'-OMe, 2'-MOE and 2'-F.

[1586] Implementation scheme 954. The modified oligonucleotide of any one of implementation schemes 943-953, wherein at least one of the ten 5' linking groups of the modified oligonucleotide is a nucleoside linking group of formula XVII.

[1587] Implementation Scheme 955. The modified oligonucleotide of Implementation Scheme 954, wherein at least two of the ten 5' linking groups of the modified oligonucleotide are nucleoside linking groups of Formula XVII.

[1588] Implementation Scheme 956. The modified oligonucleotide of Implementation Scheme 954, wherein at least three of the ten 5' linking groups of the modified oligonucleotide are nucleoside linking groups of Formula XVII.

[1589] Implementation Scheme 957. The modified oligonucleotide of Implementation Scheme 954, wherein at least four of the ten 5' linking groups of the modified oligonucleotide are nucleoside linking groups of Formula XVII.

[1590] Implementation scheme 958. The modified oligonucleotide of implementation scheme 954, wherein at least 5 of the ten 5' linking groups of the modified oligonucleotide are nucleoside linking groups of formula XVII.

[1591] Implementation Scheme 959. The modified oligonucleotide of Implementation Scheme 954, wherein at least 6 of the ten 5' linking groups of the modified oligonucleotide are nucleoside linking groups of Formula XVII.

[1592] Implementation scheme 960. Implementation scheme 954 modified oligonucleotide, wherein the two most 5' internucleotide linking groups are internucleotide linking groups of formula XVII.

[1593] Implementation scheme 961. The modified oligonucleotide of any one of implementation schemes 943-960, wherein at least one of the ten 3' internucleotide linking groups of the modified oligonucleotide is an internucleotide linking group of formula XVII.

[1594] Implementation Scheme 962. The modified oligonucleotide of Implementation Scheme 961, wherein at least two of the ten 3' internucleotide linking groups of the modified oligonucleotide are internucleotide linking groups of Formula XVII.

[1595] Implementation scheme 963. The modified oligonucleotide of implementation scheme 961, wherein at least three of the ten 3' internucleotide linking groups are internucleotide linking groups of formula XVII.

[1596] Implementation scheme 964. The modified oligonucleotide of implementation scheme 961, wherein at least four of the ten 3' internucleotide linking groups are internucleotide linking groups of formula XVII.

[1597] Implementation scheme 965. The modified oligonucleotide of implementation scheme 961, wherein at least 5 of the ten 3' internucleotide linking groups are internucleotide linkers of formula XVII 961.

[1598] Implementation scheme 966. The modified oligonucleotide of implementation scheme 961, wherein at least 6 of the ten 3' internucleotide linking groups are internucleotide linking groups of formula XVII.

[1599] Implementation Scheme 967. The modified oligonucleotide of Implementation Scheme 961, wherein the two 3' internucleotide linking groups of the modified oligonucleotide are internucleotide linking groups of Formula XVII.

[1600] Implementation scheme 968. The modified oligonucleotide of any one of implementation schemes 943-953, wherein the modified oligonucleotide comprises at least one block having at least three consecutive internucleotide linking groups of formula XVII.

[1601] Implementation scheme 969. The modified oligonucleotide of any one of implementation schemes 943-953, wherein the modified oligonucleotide comprises at least one block having at least four consecutive internucleotide linking groups of formula XVII.

[1602] Implementation scheme 970. The modified oligonucleotide of any one of implementation schemes 943-953, wherein the modified oligonucleotide comprises at least one block having at least 5 consecutive internucleotide linking groups of formula XVII.

[1603] Implementation Scheme 971. The modified oligonucleotide of any one of Implementation Schemes 943-953, wherein the modified oligonucleotide comprises at least one block having at least 6 consecutive internucleotide linking groups of Formula XVII.

[1604] Implementation scheme 972. The modified oligonucleotide of any one of implementation schemes 968-971, wherein a block of at least one consecutive nucleoside linker of formula XVII is located at the 5' end of the modified oligonucleotide.

[1605] Implementation scheme 973. The modified oligonucleotide of any one of implementation schemes 968-971, wherein a block of at least one consecutive nucleoside linker of formula XVII is located at the 3' end of the modified oligonucleotide.

[1606] Implementation scheme 974. The modified oligonucleotide of any one of implementation schemes 943-973, wherein for each nucleoside linker of formula XVII, R1 is H and T is SO2Me.

[1607] Implementation Scheme 975. An oligonucleotide modified according to any one of Implementation Schemes 943-953, wherein the nucleoside inter-bond motif is selected from: aaaaaassssssss, sssssaaaaaassss or sssssssssaaaaaa, wherein each "a" represents a nucleoside inter-bond of formula XVII, each "s" represents a thiophosphate nucleoside inter-bond, and each "o" represents a phosphodiester nucleoside inter-bond.

[1608] Implementation scheme 976. Modified oligonucleotides of implementation scheme 975, wherein each "a" represents a nucleoside internucleotide bond of methanesulfonyl phosphate.

