Compounds and methods for reducing the expression of PLN

Abstract

Provided are oligomeric agents, compounds, methods, and pharmaceutical compositions for reducing the amount or activity of PLN RNA in a cell or animal, and optionally reducing the amount of PLN protein in a cell or animal, which are useful for treating cardiomyopathy, heart failure, or arrhythmia.

Description

[Technical Field]

[0001] Sequence Listing This application has been filed with an electronic Sequence Listing, which is provided as a file entitled BIOL0421WOSEQ_ST25.txt, 499 KB in size, created on February 9, 2022. The information in the electronic format of the Sequence Listing is incorporated herein by reference in its entirety.

[0002] Provided are oligomeric agents, oligomeric compounds, methods, and pharmaceutical compositions for reducing the amount or activity of PLN RNA in a cell or animal, and optionally reducing the amount of PLN protein in a cell or animal, which are useful for treating cardiomyopathy, heart failure, or arrhythmia. [Background technology]

[0003] Heart disease is the leading cause of death worldwide. Cardiomyopathy refers to heart muscle disease that weakens the heart and makes it unable to pump efficiently. As the heart weakens during cardiomyopathy, normal heart muscle may thicken, stiffen, or thin, impairing its ability to pump blood, which can lead to heart failure. Arrhythmias are irregular or abnormal heartbeats and are a leading cause of sudden cardiac death. Arrhythmias originating in the lower heart chambers, called ventricles, are particularly dangerous, causing the heart to beat too quickly, impairing blood circulation and potentially leading to cardiac arrest. Ventricular fibrillation (VFIB) is a rapid, uncoordinated heart rhythm in which the heart's electrical signals often do not follow a normal repeating pattern. Ventricular tachycardia (VTAC) is a rapid heart rhythm that, if too fast, prevents the heart from beating efficiently or pumping blood throughout the body, potentially causing loss of consciousness. Summary of the Invention

[0004] Certain embodiments of the oligomeric agents, oligomeric compounds, methods, and pharmaceutical compositions described herein are useful for reducing or inhibiting the expression of PLN in cells or animals. In certain embodiments, the level of PLN RNA or protein can be reduced in cells or animals. Methods for treating cardiomyopathy, heart failure, or arrhythmia are also provided. DETAILED DESCRIPTION OF THE INVENTION

[0005] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not limiting. As used herein, the use of the singular includes the plural unless expressly stated otherwise. As used herein, the use of "or" means "and / or" unless expressly stated otherwise. Furthermore, the use of the term "including" and other forms such as "comprises" and "includes" is not limiting. Also, terms such as "element" or "component" include both elements and components comprising one unit and elements and components comprising two or more subunits, unless expressly stated otherwise.

[0006] The section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described. All documents or portions of documents cited in this application, including but not limited to patents, patent applications, articles, books, and treatises, are expressly incorporated herein by reference in their entirety, as well as for portions of the documents discussed herein.

[0007] definition Unless specific definitions are given, the nomenclature used in connection with, and the procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are those well known and commonly used in the art. Where permitted, all patents, patent applications, published patent applications, and other publications and other data referenced throughout this disclosure are incorporated herein by reference in their entirety.

[0008] Unless otherwise indicated, the following terms have the following meanings:

[0009] As used herein, "2'-deoxynucleoside" refers to a nucleoside containing a 2'-H(H) deoxyfuranosyl sugar moiety. In certain embodiments, a 2'-deoxynucleoside is a 2'-β-D-deoxynucleoside, which contains a 2'-β-D-deoxyribosyl sugar moiety, which has the β-D ribosyl configuration found in naturally occurring deoxyribonucleic acid (DNA). In certain embodiments, a 2'-deoxynucleoside may contain a modified nucleobase or an RNA nucleobase (uracil).

[0010] As used herein, "2'-MOE" refers to a 2'-OCH2CH2OCH3 group in place of the 2'-OH group of a furanosyl sugar moiety. "2'-MOE sugar moiety" refers to a sugar moiety having a 2'-OCH2CH2OCH3 group in place of the 2'-OH group of a furanosyl sugar moiety. Unless otherwise specified, the 2'-MOE sugar moiety is in the β-D-ribosyl configuration. "MOE" refers to O-methoxyethyl.

[0011] As used herein, "2'-MOE nucleoside" means a nucleoside that includes a 2'-MOE sugar moiety.

[0012] As used herein, "2'-OMe" refers to a 2'-OCH group in place of the 2'-OH group of a furanosyl sugar moiety. A "2'-O-methyl sugar moiety" or "2'-OMe sugar moiety" refers to a sugar moiety having a 2'-OCH group in place of the 2'-OH group of a furanosyl sugar moiety. Unless otherwise specified, the 2'-MOE sugar moiety is in the β-D-ribosyl configuration.

[0013] As used herein, "2'-OMe nucleoside" means a nucleoside that includes a 2'-OMe sugar moiety.

[0014] As used herein, "2'-substituted nucleoside" refers to a nucleoside that includes a 2'-substituted sugar moiety. As used herein, "2'-substituted" with respect to the sugar moiety means that the sugar moiety includes at least one 2'-substituent other than H or OH.

[0015] As used herein, "3' target site" refers to the 3'-most nucleotide of a target nucleic acid that is complementary to an antisense oligonucleotide when the antisense oligonucleotide is hybridized to the target nucleic acid.

[0016] As used herein, "5' target site" refers to the 5'-most nucleotide of a target nucleic acid that is complementary to an antisense oligonucleotide when the antisense oligonucleotide is hybridized to the target nucleic acid.

[0017] As used herein, "5-methylcytosine" means a cytosine modified with a methyl group attached to position 5. 5-methylcytosine is a modified nucleobase.

[0018] As used herein, "abasic sugar moiety" means the sugar portion of a nucleoside that is not attached to a nucleobase. Such abasic sugar moieties are sometimes referred to in the art as "abasic nucleosides."

[0019] 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 of the atoms of the first ring, thereby forming a bicyclic structure. In certain embodiments, the first ring of the bicyclic sugar moiety is a furanosyl moiety. In certain embodiments, the bicyclic sugar moiety does not comprise a furanosyl moiety.

[0020] As used herein, a "chirally enriched population" refers to a plurality of molecules of the same molecular formula, wherein the number or percentage of molecules in the population that contain a particular stereochemical configuration at a particular chiral center is greater than the number or percentage of molecules in the population that would be expected to contain the same particular stereochemical configuration at the same particular chiral center if the particular chiral center were stereorandom. A chirally enriched population of molecules having multiple chiral centers within each molecule can contain one or more stereorandom chiral centers. In certain embodiments, the molecules are modified oligonucleotides. In certain embodiments, the molecules are oligomeric compounds comprising modified oligonucleotides.

[0021] As used herein, "cleavable moiety" means a bond or group that is cleaved under physiological conditions, eg, inside a cell, animal, or human.

[0022] As used herein, "complementary" with respect to an oligonucleotide means that when the nucleobase sequences of the oligonucleotide and another nucleic acid are aligned in opposite directions, at least 70% of the nucleobases of the oligonucleotide and the nucleobases of the other nucleic acid or one or more regions thereof are capable of hydrogen bonding with each other. A "complementary region" with respect to a region of an oligonucleotide means that when the nucleobase sequences of the oligonucleotide and another nucleic acid are aligned in opposite directions, at least 70% of the nucleobases of that region and the nucleobases of the other nucleic acid or one or more regions thereof are capable of hydrogen bonding with each other. Complementary nucleobases refer to nucleobases that can form hydrogen bonds with each other. Examples of complementary nucleobase pairs include adenine (A) and thymine (T), adenine (A) and uracil (U), cytosine (C) and guanine (G), and 5-methylcytosine (mC) and guanine (G). Certain modified nucleobases that pair with natural nucleobases or other modified nucleobases are known in the art, and unless otherwise specified, are not considered as complementary nucleobases as defined herein.For example, inosine can pair with adenosine, cytosine, or uracil, but is not considered to be complementary thereto.Complementary oligonucleotides and / or nucleic acids do not need to have nucleobase complementarity at each nucleoside.Rather, some mismatches are allowed.As used herein, "fully complementary" or "100% complementary" in relation to oligonucleotides means that an oligonucleotide is complementary to another oligonucleotide or nucleic acid at each nucleobase of the oligonucleotide.

[0023] As used herein, "conjugate group" means a group of atoms directly attached to an oligonucleotide. A conjugate group includes a conjugate moiety and a conjugate linker that connects the conjugate moiety to the oligonucleotide.

[0024] As used herein, "conjugate linker" means a single bond or a group of atoms containing at least one bond that joins a conjugate moiety to an oligonucleotide.

[0025] As used herein, "conjugate moiety" means a group of atoms that modifies one or more molecular properties, including but not limited to, pharmacodynamic properties, pharmacokinetic properties, stability, binding, absorption, tissue distribution, cellular distribution, cellular uptake, charge, and clearance, compared to the same molecule lacking the conjugate moiety.

[0026] As used herein, "constrained ethyl" or "cEt" or "cEt-modified sugar moiety" means a β-D ribosyl bicyclic sugar moiety in which the second ring of the bicyclic sugar is formed via a bridge connecting the 4'-carbon and 2'-carbon of the β-D ribosyl sugar moiety, where the bridge has the formula 4'-CH(CH3)-O-2' and the methyl group of the bridge is in the S configuration.

[0027] As used herein, "cEt nucleoside" means a nucleoside that includes a cEt modified sugar moiety.

[0028] As used herein, "deoxy region" refers to a region of 5 to 12 contiguous nucleotides in which at least 70% of the nucleosides contain a β-D-2'-deoxyribosyl sugar moiety. In certain embodiments, the deoxy region is the gap of a gapmer.

[0029] As used herein, a "hotspot region" is a range of nucleobases on a target nucleic acid that is suitable for oligomeric agent- or oligomeric compound-mediated reduction of the amount or activity of the target nucleic acid.

[0030] As used herein, an "internucleoside linkage" is a covalent bond between adjacent nucleosides in an oligonucleotide. As used herein, a "modified internucleoside linkage" means any internucleoside linkage other than a phosphodiester internucleoside linkage.

[0031] As used herein, "linked nucleosides" are nucleosides that are joined in contiguous sequence (ie, there are no additional nucleosides between the linked nucleosides).

[0032] As used herein, "linker nucleoside" refers to a nucleoside that connects an oligonucleotide to a conjugate moiety, either directly or indirectly. The linker nucleoside is located within the conjugate linker of an oligomeric compound. Linker nucleosides are not considered part of the oligonucleotide moiety of the oligomeric compound, even if they are contiguous with the oligonucleotide.

[0033] As used herein, "mismatch" or "non-complementary" means a nucleobase of a first nucleic acid sequence that is not complementary to the corresponding nucleobase of a second nucleic acid sequence, or target nucleic acid, when the first and second nucleic acid sequences are aligned.

[0034] As used herein, "motif" means a pattern of unmodified and / or modified sugar moieties, nucleobases, and / or internucleoside linkages in an oligonucleotide.

[0035] As used herein, "modified nucleoside" means a nucleoside that includes a modified nucleobase and / or a modified sugar moiety.