[1609] Implementation Scheme 977. The modified oligonucleotide of any one of Implementation Schemes 705-841, wherein the modified oligonucleotide comprises a deoxygenated region consisting of 6-11 linked nucleosides, wherein each nucleoside of the deoxygenated region is a modified nucleoside or a stereostandard DNA nucleoside, and wherein at least 3 consecutive nucleosides of the deoxygenated region are stereostandard DNA nucleosides, and no more than 3 nucleosides of the deoxygenated region are modified nucleosides.

[1610] Implementation scheme 978. The modified oligonucleotide of implementation scheme 977, wherein at least 5 consecutive nucleosides in the deoxygenated region are stereostandard DNA nucleosides.

[1611] Implementation scheme 979. The modified oligonucleotide of implementation scheme 977, wherein at least 6 consecutive nucleosides in the deoxygenated region are stereostandard DNA nucleosides.

[1612] Implementation scheme 980. The modified oligonucleotide of implementation scheme 977, wherein at least 7 consecutive nucleosides in the deoxy region are stereostandard DNA nucleosides.

[1613] Implementation scheme 981. The modified oligonucleotide of implementation scheme 977, wherein at least 8 consecutive nucleosides in the deoxygenated region are stereostandard DNA nucleosides.

[1614] Implementation scheme 982. The modified oligonucleotide of any one of implementation schemes 977-981, wherein the deoxygenated region is composed of 8-10 linking nucleosides.

[1615] Implementation scheme 983. The modified oligonucleotide of any one of implementation schemes 977-981, wherein the deoxy region is composed of 9 linked nucleosides.

[1616] Implementation scheme 984. The modified oligonucleotide of any one of implementation schemes 977-981, wherein the deoxygenated region consists of 10 linked nucleosides.

[1617] Implementation scheme 985. The modified oligonucleotide of any one of implementation schemes 977-981, wherein the deoxygenated region consists of 11 linked nucleosides.

[1618] Implementation scheme 986. The modified oligonucleotide of any one of implementation schemes 977-981, wherein at least 6 nucleotides of the deoxygenated region are stereostandard DNA nucleotides.

[1619] Implementation scheme 987. The modified oligonucleotide of any one of implementation schemes 977-981, wherein at least 7 nucleotides of the deoxygenated region are stereostandard DNA nucleotides.

[1620] Implementation scheme 988. The modified oligonucleotide of any one of implementation schemes 977-981, wherein at least 8 nucleotides of the deoxygenated region are stereostandard DNA nucleotides.

[1621] Implementation scheme 989. The modified oligonucleotide of any one of implementation schemes 977-981, wherein at least nine nucleotides in the deoxygenated region are stereostandard DNA nucleotides.

[1622] Implementation scheme 990. The modified oligonucleotide of any one of implementation schemes 977-989, wherein exactly two nucleosides of the deoxy region are modified nucleosides.

[1623] Implementation scheme 991. The modified oligonucleotide of any one of implementation schemes 977-989, wherein exactly one nucleoside of the deoxy region is a modified nucleoside.

[1624] Implementation Scheme 992. The modified oligonucleotide of any one of Implementation Schemes 977-991, wherein at least one modified nucleoside in the deoxygenated region is a stereostandard modified nucleoside or bicyclic nucleoside selected from β-D-LNA nucleoside, α-L-LNA nucleoside, ENA nucleoside, cEt nucleoside, 2'-MOE nucleoside, 2'-OMe nucleoside, 2'-F nucleoside and 5'-alkyl nucleoside.

[1625] Implementation scheme 993. The modified oligonucleotide of any one of implementation schemes 977-991, wherein at least one modified nucleoside of the deoxy region is a stereonon-standard nucleoside.

[1626] Implementation scheme 994. The modified oligonucleotide of implementation scheme 993, wherein at least one stereonon-standard nucleoside of the deoxygenated region is a stereonon-standard DNA nucleoside.

[1627] Implementation Scheme 995. The modified oligonucleotide of Implementation Scheme 994, wherein the stereononstandard DNA nucleoside is selected from stereononstandard DNA nucleosides having Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI and Formula VII.

[1628] Implementation scheme 996. The modified oligonucleotide of implementation scheme 995, wherein the stereonon-standard DNA nucleoside is selected from stereonon-standard DNA nucleosides having formula V and formula II.

[1629] Implementation Scheme 997. The modified oligonucleotide of Implementation Scheme 996, wherein at least one stereonon-standard nucleoside of the deoxy region is a substituted stereonon-standard nucleoside.

[1630] Implementation scheme 998. The modified oligonucleotide of implementation scheme 997, wherein at least one substituted stereononstandard nucleoside has a 2'-substituent selected from 2'-MOE, 2'-OMe, 2'-F or 2'-OH.

[1631] Implementation scheme 999. The modified oligonucleotide of any one of implementation schemes 977-998, wherein the second nucleoside from the 5' end of the deoxy region is a modified nucleoside.

[1632] Implementation scheme 1000. The modified oligonucleotide of any one of implementation schemes 977-998, wherein the third nucleoside from the 5' end of the deoxy region is a modified nucleoside.

[1633] Implementation scheme 1001. The modified oligonucleotide of any one of implementation schemes 977-998, wherein the fourth nucleoside from the 5' end of the deoxy region is a modified nucleoside.