[0036] As used herein, "non-bicyclic modified sugar moiety" means a modified sugar moiety that includes modifications such as substituents that do not form a bridge between two atoms of the sugar to form a second ring.

[0037] As used herein, "nucleobase" refers to an unmodified nucleobase or a modified nucleobase. A nucleobase is a heterocyclic moiety. As used herein, an "unmodified nucleobase" is adenine (A), thymine (T), cytosine (C), uracil (U), or guanine (G). As used herein, a "modified nucleobase" is an atomic group other than unmodified A, T, C, U, or G that can pair with at least one other nucleobase. "5-methylcytosine" is a modified nucleobase. A universal base is a modified nucleobase that can pair with any one of the five unmodified nucleobases.

[0038] As used herein, "nucleobase sequence" means the order of consecutive nucleobases in a nucleic acid or oligonucleotide, independent of any sugar or internucleoside linkage modifications.

[0039] As used herein, "nucleoside" means a compound or fragment of a compound that includes a nucleobase and a sugar moiety, each of which independently is unmodified or modified.

[0040] As used herein, "oligomeric agent" refers to an oligomeric compound and optionally one or more additional features, such as a second oligomeric compound. An oligomeric agent may be a single-stranded oligomeric compound or an oligomeric duplex formed by two complementary oligomeric compounds.

[0041] As used herein, "oligomeric compound" refers to an oligonucleotide and, optionally, one or more additional features, such as a conjugate group or a terminal group. An oligomeric compound may be paired with a second oligomeric compound complementary to the first oligomeric compound, or may be unpaired. A "single-stranded oligomeric compound" is an unpaired oligomeric compound.

[0042] The term "oligomeric duplex" means a duplex formed by two oligomeric compounds having complementary nucleobase sequences.

[0043] As used herein, "oligonucleotide" refers to a chain of linked nucleosides connected via internucleoside linkages, where each nucleoside and internucleoside linkage may be modified or unmodified. Unless otherwise specified, an oligonucleotide consists of 8 to 50 linked nucleosides. As used herein, "modified oligonucleotide" refers to an oligonucleotide in which at least one nucleoside or internucleoside linkage is modified. As used herein, "unmodified oligonucleotide" refers to an oligonucleotide that does not contain any nucleoside or internucleoside modifications.

[0044] As used herein, "pharmaceutically acceptable carrier or diluent" means any substance suitable for use in administration to an animal. Certain such carriers enable the pharmaceutical composition to be formulated as, for example, tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, and lozenges for oral ingestion by a subject. In certain embodiments, the pharmaceutically acceptable carrier or diluent is sterile water, sterile saline, sterile buffer solution, or sterile artificial cerebrospinal fluid.

[0045] As used herein, "pharmaceutically acceptable salt" refers to a physiologically and pharmaceutically acceptable salt of a compound that retains the desired biological activity of the parent compound and does not impart undesired toxicological effects thereto.

[0046] As used herein, "pharmaceutical composition" refers to a mixture of substances suitable for administration to a subject. For example, a pharmaceutical composition may comprise an oligomeric compound and a sterile aqueous solution. In certain embodiments, the pharmaceutical composition exhibits activity in a free uptake assay in certain cell lines.

[0047] As used herein, a "phosphodiester bond" refers to a linking group having the following structure: [ka] In certain embodiments, a phosphodiester bond is an internucleoside linkage. In certain embodiments, a phosphodiester bond links a conjugate moiety to a modified oligonucleotide.

[0048] As used herein, "prodrug" refers to a first form of a therapeutic agent that is converted to a second form in vitro within an animal or its cells. Typically, the conversion of a prodrug in an animal is facilitated by the action of enzymes (e.g., endogenous or viral enzymes) or chemicals present in cells or tissues and / or by physiological conditions. In certain embodiments, the first form of the prodrug is less active than the second form. In certain embodiments, a prodrug comprises a cell-targeting moiety and at least one active compound.

[0049] As used herein, a "stabilized phosphate group" refers to a 5'-phosphate analog that is more metabolically stable than the 5'-phosphate that naturally occurs on DNA or RNA.

[0050] As used herein, "standard cellular assay" refers to the assays described in the Examples as well as reasonable variations thereof.

[0051] As used herein, "stereorandom chiral center" in the context of a population of molecules of the same molecular formula refers to a chiral center having a random stereochemical configuration. For example, in a population of molecules containing stereorandom chiral centers, the number of molecules having stereorandom chiral centers in the (S) configuration may be, but is not necessarily, the same as the number of molecules having stereorandom chiral centers in the (R) configuration. The stereochemical configuration of a chiral center is considered random if it is the result of a synthetic method not designed to control the stereochemical configuration. In certain embodiments, the stereorandom chiral center is a stereorandom phosphorothioate internucleoside linkage.

[0052] As used herein, "sugar moiety" refers to an unmodified sugar moiety or a modified sugar moiety. As used herein, "unmodified sugar moiety" refers to a 2'-OH(H) ribosyl moiety as found in RNA (an "unmodified RNA sugar moiety"), or a 2'-H(H) deoxyribosyl sugar moiety as found in DNA (an "unmodified DNA sugar moiety"). An unmodified sugar moiety has one hydrogen at each of the 1', 3', and 4' positions, an oxygen at the 3' position, and two hydrogens at the 5' position. As used herein, "modified sugar moiety" or "modified sugar" refers to a modified furanosyl sugar moiety or sugar surrogate.

[0053] As used herein, "sugar surrogate" refers to a modified sugar moiety having other than a furanosyl moiety that can attach a nucleobase to another group, such as an internucleoside linkage, a conjugate group, or a terminal group in an oligonucleotide. Modified nucleosides, including sugar surrogates, can be incorporated at one or more positions within an oligonucleotide, and such oligonucleotides are capable of hybridizing to a complementary oligomeric compound or target nucleic acid.

[0054] As used herein, "target nucleic acid" and "target RNA" refer to a nucleic acid to which an oligomeric compound is designed to act. Target RNA refers to an RNA transcript, and includes pre-mRNA and mRNA, unless otherwise specified.

[0055] As used herein, "target region" means a portion of a target nucleic acid to which an oligomeric compound is designed to hybridize.

[0056] As used herein, "terminal group" means a chemical group or group of atoms covalently attached to the end of an oligonucleotide.

[0057] As used herein, "antisense activity" refers to any detectable and / or measurable change that can be attributed to the hybridization of an antisense compound to its target nucleic acid. In certain embodiments, antisense activity is a decrease in the amount or expression of a target nucleic acid or a protein encoded by such a target nucleic acid compared to the target nucleic acid level or target protein level in the absence of an antisense compound. In certain embodiments, antisense activity is modulation of splicing of a target pre-mRNA.

[0058] As used herein, "antisense agent" means an antisense compound and optionally one or more additional features, such as a sense compound.

[0059] As used herein, "antisense compound" means an antisense oligonucleotide and optionally one or more additional features, such as a conjugate group.

[0060] As used herein, "sense compound" means a sense oligonucleotide and optionally one or more additional features, such as a conjugate group.

[0061] As used herein, "antisense oligonucleotide" refers to an oligonucleotide that comprises an oligonucleotide portion of an antisense compound that is capable of hybridizing to a target nucleic acid and is capable of at least one antisense activity. Antisense oligonucleotides include, but are not limited to, antisense RNAi oligonucleotides and antisense RNase H oligonucleotides.

[0062] As used herein, "sense oligonucleotide" means an oligonucleotide that includes an oligonucleotide portion of a sense compound that is capable of hybridizing to an antisense oligonucleotide.

[0063] As used herein, "gapmer" refers to a modified oligonucleotide comprising an internal region disposed between external regions having one or more nucleosides, wherein the nucleosides comprising the internal region are chemically distinct from the nucleosides comprising the external regions, and the modified oligonucleotide supports RNAse H cleavage. The internal region may be referred to as a "gap," and the external regions may be referred to as "wings." In certain embodiments, the internal region is a deoxy region. The position of the internal region or gap refers to the order of the nucleosides in the internal region, counted from the 5' end of the internal region. Unless otherwise indicated, "gapmer" refers to a sugar motif. In certain embodiments, each nucleoside in the gap is a 2'-β-D-deoxynucleoside. In certain embodiments, the gap comprises one 2'-substituted nucleoside at position 1, 2, 3, 4, or 5 of the gap, with the remainder of the nucleosides in the gap being 2'-β-D-deoxynucleosides. As used herein, the term "MOE gapmer" refers to a gapmer having a gap comprising a 2'-β-D-deoxynucleoside and wings comprising 2'-MOE nucleosides. As used herein, the term "mixed-winged gapmer" refers to a gapmer having wings comprising modified nucleosides comprising at least two different sugar modifications. Unless otherwise indicated, a gapmer may comprise one or more modified internucleoside linkages and / or modified nucleobases, and such modifications do not necessarily follow the gapmer pattern of sugar modifications.

[0064] As used herein, "cell targeting moiety" means a conjugate group or portion of a conjugate group that is capable of binding to a specific cell type(s).

[0065] As used herein, "hybridization" refers to the annealing of oligonucleotides and / or nucleic acids. While not limited to a particular mechanism, the most common mechanism of hybridization involves hydrogen bonding, which may be Watson-Crick, Hoogsteen, or reversed Hoogsteen hydrogen bonding, between complementary nucleobases. In certain embodiments, complementary nucleic acid molecules include, but are not limited to, antisense compounds and nucleic acid targets. In certain embodiments, complementary nucleic acid molecules include, but are not limited to, oligonucleotides and nucleic acid targets.

[0066] As used herein, "RNAi agent" refers to an antisense agent that acts, at least in part, via RISC or Ago2 to regulate a target nucleic acid and / or a protein encoded by the target nucleic acid. RNAi agents include, but are not limited to, double-stranded siRNA, single-stranded RNAi (ssRNAi), and microRNAs, including microRNA mimics. RNAi agents may include conjugate groups and / or terminal groups. In certain embodiments, RNAi agents regulate the amount and / or activity of a target nucleic acid. The term RNAi agent excludes antisense agents that act via RNase H.

[0067] As used herein, "RNase H agent" refers to an antisense agent that acts through RNase H to modulate a target nucleic acid and / or a protein encoded by a target nucleic acid. In certain embodiments, the RNase H agent is single-stranded. In certain embodiments, the RNase H agent is double-stranded. The RNase H compound may include a conjugate group and / or a terminal group. In certain embodiments, the RNase H agent modulates the amount and / or activity of a target nucleic acid. The term RNase H agent excludes antisense agents that act primarily through RISC / Ago2.

[0068] As used herein, "treating" refers to improving a disease or condition in a subject by administering an oligomeric agent or oligomeric compound described herein. In certain embodiments, treating a subject improves symptoms compared to the same symptoms without treatment. In certain embodiments, treatment reduces the severity or frequency of symptoms, or delays the onset of symptoms, delays the progression of symptoms, or reduces the severity or frequency of symptoms.

[0069] As used herein, a "therapeutically effective amount" refers to an amount of an agent or composition that provides a therapeutic benefit to an animal, e.g., ameliorates a symptom of a disease.