[1634] Implementation scheme 1002. The modified oligonucleotide of any one of implementation schemes 999-1001, wherein the modified nucleoside in the deoxy region is a 2'-OMe nucleoside.

[1635] Implementation scheme 1003. The modified oligonucleotide of any one of implementation schemes 977-989, wherein each nucleoside in the deoxygenated region is a stereostandard DNA nucleoside.

[1636] Implementation scheme 1004. The modified oligonucleotide of any one of implementation schemes 977-1003, wherein at least one internucleotide linker in the deoxy region is an internucleotide linker of formula XVII.

[1637] Implementation scheme 1005. The modified oligonucleotide of any one of implementation schemes 977-1004, wherein the internucleotide linking group connecting the first and second nucleosides of the deoxygenated region, counted from the 5' end of the deoxygenated region, is an internucleotide linking group of formula XVII.

[1638] Implementation scheme 1006. The modified oligonucleotide of any one of implementation schemes 977-1005, wherein the internucleotide linking group connecting the second and third nucleosides of the deoxygenated region, counted from the 5' end of the deoxygenated region, is an internucleotide linking group of formula XVII.

[1639] Implementation scheme 1007. The modified oligonucleotide of any one of implementation schemes 977-1006, wherein the internucleotide linking group connecting the third and fourth nucleosides of the deoxygenated region, counted from the 5' end of the deoxygenated region, is an internucleotide linking group of formula XVII.

[1640] Implementation scheme 1008. The modified oligonucleotide of any one of implementation schemes 977-1007, wherein the internucleotide linking group connecting the fourth and fifth nucleosides of the deoxygenated region, counted from the 5' end of the deoxygenated region, is an internucleotide linking group of formula XVII.

[1641] Implementation scheme 1009. The modified oligonucleotide of any one of implementation schemes 977-1008, wherein one of the internucleotide linking groups in the deoxygenated region is a linking group of formula XVII, and the other internucleotide linking groups in the deoxygenated region are independently selected from phosphate diester and thiophosphate internucleotide linking groups.

[1642] Implementation scheme 1010. The modified oligonucleotide of any one of implementation schemes 977-1008, wherein the two internucleotide linking groups in the deoxygenated region are linking groups of formula XVII, and the other internucleotide linking groups in the deoxygenated region are independently selected from phosphate diester and thiophosphate internucleotide linking groups.

[1643] Implementation scheme 1011. The modified oligonucleotide of any one of implementation schemes 977-1008, wherein the three internucleotide linking groups in the deoxygenated region are linking groups of formula XVII, and the other internucleotide linking groups in the deoxygenated region are independently selected from phosphate diester and thiophosphate internucleotide linking groups.

[1644] Implementation scheme 1012. The modified oligonucleotide of any one of implementation schemes 977-1008, wherein the four internucleotide linking groups in the deoxygenated region are linking groups of formula XVII, and the other internucleotide linking groups in the deoxygenated region are each phosphate diester or thiophosphate internucleotide linking groups.

[1645] Implementation Scheme 1013. An oligonucleotide modified according to any one of Implementation Schemes 1009-1012, wherein the internucleotide linking group of Formula XVII is linked to the first and second, second and third, third and fourth and / or fourth and fifth nucleosides of the deoxygenated region, counted from the 5' end of the deoxygenated region.

[1646] Implementation scheme 1014. The modified oligonucleotide of any one of implementation schemes 877-1013, wherein the deoxygenated region comprises at least one region having structure A, B, C, D or E.

[1647] Implementation Scheme 1015. The modified oligonucleotide of Implementation Scheme 1014, wherein the region having structure A, B, C, D or E is at the 3' end of the deoxygenated region.

[1648] Implementation Scheme 1016. The modified oligonucleotide of Implementation Scheme 1014, wherein the region having structure A, B, C, D or E is at the 5' end of the deoxygenated region.

[1649] Implementation scheme 1017. The oligonucleotide modified by any one of implementation schemes 877-1016, wherein the deoxygenated region comprises at least one having the formula (N g1 ) L1 (N g2 ) L2 (N g3 ) L3 The region, where each N g Each L is a nucleoside, and each L is an inter-nucleoside linking group; wherein each of L1 and L2 is a phosphate diester inter-nucleoside linking group, a thiophosphate inter-nucleoside linking group, or an inter-nucleoside linking group of formula XVII:

[1650]

[1651] L3 is absent or is either a phosphate diester nucleoside linker, a thiophosphate nucleoside linker, or a nucleoside linker of formula XVII.

[1652] At least one of L1, L2, and L3 is a nucleoside linking group of formula XVII; and at least one of L1, L2, and L3 is a thiophosphate or phosphate diester nucleoside linking group.

[1653] For each nucleoside linker of formula XVII in the modified oligonucleotide, independently:

[1654] X is selected from O or S;

[1655] R1 is selected from H, C1-C6 alkyl groups, and substituted C1-C6 alkyl groups; and

[1656] T is selected from SO2R2, C(=O)R3 and P(=O)R4R5, where:

[1657] 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 conjugate groups.

[1658] R3 is selected from aryl, substituted aryl, CH3, N(CH3)2, OCH3 and conjugates;

[1659] R4 is selected from OCH3, OH, C1-C6 alkyl, substituted C1-C6 alkyl, and conjugates; and

[1660] R5 is selected from OCH3, OH, C1-C6 alkyl, and substituted C1-C6 alkyl.