[0070] Specific Embodiments An oligomeric compound comprising a modified oligonucleotide consisting of 1.8 to 80 linked nucleosides, wherein the nucleic acid base sequence of the modified oligonucleotide is at least 80% complementary to an equal length portion of a PLN nucleic acid, and the modified oligonucleotide has at least one modification selected from a modified sugar moiety and a modified internucleoside linkage.

[0071] 2. The oligomeric compound of embodiment 1, wherein the PLN nucleic acid has the nucleobase sequence of SEQ ID NO: 1 or 2.

[0072] 3. The nucleic acid base sequence of the modified oligonucleotide is selected from the group consisting of nucleic acid bases 3278 to 3293, 3281 to 3296, 3282 to 3297, 3284 to 3299, 3286 to 3301, 3287 to 3302, 3288 to 3303, 3327 to 3342, 3329 to 3344, 3332 to 3347, 3333 to 3348, 3336 to 3351, 3337 to 3352, 3338 to 3353, 3339 to 3354, 3340 to 3355, 3341 to 3356, 3343 to 3358, 3345 to 3360, 3348 to 3363, 3349 to 3364, and 3350 of SEQ ID NO: 2. ~3365, 3351~3366, 3352~3367, 3353~3368, 3354~3369, 3355~3370, 3356~3371, 3357~3372, 3358~3373, 3395~3410, 3396~3411, 3405~3420, 3406~342 1, 3408~3423, 3409~3424, 3410~3425, 3412~3427, 3496~3511, 3497~3512, 3498~3513, 3499~3514, 3598~3613, 3612~3627, 3614~3629, 3615~3630, 361 6~3631, 3617~3632, 3618~3633, 3619~3634, 3620~3635, 3622~3637, 3703~3718, 3704~3719, 3715~3730, 3716~3731, 3723~3738, 3724~3739, 3799~38 14, 3801~3816, 3802~3817, 3803~3818, 3804~3819, 3805~3820, 3806~3821, 3807~3822, 3808~3823, 3809~3824, 3811~3826, 3814~3829, 3815~3830, 3 816~3831, 3817~3832, 3821~3836, 3823~3838, 3830~3845, 3831~3846, 3848~3863, 3849~3864, 3850~3865, 3851~3866, 3861~3876, 3863~3878, 3864~ 3879, 3869~3884, 3871~3886, 3976~3991, 3977~3992, 3978~3993, 3980~3995, 3981~3996, 4116~4131, 4159~4174, 4204~4219, 4207~4222, 4208~4223,4209~4224、4210~4225、4211~4226、4212~4227、4214~4229、4221~4236、4231~4246、4232~4247、4233~4248、4234~4249、4235~4250、4236~4251、4238~4253、4252~4267、4253~4268、4266~4281、4348~4363、4349~4364、4350~4365、4367~4382、4373~4388、4374~4389、4375~4390、4510~4525、4511~4526、4513~4528、4515~4530、4516~4531、4517~4532、4518~4533、4519~4534、4530~4545、4537~4552、4539~4554、4540~4555、4541~4556、4542~4557、4543~4558、4544~4559、4545~4560、4562~4577、4614~4629、4617~4632、4619~4634、4620~4635、4621~4636、4622~4637、4623~4638、4624~4639、4638~4653、4640~4655、4641~4656、4642~4657、4643~4658、4665~4680、4672~4687、4693~4708、4694~4709、4695~4710、4696~4711、4697~4712、4750~4765、4751~4766、4752~4767、4753~4768、4774~4789、4802~4817、4804~4819、4805~4820、4806~4821、4807~4822、4823~4838、4825~4840、4826~4841、4828~4843、4860~4875、4862~4877、4869~4884、4872~4887、4874~4889、4878~4893、4881~4896、4883~4898、4884~4899、4942~4957、4943~4958、4945~4960、4946~4961、4957~4972、4958~4973、4960~4975、4961~4976、4964~4979、4965~4980、4966~4981、4968~4983、4969~4984、4971~4986、4972~4987、4974~4989、4984~4999、4985~5000、4987~5002、4988~5003、5024~5039、5127~5142、5133~5148、5134~5149、5158~5173、5159~5174、5160~5175、5163~5178、5294~5309、5341~5356、5359~5374、5394~5409、5399~5414、5400~5415、5401~5416、5402~5417、5404~5419、5411~5426、5413~5428、5414~5429、5415~5430、5416~5431、5417~5432、5418~5433、5419~5434、5421~5436、5427~5442、5428~5443、5489~5504、5494~5509、5495~5510、5497~5512、5498~5513、5498~5515、5498~5517、5499~5514、5499~5515、5499~5516、5499~5518、5500~5515、5500~5516、5500~5517、5501~5516、5501~5514、5501~5517、5502~5517、5502~5515、5503~5518、5504~5519、5505~5520、5506~5521、5511~5526、5532~5547、5533~5548、5534~5549、5547~5562、5557~5572、5558~5573、5559~5574、5560~5575、5562~5577、5563~5578、5565~5580、5599~5614、5673~5688、5674~5689、5675~5690、5676~5691、5677~5692、5678~5693、5679~5694、5694~5709、5695~5710、5696~5711、5697~5712、5698~5713、5774~5789、5827~5842、5845~5860、5847~5862、5848~5863、5850~5865、5851~5866、5855~5870、5859~5874、5924~5939、5925~5940、5926~5941、5927~5942、5929~5944、5930~5945、5931~5946、5932~5947、6008~6023、6009~6024、6039~6054、6053~6068、6054~6069、6055~6070、6059~6074、6066~6081、6069~6084、6070~6085、6076~6091、6092~6107、6098~6113、6112~6127、6114~6129、6117~6132、6118~6133、6119~6134、6124~6139、6125~6140、6126~6141、6147~6162、6154~6169、6155~6170、6156~6171、6157~6172、6176~6191、6177~6192、6185~6200、6186~6201、6187~6202、6188~6203、6202~6217、6209~6224、6243~6258、6249~6264、6267~6282、6268~6283、6274~6289、6275~6290、6291~6306、6338~6353、6352~6367、6353~6368、6354~6369、6365~6380、6366~6381、6368~6383、6369~6384、6403~6418、6405~6420、6406~6421、6407~6422、6408~6423、6409~6424、6410~6425、6411~6426、6413~6428、6468~6483、6471~6486、6502~6517、6546~6561、6554~6569、6555~6570、6556~6571、6557~6572、6569~6584、6574~6589、6575~6590、6576~6591、6577~6592、6578~6593、6579~6594、6644~6659、6646~6661、6647~6662、6664~6679、6665~6680、6666~6681、6667~6682、6676~6691、6677~6692、6746~6761、6804~6819、6806~6821、6825~6840、6826~6841、6827~6842、6828~6843、6831~6846、6833~6848、6834~6849、6875~6890、6877~6892、6879~6894、6880~6895、6881~6896、6893~6908、6896~6911、6898~6913、6899~6914、6900~6915、6901~6916、6903~6918、6904~6919、6906~6921、6907~6922、6908~6923、6920~6935、6921~6936、6922~6937、6923~6938、6927~6942、6928~6943、6930~6945、6937~6952、6939~6954、6940~6955、6941~6956、6942~6957、6943~6958、6944~6959、6945~6960、6947~6962、6965~6980、6966~6981、6967~6982、6968~6983、6972~6987、6975~6990、7029~7044、7042~7057、7047~7062、7050~7065、7073~7088、7082~7097、7083~7098、7102~7117、7106~7121、7107~7122、7108~7123、7120~7135、7122~7137、7123~7138、7124~7139、7125~7140、7126~7141、7128~7143、7129~7144、7130~7145、7131~7146、7279~7294、7280~7295、7282~7297、7283~7298、7284~7299、7285~7300、7286~7301、7287~7302、7320~7335、7341~7356、7342~7357、7344~7359、7353~7368、7354~7369、7356~7371、7357~7372、7358~7373、7359~7374、7360~7375、7361~7376、7362~7377、7377~7392、7378~7393、7392~7407、7393~7408、7411~7426、7425~7440、7436~7451、7457~7472、7458~7473、7459~7474、7460~7475、7461~7476、7463~7478、7464~7479、7470~7485、7516~7531、7518~7533、7519~7534、7520~7535、7521~7536、7522~7537、7546~7561、7548~7563、7553~7568、7554~7569、7555~7570、7556~7571、7558~7573、7560~7575、7561~7576、7562~7577、7563~7578、7564~7579、7565~7580、7566~7581、7568~7583、7587~7602、7588~7603、7589~7604、7595~7610、7638~7653、7679~7694、7726~7741、 7779~7794、7797~7812、7799~7814、7806~7821、7857~7872、7859~7874、7860~7875、7861~7876、7862~7877、7863~7878、7864~7879、7865~7880、7867~7882、7876~7891、7878~7893、7888~7903、7889~7904、7893~7908、7908~7923、7929~7944、7965~7980、7967~7982、7968~7983、8047~8062、8058~8073、8061~8076、8089~8104、8090~8105、8163~8178、8182~8197、8194~8209、8195~8210、8196~8211、8197~8212、8284~8299、8285~8300、8286~8301、8287~8302、8288~8303、8326~8341、8336~8351、8352~8367、8353~8368、8368~8383、8393~8408、8412~8427、8413~8428、8415~8430、8418~8433、8427~8442、8447~8462、8493~8508、8494~8509、8495~8510、8496~8511、8498~8513、8542~8557、8573~8588、8621~8636、8627~8642、8628~8643、8638~8653、8639~8654、8641~8656、8653~8668、8655~8670、8703~8718、8708~8723、8732~8747、8733~8748、8739~8754、8774~8789、8776~8791、8777~8792、8818~8833、8823~8838、8824~8839、8826~8841、8827~8842、8850~8865、8855~8870、8942~8957、8943~8958、8944~8959、8955~8970、8961~8976、8962~8977、8963~8978、8964~8979、9377~9392、9443~9458、9474~9489、9523~9538、9524~9539、9525~9540、9526~9541、9528~9543、9536~9551、9537~9552、9538~9553、9540~9555、9541~9556、9545~9560、9549~9564、9550~9565、9587~9602、9630~9645、9641~9656、9642~9657、9646~9661、9647~9662、9648~9663、9649~9664、9651~9666、9660~9675、9668~9683、9669~9684、9672~9687、9697~9712、9702~9717、9703~9718、9706~9721、9707~9722、9708~9723、9709~9724、9710~9725、9711~9726、9720~9735、9727~9742、9752~9767、9756~9771、9788~9803、9934~9949、9936~9951、9937~9952、9938~9953、9939~9954、9940~9955、10019~10034、10054~10069、10062~10077、10081~10096、10106~10121、10117~10132、10443~10458、10444~10459、10445~10460、10480~10495、10481~10496、10486~10501、10489~10504、10490~10505、10491~10506、10532~10547、10623~10638、10638~10653、10645~10660、10718~10733、10719~10734、10720~10735、10721~10736、10722~10737、10723~10738、10724~10739、10747~10762、10770~10785、11066~11081、11068~11083、11104~11119、11111~11126、11112~11127、11115~11130、11116~11131、11118~11133、11130~11145、11144~11159、11224~11239、11225~11240、11237~11252、11258~11273、11259~11274、11302~11317、11353~11368、11356~11371、11368~11383、11369~11384、11409~11424、11410~11425、11411~11426、11412~11427、11413~11428、11414~11429、11415~11430、11417~11432、11457~11472、11458~11473、11467~11482、11474~11489、11475~11490、11509~11524、11510~11525、11511~11526、11524~11539、11525~11540、11526~11541、11527~11542、11529~11544、11530~11545、11622~11637、11631~11646、11632~11647、11633~11648、11634~11649、11635~11650、11636~11651、11639~11654、11670~11685、11678~11693、11679~11694、11680~11695、11681~11696、11682~11697、11684~11699、11685~11700、11726~11741、11727~11742、11740~11755、11741~11756、11742~11757、11743~11758、11799~11814、11832~11847、11833~11848、11854~11869、11855~11870、11856~11871、11857~11872、11858~11873、11859~11874、11900~11915、11931~11946、11956~11971、11988~12003、11989~12004、11990~12005、11991~12006、11992~12007、11993~12008、11994~12009、11995~12010、11997~12012、11998~12013、11999~12014、12000~12015、12015~12030、12016~12031、12017~12032、12027~12042、12032~12047、12040~12055、12041~12056、12042~12057、12076~12091、12080~12095、12081~12096、12082~12097、12084~12099、12085~12100、12086~12101、12087~12102、12088~12103、12089~12104、12090~12105、12092~12107、12194~12209、12195~12210、12238~12253、12239~12254、12241~12256、12242~12257、12243~12258、12246~12261、12282~12297、12283~12298、12285~12300、12286~12301、12287~12302、12288~12303、12307~12322、12308~12323、12310~12325、12312~12327、12315~12330、12348~12363、12355~12370、12356~12371、12357~12372、12368~12383、12388~12403、