[1661] Implementation Scheme 1018. The modified oligonucleotide of Implementation Scheme 1017, wherein the oligonucleotide has the formula (N g1 ) L1 (N g2 ) L2 (N g3 ) L3 The region is located at the 3' end of the deoxygenation region.

[1662] Implementation Scheme 1019. The modified oligonucleotide of Implementation Scheme 1017, wherein the oligonucleotide has the formula (N g1 ) L1 (N g2 ) L2 (N g3 ) L3 The region is located at the 5' end of the deoxygenation region.

[1663] Implementation scheme 1020. Oligonucleotides modified in any of Implementation schemes 1004-1019, wherein for each nucleoside internucleotide bond of formula XVII, R1 is H and T is SO2Me.

[1664] Implementation Scheme 1021. An oligonucleotide modified according to any one of Implementation Schemes 877-1020, wherein the deoxygenated region is side-mounted on the 5' side by a 5' region consisting of 1-6 linked 5' region nucleotides, and on the 3' side by a 3' region consisting of 1-6 linked 3' region nucleotides; wherein

[1665] The 3'most nucleotide in the 5' region contains a modified sugar moiety; and

[1666] The 5' nucleotide in the 3' region contains a modified sugar moiety.

[1667] Implementation Scheme 1022. The modified oligonucleotide of Implementation Scheme 1021, wherein the deoxygenated region consists of 7-11 linked nucleosides and has the following formula:

[1668] (N d1 ) L1 (N d2 ) L2 (N d3 ) L3 (N d4 ) L4 [(N d ) L5 ]q ;

[1669] Where N d1 N d2 N d3 N d4 Independently selected from stereostandard DNA nucleosides, stereononstandard DNA nucleosides, or 2'-substituted nucleosides; condition: N d1 N d2 N d3 or N d4 No more than one of them is a 2'-substituted nucleoside;

[1670] Each N d Independently selected from stereostandard DNA nucleosides and stereonon-standard DNA nucleosides;

[1671] q is 3-8;

[1672] Each of L1, L2, L3, L4 and each of L5 are nucleotide inter-bonds;

[1673] At least two of L1, L2, L3, and L4 are nucleoside inter-bonds of formula XVII.

[1674] Implementation Scheme 1023. The modified oligonucleotide of Implementation Scheme 1022, wherein N d1 N d2 N d3 or N d4 One of them is a 2'-substituted nucleoside.

[1675] Implementation scheme 1024. The modified oligonucleotide of implementation scheme 1023, wherein the 2'-substituted nucleoside is 2'-OMe nucleoside.

[1676] Implementation scheme 1025. Modified oligonucleotide of implementation scheme 1024, wherein the 2'-OMe nucleoside is a stereostandard 2'-OMe nucleoside.

[1677] Implementation Scheme 1026. An oligonucleotide modified according to any one of Implementation Schemes 1022-1025, wherein the 2'-substituted nucleoside is N d2 .

[1678] Implementation Scheme 1027. The modified oligonucleotide of Implementation Scheme 1022, wherein N d1 N d2 N d3 N d4 Each and each N in d It is a DNA nucleoside.

[1679] Implementation scheme 1028. Modified oligonucleotides of implementation scheme 1027, wherein each DNA nucleoside is a stereostandard DNA nucleoside.

[1680] Implementation scheme 1029. An oligonucleotide modified by any of Implementation schemes 1022-1028, wherein L1 and L2 are nucleoside bonds of formula XVII.

[1681] Implementation scheme 1030. An oligonucleotide modified by any of implementation schemes 1022-1028, wherein L2 and L3 are nucleoside internucleotides of formula XVII.

[1682] Implementation scheme 1031. An oligonucleotide modified by any of Implementation schemes 1022-1028, wherein L3 and L4 are nucleoside internucleotides of formula XVII.

[1683] Implementation scheme 1032. An oligonucleotide modified by any of Implementation schemes 1022-1028, wherein L1, L2 and L3 are nucleoside internucleotides of formula XVII.

[1684] Implementation scheme 1033. An oligonucleotide modified by any one of implementation schemes 1022-1028, wherein L2, L3 and L4 are nucleoside internucleotides of formula XVII.

[1685] Implementation scheme 1034. An oligonucleotide modified by any one of implementation schemes 1022-1028, wherein L1, L2, L3 and L4 are nucleoside internucleotides of formula XVII.

[1686] Implementation scheme 1035. Modified oligonucleotides of implementation schemes 1029-1034, wherein each nucleoside internucleotide bond that is not of formula XVII is a phosphate thioester nucleoside internucleotide bond.

[1687] Implementation Scheme 1036. An oligonucleotide modified according to any one of Implementation Schemes 1029-1035, wherein for each nucleoside internucleotide bond of Formula XVII, R1 is H and T is SO2Me.

[1688] Implementation scheme 1037. The modified oligonucleotide of any one of implementation schemes 1021-1036, wherein the 5' region is composed of 2-5 linking nucleosides.