12389~12404、12390~12405、12391~12406、12392~12407、12470~12485、12471~12486、12472~12487、12473~12488、12474~12489、12498~12513、12529~12544、12530~12545、12546~12561、12548~12563、12550~12565、12551~12566、12585~12600、12721~12736、12722~12737、12723~12738、12724~12739、12727~12742、12732~12747、12733~12748、12734~12749、12735~12750、12760~12775、12812~12827、12813~12828、12817~12832、12818~12833、12912~12927、12915~12930、12929~12944、12943~12958、12946~12961、13243~13258、13327~13342、13409~13424、13431~13446、13438~13453、13460~13475、13461~13476、13484~13499、13485~13500、13486~13501、13489~13504、13490~13505、13491~13506、13492~13507、13493~13508、13525~13540、13528~13543、13529~13544、13530~13545、13717~13732、13736~13751、13770~13785、13776~13791、13777~13792、13786~13801、13814~13829、13816~13831、13818~13833、13819~13834、13820~13835、13821~13836、13822~13837、13823~13838、13835~13850、13836~13851、13837~13852、13838~13853、13839~13854、13843~13858、13870~13885、13872~13887、13875~13890、13876~13891、13877~13892、13878~13893、13879~13894、13880~13895、13881~13896、13882~13897、13883~13898、13885~13900、13904~13919、13905~13920、13906~13921、13907~13922、13908~13923、13910~13925、13912~13927、13918~13933、13924~13939、13926~13941、13927~13942、13930~13945、13934~13949、13935~13950、13936~13951、13937~13952、13938~13953、13939~13954、13940~13955、13941~13956、13942~13957、13943~13958、13944~13959、13945~13960、13946~13961、13952~13967、13953~13968、13954~13969、13955~13970、13956~13971、13957~13972、13958~13973、13959~13974、13960~13975、13961~13976、13962~13977、13963~13978、13964~13979、13965~13980、13966~13981、13967~13982、13968~13983、13969~13984、13970~13985、13973~13988、13976~13991、14000~14015、14003~14018、14028~14043、14030~14045、14032~14047、14035~14050、14036~14051、14038~14053、14039~14054、14040~14055、14041~14056、14045~14060、14047~14062、14048~14063、14049~14064、14050~14065、14051~14066、 14053~14068、14054~14069、14055~14070、14056~14071、14059~14074、14060~14075、14061~14076、14062~14077、14063~14078、14064~14079、14065~14080、14066~14081、14078~14093、14081~14096、14082~14097、14084~14099、14085~14100、14086~14101、14087~14102、14088~14103、14089~14104、14090~14105、14091~14106、14092~14107、14093~14108、14095~14110、14096~14111、14097~14112、14098~14113、14099~14114、14100~14115、14102~14117、14105~14120、14110~14125、14111~14126、14112~14127、14113~14128、14115~14130、14117~14132、14119~14134、14130~14145、14163~14178、14165~14180、14166~14181、14167~14182、14169~14184、14170~14185、14174~14189、14180~14195、14181~14196、14203~14218、14207~14222、14209~14224、14212~14227、14217~14232、14220~14235、14222~14237、14223~14238、14224~14239、14225~14240、14232~14247、14233~14248、14235~14250、14242~14257、14244~14259、14247~14262、14248~14263、14249~14264、14250~14265、14251~14266、14252~14267、14253~14268、14254~14269、14255~14270、14256~14271、14257~14272、14316~14331、14317~14332、14318~14333、14319~14334、14321~14336、14324~14339、14327~14342、14337~14352、14338~14353、14339~14354、14340~14355、14341~14356、14342~14357、14343~14358、14344~14359、14345~14360、14346~14361、14347~14362、14398~14413、14400~14415、14401~14416、14403~14418、14404~14419、14405~14420、14406~14421、14408~14423、14409~14424、14410~14425、14412~14427、14443~14458、14479~14494、14480~14495、14482~14497、14504~14519、14507~14522、14508~14523、14509~14524、14510~14525、14511~14526、14512~14527、14513~14528、14514~14529、14515~14530、14515~14532、14515~14534、14516~14531、14516~14532、14516~14533、14517~14532、14517~14533、14518~14531、14519~14534、14520~14535、14522~14537、14534~14549、14535~14550、14553~14568、14569~14584、14570~14585、14571~14586、14573~14588、14601~14616、14602~14617、14603~14618、14605~14620、14606~14621、14607~14622、14608~14623、14609~14624、14610~14625、14611~14626、14612~14627、14613~14628、14614~14629、14615~14630、14616~14631、14655~14670、14656~14671、14658~14673、14659~14674、14681~14696、14683~14698、14684~14699、14684~14701、14684~14703、14685~14700、14685~14701、14685~14702、14686~14701、14686~14702、14687~14702、14687~14700、14688~14703、14689~14704、14691~14706、14692~14707、14696~14711、14703~14718、14704~14719、14705~14720、14706~14721、14707~14722、14708~14723、14709~14724、14710~14725、14711~14726、14712~14727、14713~14728、14714~14729、14759~14774、14760~14775、14761~14776、14762~14777、14763~14778、14764~14779、14765~14780、14766~14781、14767~14782、14768~14783、14769~14784、14770~14785、14771~14786、14772~14787、14773~14788、14774~14789、14775~14790、14776~14791、14779~14794、14787~14802、14792~14807、14793~14808、14794~14809、14797~14812、14798~14813、14800~14815、14818~14833、14822~14837、14823~14838、14824~14839、14825~14840、14826~14841、14827~14842、14828~14843、14829~14844、14830~14845、14831~14846、14832~14847、14833~14848、14834~14849、14835~14850、14841~14856、14842~14857、14843~14858、14844~14859、14845~14860、14846~14861、14847~14862、14848~14863、14849~14864、14850~14865、14851~14866、14852~14867、14853~14868、14855~14870、14856~14871、14857~14872、14858~14873、14859~14874、14861~14876、14862~14877、14863~14878、14864~14879、14866~14881、14877~14892、14878~14893、14880~14895、14881~14896、14889~14904、14898~14913、14899~14914、14901~14916、14903~14918、14904~14919、14905~14920、14906~14921、14913~14928、14915~14930、14916~14931、14917~14932、14918~14933、14919~14934、14921~14936、14922~14937、14923~14938、14924~14939、14925~14940、14926~14941、14927~14942、14928~14943、14929~14944、14930~14945、14931~14946、14932~14947、14933~14948、14934~14949、14935~14950、14936~14951、14937~14952、14938~14953、14938~14955、14938~14957、14939~14954、14939~14955、14939~14956、14939~14958、14940~14955、14940~14956、14940~14957、14940~14959、14941~14956、14941~14954、14941~14957、14941~14958、14941~14960、14942~14957、14942~14955、14942~14958、14942~14959、14942~14961、14943~14958、14943~14956、14943~14959、14943~14960、14943~14962、14944~14959、14944~14957、14944~14960、14944~14961、14945~14960、14945~14958、14945~14961、14946~14961、14946~14959、14948~14963、14956~14971、14957~14972、14958~14973、14959~14974、14960~14975、14961~14976、14962~14977、14963~14978、14964~14979、14965~14980、14966~14981、14968~14983、14969~14984、14970~14985、14987~15002、14992~15007、14993~15008、14994~15009、14995~15010、14996~15011、15003~15018、15005~15020、15006~15021、15007~15022、15008~15023、15009~15024、15010~15025、15011~15026、15012~15027、15013~15028、15014~15029、15015~15030、15016~15031、15017~15032、15019~15034、15142~15157、15143~15158、15150~15165、15151~15166、15152~15167、15153~15168、15154~15169、15155~15170、15156~15171、15157~15172、15158~15173、15159~15174、15160~15175、15161~15176、15162~15177、15163~15178、15164~15179、15182~15197、15184~15199、15185~15200、15186~15201、15195~15210、15197~15212、15198~15213、15199~15214、15200~15215、15201~15216、15202~15217、15203~15218、15204~15219、15205~15220、15206~15221、15207~15222、15208~15223、15209~15224、15210~15225、15211~15226、15214~15229、15215~15230、15216~15231、15217~15232、15218~15233、15219~15234、15220~15235、15221~15236、15222~15237、15222~15239、15222~15241、15223~15238、15223~15239、15223~15240、15224~15239、15224~15240、15225~15240、15225~15238、15227~15242、15228~15243、15229~15244、15230~15245、15231~15246、15232~15247、15233~15248、15234~15249、15235~15250、15236~15251、15237~15252、15238~15253、15239~15254、15247~15262、15248~15263、 15249~15264、15250~15265、15251~15266、15252~15267、15253~15268、15254~15269、15255~15270、15256~15271、15257~15272、15258~15273、15259~15274、15260~15275、15261~15276、15293~15308、15299~15314、15301~15316、15302~15317、15303~15318、15304~15319、15305~15320、15320~15335、15321~15336、15323~15338、15411~15426、15414~15429、15415~15430、15416~15431、15417~15432、15496~15511、15501~15516、15504~15519、15505~15520、15506~15521、15507~15522、15508~15523、15509~15524、15510~15525、15511~15526、15512~15527、15513~15528、15515~15530、15556~15571、15558~15573、15559~15574、15560~15575、15562~15577、15569~15584、15571~15586、15574~15589、15593~15608、15594~15609、15595~15610、15596~15611、15598~15613、15599~15614、15600~15615、15601~15616、15602~15617、15603~15618、15604~15619、15605~15620、15627~15642、15629~15644、15630~15645、15631~15646、15632~15647、15633~15648、15635~15650、15636~15651、15639~15654、15640~15655、15641~15656、15642~15657、15658~15673、15659~15674、15660~15675、15661~15676、15665~15680、15666~15681、15667~15682、15668~15683、15671~15686、15673~15688、15674~15689、15675~15690、15681~15696、15682~15697、15683~15698、15684~15699、15685~15700、15686~15701、15687~15702、15740~15755、15741~15756、15753~15768、15757~15772、15758~15773、15761~15776、15762~15777、15763~15778、15765~15780、15788~15803、15812~15827、15813~15828、15814~15829、15815~15830、15816~15831、15826~15841、15827~15842、15833~15848、15858~15873、15861~15876、15863~15878、15864~15879、15865~15880、15866~15881、15867~15882、15868~15883、15869~15884、15870~15885、15871~15886、15872~15887、15873~15888、15874~15889、15875~15890、15876~15891、15877~15892、15878~15893、15882~15897、15883~15898、15910~15925、15911~15926、15912~15927、15913~15928、15914~15929、15943~15958、15947~15962、15949~15964、15950~15965、15951~15966、15955~15970、15973~15988、15974~15989、15979~15994、15980~15995、16000~16015、16008~16023、16010~16025、16026~16041、16027~16042、16030~16045、16032~16047、16034~16049、16036~16051、16037~16052、16038~16053、16039~16054、16056~16071、16057~16072、16080~16095、16117~16132、16118~16133、16216~16231、16248~16263、16265~16280、16266~16281、16268~16283, 16269~16284, 16273~16288, 16300~16315, 16305~16320, 16306~16321, 16327~16342, 16329~16344, 16422~16437, 16427~16442, 16428~16443, 16550 3. The oligomeric compound of embodiment 1 or 2, which is at least 80% complementary to an isometric portion within 16565, 16557, 16572, 16564, 16579, 16569, 16584, 16582, 16597, 16592, 16607, 16617, 16632, or 16676, 16691,