[1689] Implementation scheme 1038. Modified oligonucleotide of implementation scheme 1037, wherein the 5' region is composed of 3 linking nucleosides.

[1690] Implementation scheme 1039. Modified oligonucleotide of implementation scheme 1037, wherein the 5' region is composed of 5 linked nucleosides.

[1691] Implementation scheme 1040. The modified oligonucleotide of any one of implementation schemes 1021-1039, wherein each nucleoside in the 5' region is a modified nucleoside.

[1692] Implementation scheme 1041. A modified oligonucleotide of any one of implementation schemes 1021-1040, wherein each nucleoside in the 5' region is a modified nucleoside containing a modified sugar.

[1693] Implementation Scheme 1042. The modified oligonucleotide of any one of Implementation Schemes 1021-1041, wherein at least one nucleoside in the 5' region comprises a 2'-substituted furanyl sugar moiety.

[1694] Implementation scheme 1043. The modified oligonucleotide of any one of implementation schemes 1021-1041, wherein each nucleoside in the 5' region comprises a 2'-substituted furanyl sugar moiety.

[1695] Implementation Scheme 1044. The modified oligonucleotide of any one of Implementation Schemes 1021-1043, wherein each 2'-substituted furanose glycosyl moiety of the 5' region has a 2'-substituent selected from 2'-MOE, 2'-OMe and 2'-NMA.

[1696] Implementation scheme 1045. An oligonucleotide modified according to any one of implementation schemes 1021-1042 or 1044, wherein at least one nucleoside in the 5' region comprises a bicyclic furanyl sugar moiety.

[1697] Implementation scheme 1046. An oligonucleotide modified according to any one of implementation schemes 1021-1042 or 1044-1045, wherein each nucleoside in the 5' region comprises a bicyclic furanyl sugar moiety.

[1698] Implementation scheme 1047. The modified oligonucleotide of implementation scheme 341 or 342, wherein each bicyclic sugar moiety of the 5' region is selected from cEt, LNA and ENA.

[1699] Implementation scheme 1048. Modified oligonucleotide of implementation scheme 1047, wherein each bicyclic sugar moiety of the 5' region is a cEt sugar moiety.

[1700] Implementation scheme 1049. The modified oligonucleotide of any one of implementation schemes 1021-1039, 1042 or 1045, wherein at least one nucleoside in the 5' region is a stereostandard DNA nucleoside.

[1701] Implementation scheme 1050. The modified oligonucleotide of any one of implementation schemes 1021-1048, wherein at least one nucleoside in the 5' region is a stereononstandard nucleoside.

[1702] Implementation scheme 1051. An oligonucleotide modified according to any one of implementation schemes 1021-1050, wherein each nucleobase in the 5' region is independently selected from thymine, uracil, guanine, cytosine, 5-methylcytosine, and adenine.

[1703] Implementation scheme 1052. The modified oligonucleotide of any one of implementation schemes 1021-1051, wherein the 3' region is composed of 2-5 linking nucleosides.

[1704] Implementation scheme 1053. The modified oligonucleotide of implementation scheme 1052, wherein the 3' region is composed of 3 linked nucleosides.

[1705] Implementation scheme 1054. The modified oligonucleotide of implementation scheme 1052, wherein the 3' region is composed of 5 linked nucleosides.

[1706] Implementation scheme 1055. The modified oligonucleotide of any one of implementation schemes 1021-1054, wherein each nucleoside in the 3' region is a modified nucleoside.

[1707] Implementation scheme 1056. The modified oligonucleotide of any one of implementation schemes 1021-1055, wherein each nucleoside in the 3' region is a modified nucleoside containing a modified sugar.

[1708] Implementation scheme 1057. The modified oligonucleotide of any one of implementation schemes 1021-1056, wherein at least one nucleoside in the 3' region comprises a 2'-substituted furanyl sugar moiety.

[1709] Implementation scheme 1058. The modified oligonucleotide of any one of implementation schemes 1021-1057, wherein each nucleoside in the 3' region comprises a 2'-substituted furanyl sugar moiety.

[1710] Implementation Scheme 1059. The modified oligonucleotide of any one of Implementation Schemes 1021-1058, wherein each 2'-substituted furanose sugar moiety of the 3' region has a 2'-substituent selected from 2'-MOE, 2'-OMe and 2'-NMA.

[1711] Implementation scheme 1060. The modified oligonucleotide of any one of implementation schemes 1021-1057 or 1059, wherein at least one nucleoside in the 3' region comprises a bicyclic furanyl sugar moiety.

[1712] Implementation scheme 1061. An oligonucleotide modified according to any one of implementation schemes 1021-1057 or 1059-1060, wherein each nucleoside in the 3' region comprises a bicyclic furanyl sugar moiety.

[1713] Implementation scheme 1062. The modified oligonucleotide of implementation scheme 1060 or 1061, wherein each bicyclic sugar moiety in the 3' region is selected from cEt, LNA and ENA.

[1714] Implementation scheme 1063. The modified oligonucleotide of implementation scheme 1062, wherein each bicyclic sugar moiety of the 3' region is a cEt sugar moiety.

[1715] Implementation scheme 1064. The modified oligonucleotide of any one of implementation schemes 1021-1054, 1057 or 1060, wherein at least one nucleoside in the 3' region is a stereostandard DNA nucleoside.

[1716] Implementation scheme 1065. The modified oligonucleotide of any one of implementation schemes 1021-1064, wherein at least one nucleoside in the 3' region is a stereononstandard nucleoside.

[1717] Implementation scheme 1066. An oligonucleotide modified according to any one of implementation schemes 1021-1065, wherein each nucleobase in the 3' region is independently selected from thymine, uracil, guanine, cytosine, 5-methylcytosine, and adenine.

[1718] Implementation scheme 1067. The modified oligonucleotide of any one of implementation schemes 1021-1066, wherein the modified oligonucleotide is a nicked polymer.

[1719] Implementation Scheme 1068. A modified oligonucleotide of any one of Implementation Schemes 1021-1066, wherein the modified oligonucleotide has a glycosyl motif selected from kkkddddddddddkkk and kkkdyddddddddkkk, wherein each "k" represents a cEt sugar motif, "y" represents a 2'-OMe sugar motif, and each "d" represents a β-D-2'-deoxyribosyl sugar motif.

[1720] Modified oligonucleotides of any one of embodiments 1021 - 1066, wherein the modified oligonucleotide has an internucleoside linkage motif selected from: sssssssssssssssa, ssssssssssssssas, sssssssssssssass, ssssssssssssasss, sssssssssssassss, ssssssssssasssss, sssssssssassssss, ssssssssasssssss, sssssssassssssss, ssssssasssssssss, sssssassssssssss, sssasssssssssss, ssassssssssssss, sasssssssssssss, assssssssssssss, ssssssssssssssaa, sssssssssssssaas, ssssssssssssaass, sssssssss...

Claims

1. An oligomeric compound comprising a modified oligonucleotide consisting of 12-30 linked nucleosides connected by internucleotide linking groups, wherein... At least one nucleoside contains a modified sugar moiety. The modified oligonucleotide contains a deoxygenated region consisting of 6-11 linked nucleosides. Each nucleoside in the deoxygenated region is a stereostandard DNA nucleoside. The deoxygenated region is adjacent to a 5' region consisting of 1-6 linked 5' region nucleotides on the 5' side, and to a 3' region consisting of 1-6 linked 3' region nucleotides on the 3' side; wherein The 3'most nucleotide in the 5' region contains a modified sugar moiety; and The 5' nucleotide in the 3' region contains a modified sugar moiety; The two, three, or four internucleotide linking groups in the deoxygenated region are linking groups of formula XVII: Wherein, for each nucleoside linker group of formula XVII of the modified oligonucleotide, independently: X is O; R1 is H; and T is SO2Me; The other internucleotide linking groups in the deoxygenated region are independently selected from phosphodiester internucleotide linking groups and thiophosphate internucleotide linking groups; and The internucleotide linking group of formula XVII is connected to the first and second, second and third, third and fourth and / or fourth and fifth nucleosides of the deoxygenated region, counting from the 5' end of the deoxygenated region.

2. The oligomer compound of claim 1, wherein the deoxygenated region is composed of 7-11 linked nucleosides and has the following formula: (N d1 ) L1 (N d2 ) L2 (N d3 ) L3 (N d4 ) L4 [(N d ) L5 ] q ; Where N d1 N d2 N d3 N d4 Each and each N in d It is a stereostandard DNA nucleoside; q is 3-7; Each of L1, L2, L3, L4 and each of L5 are nucleotide inter-bonds; At least two of L1, L2, L3, and L4 are nucleoside inter-bonds of formula XVII.

3. The oligomer compound of claim 2, wherein L1 and L2 are nucleoside internucleotide bonds of formula XVII.

4. The oligomer compound of claim 3, wherein each L5 is a thiophosphate nucleoside internucleotide bond.

5. The oligomer compound of claim 3, wherein each nucleoside internucleotide bond that is not of formula XVII is a thiophosphate nucleoside internucleotide bond.

6. The oligomer compound of claim 2, wherein L2 and L3 are nucleoside internucleotide bonds of formula XVII.

7. The oligomer compound of claim 6, wherein each L5 is a thiophosphate nucleoside internucleotide bond.

8. The oligomer compound of claim 6, wherein each nucleoside internucleotide bond that is not of formula XVII is a thiophosphate nucleoside internucleotide bond.

9. The oligomer compound of claim 2, wherein L3 and L4 are nucleoside internucleotide bonds of formula XVII.

10. The oligomeric compound of claim 9, wherein each L5 is a thiophosphate nucleoside internucleotide bond.

11. The oligomer compound of claim 9, wherein each nucleoside internucleotide bond that is not of formula XVII is a phosphate thioester nucleoside internucleotide bond.

12. The oligomer compound of claim 2, wherein L1, L2 and L3 are nucleoside internucleotide bonds of formula XVII.

13. The oligomer compound of claim 12, wherein each L5 is a thiophosphate nucleoside internucleotide bond.

14. The oligomer compound of claim 12, wherein each nucleoside internucleotide bond that is not of formula XVII is a thiophosphate nucleoside internucleotide bond.