[0073] 4. The oligomeric compound of any of embodiments 1-3, wherein the nucleobase sequence of said modified oligonucleotide is at least 80% complementary to an isometric portion within nucleobases 3341-3368, 4516-4533, 5498-5517, 14337-14357, 14569-14588, 14607-14631, 14683-14703, 14828-14848, 14939-14958, 15222-15243, or 15251-15273 of SEQ ID NO:2.

[0074] 5. The oligomeric compound of any of embodiments 1-4, wherein the nucleobase sequence of said modified oligonucleotide is at least 80% complementary to an isometric portion within nucleobases 5499-5514, 5500-5515, 5501-5516, 14686-14701, 14941-14956, 14942-14957, or 15224-15239 of SEQ ID NO:2.

[0075] 6. The oligomeric compound of any one of embodiments 1 to 5, wherein the nucleobase sequence of the modified oligonucleotide is at least 85%, at least 90%, at least 95%, or 100% complementary to an equal length portion of the PLN nucleic acid.

[0076] 7. An oligomeric compound comprising a modified oligonucleotide consisting of 8 to 80 linked nucleosides, wherein the nucleobase sequence of the modified oligonucleotide comprises at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, or at least 20 consecutive nucleobases of any of the nucleobase sequences of SEQ ID NOs: 15 to 1712.

[0077] 8. The oligomeric compound of embodiment 7, wherein the nucleobase sequence of said modified oligonucleotide comprises the nucleobase sequence of any of SEQ ID NOs: 15-1712.

[0078] 9. The oligomeric compound of embodiment 8, wherein the modified oligonucleotide has a nucleobase sequence consisting of the nucleobase sequence of any of SEQ ID NOs: 15 to 1712.

[0079] 10. The oligomeric compound of any of embodiments 7-9, wherein said modified oligonucleotide has a nucleobase sequence comprising at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, or at least 16 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 45, 120, 185, 609, 675, 737, or 752.

[0080] 11. The oligomeric compound of embodiment 10, wherein the modified oligonucleotide consists of 16 to 80 linked nucleosides and the nucleobase sequence of the modified oligonucleotide comprises the nucleobase sequence of any of SEQ ID NOs: 45, 120, 185, 609, 675, 737, or 752.

[0081] 12. The oligomeric compound of embodiment 11, wherein said modified oligonucleotide consists of 16 linked nucleosides and has a nucleobase sequence consisting of the nucleobase sequence of any one of SEQ ID NOs: 45, 120, 185, 609, 675, 737, or 752.

[0082] 13. The oligomeric compound of any of embodiments 7 to 11, wherein the nucleobase sequence of the modified oligonucleotide is at least 85%, at least 90%, at least 95%, or 100% complementary to an equal-length portion of a PLN nucleic acid, and the PLN nucleic acid has the nucleobase sequence of SEQ ID NO: 1 or 2.

[0083] 14. The modified oligonucleotide is selected from the group consisting of 10 to 25, 10 to 30, 10 to 50, 12 to 20, 12 to 25, 12 to 30, 12 to 50, 13 to 20, 13 to 25, 13 to 30, 13 to 50, 14 to 20, 14 to 25, 14 to 30, 14 to 50, 15 to 20, 15 to 25, 15 to 30, 15 to 50, 16 to 18, 16 to 20, 16 to 25, 16 to 30, 16 to 50, 17 to 20, 17 to 25, 1 14. The oligomeric compound of any of embodiments 1-13, consisting of 7-30, 17-50, 18-20, 18-25, 18-30, 18-50, 19-20, 19-25, 19-30, 19-50, 20-25, 20-30, 20-50, 21-25, 21-30, 21-50, 22-25, 22-30, 22-50, 23-25, 23-30, or 23-50 linked nucleosides.

[0084] 15. The oligomeric compound according to any of embodiments 1 to 14, wherein at least one nucleoside of said modified oligonucleotide comprises a modified sugar moiety.

[0085] 16. The oligomeric compound of embodiment 15, wherein said modified sugar moiety comprises a bicyclic sugar moiety.

[0086] 17. The oligomeric compound according to embodiment 16, wherein said bicyclic sugar moiety comprises a 2'-4' bridge selected from -O-CH2- and -O-CH(CH3)-.

[0087] 18. The oligomeric compound of embodiment 15, wherein said modified sugar moiety comprises a non-bicyclic modified sugar moiety.

[0088] 19. The oligomeric compound of embodiment 18, wherein said non-bicyclic modified sugar moiety is a 2'-MOE sugar moiety or a 2'-OMe sugar moiety.

[0089] 20. The oligomeric compound according to any of embodiments 1-19, wherein at least one nucleoside of said modified oligonucleotide compound comprises a sugar surrogate.

[0090] 21. The oligomeric compound according to any of embodiments 1 to 20, wherein said modified oligonucleotide comprises at least one modified internucleoside linkage.

[0091] 22. The oligomeric compound according to embodiment 21, wherein at least one modified internucleoside linkage is a phosphorothioate internucleoside linkage.

[0092] 23. The oligomeric compound according to embodiment 22, wherein each internucleoside linkage is a modified internucleoside linkage.

[0093] 24. The oligomeric compound according to embodiment 23, wherein said modified internucleoside linkage is a phosphorothioate internucleoside linkage.

[0094] 25. The oligomeric compound according to any of embodiments 1-20, wherein each internucleoside linkage of said modified oligonucleotide is independently selected from a phosphodiester internucleoside linkage and a phosphorothioate internucleoside linkage.

[0095] 26. The oligomeric compound according to any of embodiments 1 to 25, wherein said modified oligonucleotide comprises at least one modified nucleobase.

[0096] 27. The oligomeric compound according to embodiment 26, wherein said modified nucleobase is 5-methylcytosine.

[0097] 28. The oligomeric compound according to embodiment 27, wherein each cytosine is a 5-methylcytosine.

[0098] 29. The oligomeric compound according to any of embodiments 1 to 28, wherein said modified oligonucleotide comprises a deoxy region consisting of 5 to 12 consecutive 2'-deoxynucleosides.

[0099] 30. The oligomeric compound according to embodiment 29, wherein each nucleoside of said deoxy region is a 2'-β-D-deoxynucleoside.

[0100] 31. The oligomeric compound according to embodiment 29 or 30, wherein said deoxy region consists of 6, 7, 8, 9, 10, or 6-10 linked nucleosides.

[0101] 32. The oligomeric compound according to any of embodiments 29-31, wherein each nucleoside immediately adjacent to said deoxy region comprises a modified sugar moiety.

[0102] 33. The deoxy region has a 5' region consisting of 1 to 6 linked 5' region nucleosides on the 5' side and a 3' region consisting of 1 to 6 linked 3' region nucleosides on the 3' side; the 3'-most nucleoside of the 5' exoregion comprises a modified sugar moiety; and 33. The oligomeric compound of any of embodiments 29-32, wherein the 5'-most nucleoside of said 3' exoregion comprises a modified sugar moiety.

[0103] 34. The oligomeric compound according to embodiment 33, wherein each nucleoside of said 3' exogenous region comprises a modified sugar moiety.

[0104] 35. The oligomeric compound according to embodiment 33 or 34, wherein each nucleoside of said 5' exogenous region comprises a modified sugar moiety.

[0105] 36. The modified oligonucleotide, a 5' exoregion consisting of 1 to 6 linked nucleosides; a deoxy region consisting of 6 to 10 linked nucleosides, and a 3' exon region consisting of 1 to 6 linked nucleosides; 36. The oligomeric compound of embodiment 35, wherein each of the 5' exoregion nucleosides and each of the 3' exoregion nucleosides is a cEt nucleoside or a 2'-MOE nucleoside, and each of the deoxyregion nucleosides is a 2'-β-D-deoxynucleoside.

[0106] 37. The modified oligonucleotide, a 5' exoregion consisting of 3 to 6 linked nucleosides; a deoxy region consisting of 7-8 linked nucleosides, and A 3' exoregion consisting of 3 to 6 linked nucleosides and having a glycomotif comprising Each of the 3' exoregion nucleosides is selected from a 2'-MOE nucleoside and a cEt nucleoside, and the 5' exoregion has the following formula: (Nk)n(Nd)(Nx) wherein each Nk is a bicyclic nucleoside, Nx is a 2'-OMe nucleoside, Nd is a 2'-β-D-deoxynucleoside, and n is 1 to 4.

[0107] 38. The modified oligonucleotide is kkkddddddddddkkk, kkdddddddddkekek, kkkddddddddddkkke, kkkdyddddddddkkk, kkddddddddddkk, kkkddddddddddkeee, kkkdddddddd ddkkee, kkkddddddddddkkkk, kkkkddddddddddkkk, kkkddddddddddkeeee, kkkddddddddddkkeee, kkkkddddddddddkkkk, kkkkkddddddddddkkkkk, ekdddddddd 29. The oligomeric compound of any of embodiments 1-28, having a sugar motif (5' to 3') selected from: dkekek, ekkddddddddddkkk, ekkdddddddddkkke, kedddddddddkekek, kekddddddddddkkk, kekdddddddddkkke, kkeddddddddddkkk, and kkedddddddddkkke, wherein each "d" represents a 2'-β-D-deoxyribosyl sugar moiety, each "y" represents a 2'-OMe sugar moiety, each "e" represents a 2'-MOE sugar moiety, and each "k" represents a cEt-modified sugar moiety.