15. The oligomer compound of claim 2, wherein L2, L3 and L4 are nucleoside internucleotide bonds of formula XVII.

16. The oligomeric compound of claim 15, wherein each L5 is a thiophosphate nucleoside internucleotide bond.

17. The oligomer compound of claim 15, wherein each nucleoside internucleotide bond that is not of formula XVII is a thiophosphate nucleoside internucleotide bond.

18. The oligomer compound of claim 2, wherein L1, L2, L3 and L4 are nucleoside internucleotide bonds of formula XVII.

19. The oligomeric compound of claim 18, wherein each L5 is a thiophosphate nucleoside internucleotide bond.

20. The oligomer compound of claim 18, wherein each nucleoside internucleotide bond that is not of formula XVII is a thiophosphate nucleoside internucleotide bond.

21. The oligomeric compound of claim 1, wherein the modified oligonucleotide has a nucleoside internucleotide motif selected from the following: ssssssssaasssss, sssssssaassssss, sssssaasssssss, sssssaassssssss, ssssaasssssssss, sssaasssssssss, ssaassssssssss, saass sssssssssss, sssaaasssssssss, ssssaaasssssssss, sssaaaassssssss, ssaaassssssssss, ssaaaasssssssss, aoaaaassssssaoa, aoosaassssssssoa, aosaassssssssoa, aooaaaasssssaoa,sssss aaasssssss, ssssssaaassssss, sssssssaaasssss, ssssaaaassssss, sssssaaassssss, sssaassssssaass, sssaasssssaass, sssaasssssaass, ssaasssssssaass, ssssaasssssaass, aooooosaasssssssooaa, soooooaasssssssssooss, soooosaassssssssooss or sooooossaassssssooss, where each "a" represents a nucleoside bond in formula XVII, each "s" represents a thiophosphate nucleoside bond, and each "o" represents a phosphodiester nucleoside bond.

22. The oligomeric compound of claim 21, wherein the modified oligonucleotide has a nucleoside internucleotide motif selected from the following: sssaaaassssssss, sssaaasssssssss, ssssaaassssssss, ssssaassssssaass, sssaasssssssss, ssssaasssssssss, or sssssaasssssssss, wherein each "a" represents a nucleoside internucleotide of formula XVII, each "s" represents a thiophosphate nucleoside internucleotide, and each "o" represents a phosphodiester nucleoside internucleotide.

23. The oligomeric compound of claim 1, wherein the modified oligonucleotide is an antisense oligonucleotide.

24. The oligomeric compound of claim 23, wherein it comprises a conjugation group.

25. The oligomeric compound of claim 24, wherein the conjugation group comprises at least one GalNAc.

26. The oligomeric compound according to any one of claims 1-25, wherein the 5' region is composed of 2-5 linked nucleosides.

27. The oligomer of claim 26, wherein the 5' region is composed of three linking nucleosides.

28. The oligomeric compound of claim 26, wherein the 5' region is composed of 5 linked nucleosides.

29. The oligomeric compound according to any one of claims 1-25, wherein each nucleoside in the 5' region is a modified nucleoside comprising a modified sugar.

30. The oligomer of claim 29, wherein at least one nucleoside in the 5' region comprises a 2'-substituted furanyl sugar moiety.

31. The oligomer of claim 30, wherein each 2'-substituted furanose glycoside moiety in the 5' region has a 2'-substituent selected from 2'-MOE, 2'-OMe and 2'-NMA.

32. The oligomeric compound of claim 29, wherein each nucleoside in the 5' region comprises a 2'-substituted furanyl sugar moiety.

33. The oligomer of claim 32, wherein each 2'-substituted furanose glycoside moiety in the 5' region has a 2'-substituent selected from 2'-MOE, 2'-OMe and 2'-NMA.

34. The oligomer of claim 29, wherein at least one nucleoside in the 5' region comprises a bicyclic furanyl sugar moiety.

35. The oligomer compound of claim 34, wherein each bicyclic sugar moiety in the 5' region is selected from cEt, LNA, and ENA.

36. The oligomer of claim 35, wherein each bicyclic sugar moiety in the 5' region is a cEt sugar moiety.

37. The oligomeric compound of claim 29, wherein each nucleoside in the 5' region comprises a bicyclic furanyl sugar moiety.

38. The oligomer compound of claim 37, wherein each bicyclic sugar moiety in the 5' region is selected from cEt, LNA, and ENA.

39. The oligomer of claim 38, wherein each bicyclic sugar moiety in the 5' region is a cEt sugar moiety.

40. The oligomeric compound of claim 29, wherein each nucleobase of the modified oligonucleotide is independently selected from thymine, uracil, guanine, cytosine, 5-methylcytosine, and adenine.

41. The oligomeric compound according to any one of claims 1-25, wherein the 3' region is composed of 2-5 linked nucleosides.

42. The oligomer of claim 41, wherein the 3' region is composed of three linked nucleosides.

43. The oligomer of claim 41, wherein the 3' region is composed of 5 linked nucleosides.

44. The oligomeric compound according to any one of claims 1-25, wherein each nucleoside in the 3' region is a modified nucleoside comprising a modified sugar.

45. The oligomer of claim 44, wherein at least one nucleoside in the 3' region comprises a 2'-substituted furanyl sugar moiety.