[0108] 39. Oligomeric compounds comprising modified oligonucleotides according to the following chemical designations: m C ks m C ks A ks T ds A ds m C ds T ds T ds G ds A ds T ds T ds m C ds T ks m C ks A k (SEQ ID NO: 185), wherein A = adenine nucleobase, m C=5-methylcytosine nucleobase, G = guanine nucleobase; T=thymine nucleobase, k=cEt sugar moiety, d=2'-β-D-deoxyribosyl sugar moiety, and s = phosphorothioate internucleoside linkage.

[0109] 40. Oligomeric compounds comprising modified oligonucleotides according to the following chemical designations: G ks T ks A ks G ds T ds T ds A ds A ds G ds A ds T ds T ds T ds T ks G ks m C k (SEQ ID NO: 752), wherein: A = adenine nucleobase, m C=5-methylcytosine nucleobase, G = guanine nucleobase; T=thymine nucleobase, k=cEt sugar moiety, d=2'-β-D-deoxyribosyl sugar moiety, and s = phosphorothioate internucleoside linkage.

[0110] 41. Oligomeric compounds comprising modified oligonucleotides according to the following chemical designations: A ks m C ks A ks m C ds G ds A ds G ds T ds A ds T ds A ds T ds T ds A ks G ks Gk (SEQ ID NO: 609), wherein A = adenine nucleobase, m C=5-methylcytosine nucleobase, G = guanine nucleobase; T=thymine nucleobase, k=cEt sugar moiety, d=2'-β-D-deoxyribosyl sugar moiety, and s = phosphorothioate internucleoside linkage.

[0111] 42. Oligomeric compounds comprising modified oligonucleotides according to the following chemical designations: A ks A ks G ds A ds T ds A ds T ds A ds G ds T ds A ds T ks G es G ks T es A k (SEQ ID NO: 45), wherein A = adenine nucleobase, G = guanine nucleobase; T=thymine nucleobase, e=2'-MOE sugar moiety, k=cEt sugar moiety, d=2'-β-D-deoxyribosyl sugar moiety, and s = phosphorothioate internucleoside linkage.

[0112] 43. Oligomeric compounds comprising modified oligonucleotides according to the following chemical designations: A ks m C ks G ds A ds G ds T ds A ds T ds A ds T ds Tds A ks G es G ks A es A k (SEQ ID NO: 737), wherein: A = adenine nucleobase, m C=5-methylcytosine nucleobase, G = guanine nucleobase; T=thymine nucleobase, e=2'-MOE sugar moiety, k=cEt sugar moiety, d=2'-β-D-deoxyribosyl sugar moiety, and s = phosphorothioate internucleoside linkage.

[0113] 44. Oligomeric compounds comprising modified oligonucleotides according to the following chemical designations: A ks A ks A ds G ds A ds T ds A ds T ds A ds G ds T ds A ks T es G ks G es T k (SEQ ID NO: 120), wherein A = adenine nucleobase, G = guanine nucleobase; T=thymine nucleobase, e=2'-MOE sugar moiety, k=cEt sugar moiety, d=2'-β-D-deoxyribosyl sugar moiety, and s = phosphorothioate internucleoside linkage.

[0114] 45. Oligomeric compounds comprising modified oligonucleotides according to the following chemical designations: m C ks A ks m C ksG ds A ds G ds T ds A ds T ds A ds T ds T ds A ks G ks G ks A e (SEQ ID NO: 675), wherein A = adenine nucleobase, m C=5-methylcytosine nucleobase, G = guanine nucleobase; T=thymine nucleobase, e=2'-MOE sugar moiety, k=cEt sugar moiety, d=2'-β-D-deoxyribosyl sugar moiety, and s = phosphorothioate internucleoside linkage.

[0115] 46. ​​The oligomeric compound according to any of embodiments 1 to 45, comprising a conjugate group.

[0116] 47. The oligomeric compound according to embodiment 46, wherein the conjugate group comprises a conjugate linker and a conjugate moiety.

[0117] 48. The oligomeric compound according to embodiment 46 or 47, wherein the conjugate linker consists of a single bond.

[0118] 49. The oligomeric compound according to any of embodiments 46-48, wherein the conjugate linker is cleavable.

[0119] 50. The oligomeric compound according to any of embodiments 46-49, wherein said conjugate linker comprises 1 to 3 linker nucleosides.

[0120] 51. The oligomeric compound according to any of embodiments 46-49, wherein said conjugate linker does not comprise any linker nucleosides.

[0121] 52. The oligomeric compound according to any of embodiments 46-51, wherein the conjugate group is attached to the modified oligonucleotide at the 5' end of the modified oligonucleotide.

[0122] 53. The oligomeric compound according to any of embodiments 46-51, wherein the conjugate group is attached to the modified oligonucleotide at the 3' end of the modified oligonucleotide.

[0123] 54. The oligomeric compound of any of embodiments 46-53, wherein the conjugate group comprises C22 alkyl, C20 alkyl, C16 alkyl, C10 alkyl, C21 alkyl, C19 alkyl, C18 alkyl, C15 alkyl, C14 alkyl, C13 alkyl, C12 alkyl, C11 alkyl, C9 alkyl, C8 alkyl, C7 alkyl, C6 alkyl, C5 alkyl, C22 alkenyl, C20 alkenyl, C16 alkenyl, C10 alkenyl, C21 alkenyl, C19 alkenyl, C18 alkenyl, C15 alkenyl, C14 alkenyl, C13 alkenyl, C12 alkenyl, C11 alkenyl, C9 alkenyl, C8 alkenyl, C7 alkenyl, C6 alkenyl, or C5 alkenyl.

[0124] 55. The oligomeric compound according to any of embodiments 46-54, wherein the conjugate moiety is a 6-palmitamidohexyl conjugate moiety.

[0125] 56. The oligomeric compound of any of embodiments 46-53, wherein the conjugate group has the following structure: [ka]

[0126] 57. The oligomeric compound according to any of embodiments 46-56, wherein the conjugate group comprises a cell targeting moiety.

[0127] 58. The oligomeric compound according to embodiment 57, wherein said cell targeting moiety has affinity for TfR1.

[0128] 59. The oligomeric compound according to embodiment 58, wherein said cell targeting moiety comprises an anti-TfR1 antibody or a fragment thereof.

[0129] 60. The oligomeric compound according to embodiment 58, wherein said cell targeting moiety comprises a protein or peptide capable of binding TfR1.

[0130] 61. The oligomeric compound according to embodiment 58, wherein said cell targeting moiety comprises an aptamer capable of binding TfR1.

[0131] 62. Oligomeric compounds comprising modified oligonucleotides according to the following chemical designations: [C16-HA] o A ks A ks G ds A ds T ds A ds T ds A ds G ds T ds A ds T ks G es G ks T es A k (SEQ ID NO: 45), wherein A = adenine nucleobase, G = guanine nucleobase; T=thymine nucleobase, e=2'-MOE sugar moiety, k=cEt sugar moiety, d=2'-β-D-deoxyribosyl sugar moiety, o = phosphodiester internucleoside linkage; s = phosphorothioate internucleoside linkage, and [C16-HA] = [ka] is.

[0132] 63. Oligomeric compounds comprising modified oligonucleotides according to the following chemical designations: [C16-HA] o A ks m C ks A ks m C ds G ds A ds G ds T ds A ds T ds A ds T ds T ds A ks G ks G k (SEQ ID NO: 609), wherein A = adenine nucleobase, m C=5-methylcytosine nucleobase, G = guanine nucleobase; T=thymine nucleobase, k=cEt sugar moiety, d=2'-β-D-deoxyribosyl sugar moiety, o = phosphodiester internucleoside linkage; s = phosphorothioate internucleoside linkage, and [C16-HA] = [ka] is.

[0133] 64. Oligomeric compounds comprising modified oligonucleotides according to the following chemical designations: [C16-HA] o G ks T ks A ks G ds T ds T ds A ds A ds G ds A ds T ds T ds T ds Tks G ks m C k (SEQ ID NO: 752), wherein: A = adenine nucleobase, m C=5-methylcytosine nucleobase, G = guanine nucleobase; T=thymine nucleobase, k=cEt sugar moiety, d=2'-β-D-deoxyribosyl sugar moiety, o = phosphodiester internucleoside linkage; s = phosphorothioate internucleoside linkage, and [C16-HA] = [ka] is.

[0134] 65. Oligomeric compounds comprising modified oligonucleotides according to the following chemical designations: [C16-HA] o A ks A ks A ds G ds A ds T ds A ds T ds A ds G ds T ds A ks T es G ks G es T k (SEQ ID NO: 120), wherein A = adenine nucleobase, G = guanine nucleobase; T=thymine nucleobase, e=2'-MOE sugar moiety, k=cEt sugar moiety, d=2'-β-D-deoxyribosyl sugar moiety, o = phosphodiester internucleoside linkage; s = phosphorothioate internucleoside linkage, and [C16-HA] = [ka] is.

[0135] 66. The oligomeric compound according to any of embodiments 1-65, comprising a terminal group.

[0136] 67. The oligomeric compound according to embodiment 66, wherein the terminal group is an abasic sugar moiety.

[0137] 68. The chemical structure of: [ka] Oligomeric compounds according to (SEQ ID NO: 45).

[0138] 69. The chemical structure of: [ka] An oligomeric compound according to (SEQ ID NO: 45), or a salt thereof.

[0139] 70. The oligomeric compound according to embodiment 69, which is a sodium or potassium salt.

[0140] 71. The chemical structure of: [ka] Oligomeric compounds according to (SEQ ID NO: 609).

[0141] 72. The chemical structure of: [ka] An oligomeric compound according to (SEQ ID NO: 609), or a salt thereof.

[0142] 73. The oligomeric compound according to embodiment 72, which is a sodium or potassium salt.

[0143] 74. The chemical structure of: [ka] Oligomeric compounds according to (SEQ ID NO: 752).

[0144] 75. The chemical structure of: [ka] An oligomeric compound according to (SEQ ID NO: 752), or a salt thereof.

[0145] 76. The oligomeric compound according to embodiment 75, which is a sodium or potassium salt.

[0146] 77. The chemical structure of: [ka] An oligomeric compound according to (SEQ ID NO: 120).

[0147] 78. The chemical structure of: [ka] An oligomeric compound according to (SEQ ID NO: 120), or a salt thereof.

[0148] 79. The oligomeric compound according to embodiment 78, which is a sodium or potassium salt.

[0149] 80. The chemical structure of: [ka] A modified oligonucleotide according to (SEQ ID NO: 185).

[0150] 81. The chemical structure of: [ka] A modified oligonucleotide according to (SEQ ID NO: 185), or a salt thereof.

[0151] 82. The modified oligonucleotide of embodiment 81, which is a sodium or potassium salt.

[0152] 83. The chemical structure of: [ka] A modified oligonucleotide according to (SEQ ID NO: 752).

[0153] 84. The chemical structure of: [ka] A modified oligonucleotide according to (SEQ ID NO: 752), or a salt thereof.

[0154] 85. The modified oligonucleotide of embodiment 84, which is a sodium or potassium salt.

[0155] 86. The chemical structure of: [ka] A modified oligonucleotide according to (SEQ ID NO: 609).

[0156] 87. The chemical structure of: [ka] A modified oligonucleotide according to (SEQ ID NO: 609), or a salt thereof.

[0157] 88. The modified oligonucleotide according to embodiment 87, which is a sodium or potassium salt.

[0158] 89. The chemical structure of: [ka] A modified oligonucleotide according to (SEQ ID NO: 45).

[0159] 90. The chemical structure of: [ka] A modified oligonucleotide according to (SEQ ID NO: 45), or a salt thereof.

[0160] 91. The modified oligonucleotide of embodiment 90, which is a sodium or potassium salt.

[0161] 92. The chemical structure of: [ka] A modified oligonucleotide according to (SEQ ID NO: 737).

[0162] 93. The chemical structure of: [ka] A modified oligonucleotide according to (SEQ ID NO: 737), or a salt thereof.

[0163] 94. The modified oligonucleotide of embodiment 93, which is a sodium or potassium salt.

[0164] 95. The chemical structure of: [ka] A modified oligonucleotide according to (SEQ ID NO: 120).

[0165] 96. The chemical structure of: [ka] A modified oligonucleotide according to (SEQ ID NO: 120), or a salt thereof.

[0166] 97. The modified oligonucleotide according to embodiment 96, which is a sodium or potassium salt.

[0167] 98. The chemical structure of: [ka] A modified oligonucleotide according to (SEQ ID NO: 675).

[0168] 99. The chemical structure of: [ka] A modified oligonucleotide according to (SEQ ID NO: 675), or a salt thereof.

[0169] 100. The modified oligonucleotide of embodiment 99, which is a sodium or potassium salt.

[0170] 101. A chirally enriched population of an oligomeric compound according to any one of embodiments 1 to 79 or a modified oligonucleotide according to embodiments 80 to 100, wherein the population is enriched for modified oligonucleotides comprising at least one specific phosphorothioate internucleoside linkage having a specific stereochemical configuration.

[0171] 102. The chirally enriched population of embodiment 101, which is enriched for modified oligonucleotides comprising at least one specific phosphorothioate internucleoside linkage having the (Sp) or (Rp) configuration.

[0172] 103. The chirally enriched population of embodiment 101, which is enriched for modified oligonucleotides having a specific, independently selected stereochemical configuration at each phosphorothioate internucleoside linkage.

[0173] 104. The chirally enriched population of embodiment 101, which is enriched for modified oligonucleotides having the (Rp) configuration at one particular phosphorothioate internucleoside linkage and the (Sp) configuration at each of the remaining phosphorothioate internucleoside linkages.

[0174] 105. The chirally enriched population of embodiment 101, wherein the population is enriched for modified oligonucleotides having at least three consecutive phosphorothioate internucleoside linkages in the Sp configuration, the Sp configuration, and the Rp configuration in the 5' to 3' direction.

[0175] 106. A population of oligomeric compounds comprising a modified oligonucleotide according to any one of embodiments 1 to 79, or a population of modified oligonucleotides according to embodiments 80 to 100, wherein all of the phosphorothioate internucleoside linkages of the modified oligonucleotides are stereorandom.

[0176] 107. An oligomeric duplex comprising a first oligomeric compound and a second oligomeric compound comprising a second modified oligonucleotide, wherein the first oligomeric compound is an oligomeric compound according to any one of embodiments 1 to 59.

[0177] 108. The oligomeric duplex of embodiment 107, wherein the second oligomeric compound comprises a second modified oligonucleotide consisting of 8 to 80 linked nucleosides, and the nucleobase sequence of the second modified oligonucleotide comprises a complementary region of at least 8 nucleobases that is at least 90% complementary to an equal-length portion of the first modified oligonucleotide.

[0178] 109. An oligomeric duplex comprising: a first oligomeric compound comprising a first modified oligonucleotide consisting of 19 to 29 linked nucleosides, wherein the nucleobase sequence of the first modified oligonucleotide comprises at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 consecutive nucleobases of the nucleobase sequence of any of SEQ ID NOs: 1713-2024; and A second oligomeric compound comprising a second modified oligonucleotide consisting of 15 to 29 linked nucleosides, wherein the nucleic acid base sequence of the second modified oligonucleotide comprises a complementary region of at least 8 nucleic acid bases that is at least 90% complementary to an equal-length portion of the first modified oligonucleotide.

[0179] 110. An oligomeric duplex comprising: a first oligomeric compound comprising a first modified oligonucleotide consisting of 19 to 29 linked nucleosides, wherein the nucleobase sequence of the first modified oligonucleotide comprises at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 consecutive nucleobases of the nucleobase sequence of any of SEQ ID NOs: 1713-2024; and A second oligomeric compound comprising a second modified oligonucleotide consisting of 15 to 29 linked nucleosides, wherein the nucleobase sequence of the second modified oligonucleotide comprises at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, or at least 21 consecutive nucleobases of the nucleobase sequence of any of SEQ ID NOs: 2025 to 2336, and the nucleobase sequence of the second modified oligonucleotide is at least 90% complementary to an equal-length portion of the first modified oligonucleotide.

[0180] 111. An oligomeric duplex comprising: A first oligomeric compound comprising a first modified oligonucleotide consisting of 23 linked nucleosides, wherein the nucleic acid base sequence of the first modified oligonucleotide consists of any of the nucleic acid base sequences of SEQ ID NOs: 1713 to 2024; and A second oligomeric compound comprising a second modified oligonucleotide consisting of 21 linked nucleosides, wherein the nucleic acid base sequence of the second modified oligonucleotide consists of any of the nucleic acid base sequences of SEQ ID NOs: 2025 to 2336, and the nucleic acid base sequence of the second modified oligonucleotide is at least 90% complementary to an equal-length portion of the first modified oligonucleotide.

[0181] 112. The oligomeric duplex of any of embodiments 107-111, wherein said modified oligonucleotide of said first oligomeric compound comprises a 5'-stabilizing phosphate group.

[0182] 113. The oligomeric duplex of embodiment 112, wherein the 5'-stabilizing phosphate group comprises a cyclopropylphosphonate or a vinylphosphonate.

[0183] 114. The oligomeric duplex of any of embodiments 107-113, wherein said modified oligonucleotide of said first oligomeric compound comprises a glycol nucleic acid (GNA) sugar surrogate.

[0184] 115. The oligomeric duplex of any of embodiments 107-114, wherein said modified oligonucleotide of said first oligomeric compound comprises a 2'-NMA sugar moiety.

[0185] 116. The oligomeric duplex of any of embodiments 107-115, wherein at least one nucleoside of the second modified oligonucleotide comprises a modified sugar moiety.

[0186] 117. The oligomeric duplex of embodiment 116, wherein the modified sugar moiety of the second modified oligonucleotide comprises a bicyclic sugar moiety.

[0187] 118. The oligomeric duplex of embodiment 117, wherein the bicyclic sugar moiety of the second modified oligonucleotide comprises a 2'-4' bridge selected from -O-CH2- and -O-CH(CH3)-.

[0188] 119. The oligomeric duplex of embodiment 116, wherein the modified sugar moiety of the second modified oligonucleotide comprises a non-bicyclic modified sugar moiety.

[0189] 120. The oligomeric duplex of embodiment 119, wherein the non-bicyclic modified sugar moiety of the second modified oligonucleotide is a 2'-MOE sugar moiety, a 2'-F sugar moiety, or a 2'-OMe sugar moiety.

[0190] 121. The oligomeric duplex of any of embodiments 107-120, wherein at least one nucleoside of the second modified oligonucleotide comprises a sugar surrogate.

[0191] 122. The oligomeric duplex of any of embodiments 107-121, wherein the second modified oligonucleotide comprises at least one modified internucleoside linkage.

[0192] 123. The oligomeric duplex of embodiment 122, wherein at least one modified internucleoside linkage of said second modified oligonucleotide is a phosphorothioate internucleoside linkage.

[0193] 124. The oligomeric duplex of any of embodiments 107-123, wherein the second modified oligonucleotide comprises at least one phosphodiester internucleoside linkage.

[0194] 125. The oligomeric duplex of any of embodiments 107-124, wherein each internucleoside linkage of the second modified oligonucleotide is independently selected from a phosphodiester internucleoside linkage or a phosphorothioate internucleoside linkage.

[0195] 126. The oligomeric duplex of any of embodiments 107-125, wherein the internucleoside linkage motif of the first modified oligonucleotide is ssooooooooooooooooooooss and the internucleoside linkage motif of the second modified oligonucleotide is ssooooooooooooooooooooss, wherein each "o" represents a phosphodiester internucleoside linkage and each "s" represents a phosphorothioate internucleoside linkage.

[0196] 127. The oligomeric duplex of any of embodiments 107-126, wherein the second modified oligonucleotide comprises at least one modified nucleobase.

[0197] 128. The oligomeric duplex of embodiment 127, wherein the modified nucleobase of the second modified oligonucleotide is 5-methylcytosine.

[0198] 129. The oligomeric duplex of any of embodiments 107-128, wherein the second modified oligonucleotide comprises a conjugate group.

[0199] 130. The oligomeric duplex of embodiment 129, wherein the conjugate group comprises a conjugate linker and a conjugate moiety.

[0200] 131. The oligomeric duplex of embodiment 129 or 130, wherein the conjugate group is attached to the second modified oligonucleotide at the 5' end of the modified oligonucleotide.

[0201] 132. The oligomeric duplex of embodiment 129 or 130, wherein the conjugate group is attached to the second modified oligonucleotide at the 3' end of the modified oligonucleotide.

[0202] 133. The oligomeric duplex of any of embodiments 129-132, wherein the conjugate group comprises C22 alkyl, C20 alkyl, C16 alkyl, C10 alkyl, C21 alkyl, C19 alkyl, C18 alkyl, C15 alkyl, C14 alkyl, C13 alkyl, C12 alkyl, C11 alkyl, C9 alkyl, C8 alkyl, C7 alkyl, C6 alkyl, C5 alkyl, C22 alkenyl, C20 alkenyl, C16 alkenyl, C10 alkenyl, C21 alkenyl, C19 alkenyl, C18 alkenyl, C15 alkenyl, C14 alkenyl, C13 alkenyl, C12 alkenyl, C11 alkenyl, C9 alkenyl, C8 alkenyl, C7 alkenyl, C6 alkenyl, or C5 alkenyl.

[0203] 134. The oligomeric duplex of any of embodiments 129-133, wherein the conjugate moiety is a 6-palmitamidohexyl conjugate moiety.

[0204] 135. The oligomeric duplex of any of embodiments 129-132, wherein the conjugate group has the following structure: [ka]

[0205] 136. The oligomeric duplex of any of embodiments 129-135, wherein the conjugate group comprises a cell-targeting moiety.

[0206] 137. The oligomeric duplex of embodiment 136, wherein said cell targeting moiety has affinity for TfR1.

[0207] 138. The oligomeric duplex of embodiment 137, wherein the cell-targeting moiety comprises an anti-TfR1 antibody or a fragment thereof.