46. ​​The oligomer of claim 45, wherein each 2'-substituted furanose glycoside moiety in the 3' region has a 2'-substituent selected from 2'-MOE, 2'-OMe and 2'-NMA.

47. The oligomeric compound of claim 44, wherein each nucleoside in the 3' region comprises a 2'-substituted furanyl sugar moiety.

48. The oligomer of claim 47, wherein each 2'-substituted furanose glycoside moiety in the 3' region has a 2'-substituent selected from 2'-MOE, 2'-OMe and 2'-NMA.

49. The oligomer of claim 44, wherein at least one nucleoside in the 3' region comprises a bicyclic furanyl sugar moiety.

50. The oligomer of claim 49, wherein each bicyclic sugar moiety in the 3' region is selected from cEt, LNA, and ENA.

51. The oligomer of claim 50, wherein each bicyclic sugar moiety in the 3' region is a cEt sugar moiety.

52. The oligomeric compound of claim 44, wherein each nucleoside in the 3' region comprises a bicyclic furanyl sugar moiety.

53. The oligomer compound of claim 52, wherein each bicyclic sugar moiety in the 3' region is selected from cEt, LNA, and ENA.

54. The oligomer of claim 53, wherein each bicyclic sugar moiety in the 3' region is a cEt sugar moiety.

55. The oligomeric compound of claim 44, wherein each nucleobase of the modified oligonucleotide is independently selected from thymine, uracil, guanine, cytosine, 5-methylcytosine, and adenine.

56. The oligomeric compound according to any one of claims 1-25, wherein the 3' and 5' regions are composed of 2-5 linked nucleosides.

57. The oligomer of claim 56, wherein the 3' and 5' regions are composed of three linking nucleosides.

58. The oligomeric compound of claim 56, wherein the 3' and 5' regions are composed of five linked nucleosides.

59. The oligomeric compound according to any one of claims 1-25, wherein each nucleoside in the 3' and 5' regions is a modified nucleoside comprising a modified sugar.

60. The oligomer of claim 59, wherein at least one nucleoside in the 3' and 5' regions comprises a 2'-substituted furanyl sugar moiety.

61. The oligomer of claim 60, wherein each 2'-substituted furanose glycoside moiety in the 3' and 5' regions has a 2'-substituent selected from 2'-MOE, 2'-OMe, and 2'-NMA.

62. The oligomeric compound of claim 59, wherein each nucleoside in the 3' and 5' regions comprises a 2'-substituted furanyl sugar moiety.

63. The oligomer of claim 62, wherein each 2'-substituted furanose glycoside moiety in the 3' and 5' regions has a 2'-substituent selected from 2'-MOE, 2'-OMe, and 2'-NMA.

64. The oligomeric compound of claim 59, wherein at least one nucleoside in the 3' and 5' regions comprises a bicyclic furanyl sugar moiety.

65. The oligomer compound of claim 64, wherein each bicyclic sugar moiety in the 3' and 5' regions is selected from cEt, LNA, and ENA.

66. The oligomer of claim 65, wherein each bicyclic sugar moiety in the 3' and 5' regions is a cEt sugar moiety.

67. The oligomeric compound of claim 59, wherein each nucleoside in the 3' and 5' regions comprises a bicyclic furanyl sugar moiety.

68. The oligomer compound of claim 67, wherein each bicyclic sugar moiety in the 3' and 5' regions is selected from cEt, LNA, and ENA.

69. The oligomer of claim 68, wherein each bicyclic sugar moiety in the 3' and 5' regions is a cEt sugar moiety.

70. The oligomeric compound of claim 59, wherein each nucleobase of the modified oligonucleotide is independently selected from thymine, uracil, guanine, cytosine, 5-methylcytosine, and adenine.

71. The oligomeric compound of any one of claims 1-25, comprising at least one modified oligonucleotide, wherein the nucleobase sequence of the at least one modified oligonucleotide is complementary to that of the target nucleic acid.

72. The oligomeric compound of claim 71, wherein the nucleobase sequence of the modified oligonucleotide is at least 80% complementary to the target nucleic acid.

73. The oligomeric compound of claim 72, wherein the target nucleic acid is target RNA.

74. The oligomeric compound of claim 71, wherein the nucleobase sequence of the modified oligonucleotide is at least 85% complementary to the target nucleic acid.

75. The oligomeric compound of claim 74, wherein the target nucleic acid is target RNA.

76. The oligomeric compound of claim 71, wherein the nucleobase sequence of the modified oligonucleotide is at least 90% complementary to the target nucleic acid.

77. The oligomeric compound of claim 76, wherein the target nucleic acid is target RNA.

78. The oligomeric compound of claim 71, wherein the nucleobase sequence of the modified oligonucleotide is at least 95% complementary to the target nucleic acid.

79. The oligomeric compound of claim 78, wherein the target nucleic acid is target RNA.

80. The oligomeric compound of claim 71, wherein the nucleobase sequence of the modified oligonucleotide is 100% complementary to the target nucleic acid.

81. The oligomeric compound of claim 80, wherein the target nucleic acid is target RNA.

82. A pharmaceutical composition comprising the oligomeric compound of any one of claims 1-81 and a pharmaceutically acceptable carrier or diluent.

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