[0208] 139. The oligomeric duplex of embodiment 137, wherein the cell targeting moiety comprises a protein or peptide capable of binding TfR1.

[0209] 140. The oligomeric duplex of embodiment 137, wherein said cell targeting moiety comprises an aptamer capable of binding TfR1.

[0210] 141. The oligomeric duplex of any of embodiments 107-140, wherein the second modified oligonucleotide comprises a terminal group.

[0211] 142. The oligomeric duplex of embodiment 141, wherein the terminal group is an abasic sugar moiety.

[0212] 143. The second modified oligonucleotide is 10 to 25, 10 to 30, 10 to 50, 12 to 20, 12 to 25, 12 to 30, 12 to 50, 13 to 20, 13 to 25, 13 to 30, 13 to 50, 14 to 20, 14 to 25, 14 to 30, 14 to 50, 15 to 20, 15 to 25, 15 to 30, 15 to 50, 16 to 18, 16 to 20, 16 to 25, 16 to 30, 16 to 50, 17 to 20, 17 to 25, 1 143. The oligomeric duplex of any of embodiments 107-142, consisting of 7-30, 17-50, 18-20, 18-25, 18-30, 18-50, 19-20, 19-25, 19-30, 19-50, 20-25, 20-30, 20-50, 21-25, 21-30, 21-50, 22-25, 22-30, 22-50, 23-25, 23-30, or 23-50 linked nucleosides.

[0213] 144. The oligomeric duplex of any of embodiments 107-143, wherein the modified oligonucleotide of the first oligomeric compound consists of 23 linked nucleosides and the second modified oligonucleotide consists of 21 linked nucleosides.

[0214] 145. The oligomeric duplex of embodiment 144, wherein the modified oligonucleotide of the first oligomeric compound has the sugar motif (5' to 3'): yfyfyfyfyfyfyfyfyfyfyyy; and the second modified oligonucleotide has the sugar motif (5' to 3'): fyfyfyfyfyfyfyfyfyfyfyf, wherein each "y" represents a 2'-OMe sugar moiety and each "f" represents a 2'-F sugar moiety.

[0215] 146. An antisense agent comprising an antisense compound, wherein the antisense compound is an oligomeric compound according to any one of embodiments 1 to 79 or a modified oligonucleotide according to any one of embodiments 80 to 100.

[0216] 147. An antisense agent which is an oligomeric duplex according to any of embodiments 107-145.

[0217] 148. The antisense agent according to embodiment 146 or 147, i. RNase H agents capable of reducing the amount of PLN nucleic acids by activating RNase H; ii. RNAi agents capable of reducing the amount of PLN nucleic acid by activating RISC / Ago2 The antisense agent,

[0218] 149. The antisense agent of any of embodiments 146-148, wherein the conjugate group is a cell-targeting moiety.

[0219] 150. A pharmaceutical composition comprising an oligomeric compound according to any one of embodiments 1 to 79, a modified oligonucleotide according to any one of embodiments 80 to 100, a population according to any one of embodiments 101 to 106, an oligomeric duplex according to any one of embodiments 107 to 145, or an antisense agent according to any one of embodiments 146 to 149, and a pharmaceutically acceptable diluent or carrier.

[0220] 151. The pharmaceutical composition according to embodiment 150, wherein the pharmaceutically acceptable diluent is water or phosphate buffered saline.

[0221] 152. The pharmaceutical composition of embodiment 151, consisting essentially of the oligomeric compound, the modified oligonucleotide, the oligomeric duplex, or the antisense agent, and water or phosphate-buffered saline.

[0222] 153. A method comprising administering to a subject an oligomeric compound according to any one of embodiments 1 to 79, a modified oligonucleotide according to any one of embodiments 80 to 100, a population according to any one of embodiments 101 to 106, an oligomeric duplex according to any one of embodiments 107 to 145, an antisense agent according to any one of embodiments 146 to 149, or a pharmaceutical composition according to any one of embodiments 150 to 152.

[0223] 154. A method for treating a disease associated with PLN, comprising administering a therapeutically effective amount of an oligomeric compound according to any one of embodiments 1 to 79, a modified oligonucleotide according to any one of embodiments 80 to 100, a population according to any one of embodiments 101 to 106, an oligomeric duplex according to any one of embodiments 107 to 145, an antisense agent according to any one of embodiments 146 to 149, or a pharmaceutical composition according to any one of embodiments 150 to 152 to a subject having a disease associated with PLN, thereby treating the disease associated with PLN.

[0224] 155. The method of embodiment 154, wherein the PLN-related disease is cardiomyopathy, heart failure, or arrhythmia.

[0225] 156. The method of embodiment 155, wherein the cardiomyopathy is an inherited cardiomyopathy.

[0226] 157. The method of embodiment 156, wherein the inherited cardiomyopathy is associated with a p.Arg14del, Arg9Cys (R9C), or Arg25Cys (R25C) genetic mutation.

[0227] 158. The method of embodiment 155, wherein the cardiomyopathy is dilated cardiomyopathy (DCM).

[0228] 159. The method of embodiment 157, wherein said DCM is hereditary DCM.

[0229] 160. The method of embodiment 159, wherein the inherited DMC is associated with mutations in TTN, LMNA, RBM20, SCN5A, MYH7, TNNT2, and TPM1.

[0230] 161. The method of embodiment 158, wherein the DCM is arrhythmogenic DCM.

[0231] 162. The method of embodiment 155, wherein said heart failure is heart failure with preserved ejection fraction (HFpEF), heart failure with reduced ejection fraction (HFrEF), acute heart failure, or worsening chronic heart failure.

[0232] 163. The method of embodiment 155, wherein the arrhythmia is ventricular tachycardia (Vtac) or ventricular fibrillation (Vfib).

[0233] 164. The method of any of embodiments 155-163, wherein administering the oligomeric compound of any of embodiments 1-79, the modified oligonucleotide of any of embodiments 80-100, the population of any of embodiments 101-106, the oligomeric duplex of any of embodiments 107-145, the antisense agent of any of embodiments 146-149, or the pharmaceutical composition of any of embodiments 150-152 improves cardiac function, cardiovascular death, cardiac dilation, myocardial fibrosis, low voltage ECG, diastolic calcium uptake, ejection fraction (EF), left ventricular ejection fraction (LVEF), left ventricular end-systolic volume (LVESV), left ventricular end-diastolic volume (LVEDV), mitral valve perfusion profile, left ventricular (LV) strain, left ventricular (LV) strain rate, infarct size, heart failure hospitalization, 6-minute walk test (6MWT), Kansas City Cardiomyopathy Questionnaire score (KCCQS), heart rate, or heart rhythm in said subject.

[0234] 165. A method for reducing expression of PLN in a cell, the method comprising contacting the cell with an oligomeric compound according to any one of embodiments 1 to 79, a modified oligonucleotide according to any one of embodiments 80 to 100, a population according to any one of embodiments 101 to 106, an oligomeric duplex according to any one of embodiments 107 to 145, an antisense agent according to any one of embodiments 146 to 149, or a pharmaceutical composition according to any one of embodiments 150 to 152.

[0235] 166. The method of embodiment 157, wherein the cells are cardiac cells.

[0236] 167. Use of an oligomeric compound according to any of embodiments 1 to 79, a modified oligonucleotide according to any of embodiments 80 to 100, a population according to any of embodiments 101 to 106, an oligomeric duplex according to any of embodiments 107 to 145, an antisense agent according to any of embodiments 146 to 149, or a pharmaceutical composition according to any of embodiments 150 to 152 for treating a disease associated with PLN.

[0237] 168. Use of an oligomeric compound according to any of embodiments 1 to 79, a modified oligonucleotide according to any of embodiments 80 to 100, a population according to any of embodiments 101 to 106, an oligomeric duplex according to any of embodiments 107 to 145, an antisense agent according to any of embodiments 146 to 149, or a pharmaceutical composition according to any of embodiments 150 to 152 in the manufacture of a medicament for treating a disease associated with PLN.

[0238] 169. The use according to embodiment 159 or 160, wherein the disease associated with PLN is cardiomyopathy, heart failure, or arrhythmia.

[0239] 170. The use according to embodiment 169, wherein the cardiomyopathy is an inherited cardiomyopathy.

[0240] 171. The use according to embodiment 170, wherein the inherited cardiomyopathy is associated with the p.Arg14del, Arg9Cys (R9C), or Arg25Cys (R25C) genetic mutation.

[0241] 172. The use according to embodiment 169, wherein the cardiomyopathy is dilated cardiomyopathy (DCM).

[0242] 173. The use according to embodiment 172, wherein the DCM is hereditary DCM.

[0243] 174. The use according to embodiment 173, wherein the hereditary DMC is associated with mutations in TTN, LMNA, RBM20, SCN5A, MYH7, TNNT2, and TPM1.

[0244] 175. The use according to embodiment 172, wherein the DCM is arrhythmogenic DCM.

[0245] 176. The use according to embodiment 169, wherein said heart failure is heart failure with preserved ejection fraction (HFpEF), heart failure with reduced ejection fraction (HFrEF), acute heart failure, or worsening chronic heart failure.

[0246] 177. The use according to embodiment 176, wherein the arrhythmia is ventricular tachycardia (Vtac) or ventricular fibrillation (Vfib).

[0247] Certain Oligomeric Agents and Compounds In certain embodiments, oligomeric agents are provided that target PLN nucleic acid.In certain embodiments, the PLN nucleic acid has the sequence shown in RefSeq or GENBANK accession number NM_002667.4 or NC_000006.12, each of which is incorporated by reference in its entirety, and is truncated from nucleoside 118545001 to 118565000.In certain embodiments, the oligomeric agent is a single-stranded oligomeric compound.In certain embodiments, the oligomeric agent is an oligomeric duplex.

[0248] In certain embodiments, oligomeric compounds are provided that include a modified oligonucleotide consisting of 8 to 80 linked nucleosides, the nucleobase sequence of which is at least 80% complementary to an equal-length portion of a PLN nucleic acid, and the modified oligonucleotide has at least one modification selected from a modified sugar moiety and a modified internucleoside linkage. In certain embodiments, the PLN nucleic acid has the nucleobase sequence of SEQ ID NO: 1 or 2. In certain embodiments, the nucleobase sequence of the modified oligonucleotide comprises nucleobases 3278-3293, 3281-3296, 3282-3297, 3284-3299, 3286-3301, 3287-3302, 3288-3303, 3327-3342, 3329-3344, 3332-3347, 3333-3348, 3336-3351, 3337-3352, 3338-3353, 3339-3354, 3340-3355, 3341-3342, 3343-3344, 3345-3346, 3347-3348, 3348-3359, 3350-3351, 3351-3352, 3351-3353, 3352-3354, 3353-3355, 3356-3357, 3358-3359, 3360-3361, 3361-3362, 3362-3363, 3363-3364, 3364-3365, 3365-3366, 3366-3367, 3367-3368, 3368-3369, 3370-3371, 3372-3373, 3374-3375, 3376-3377, 3378-3380, 3379-3381, 3382-3383, 338 3355, 3341~3356, 3343~3358, 3345~3360, 3348~3363, 3349~3364, 3350~3365, 3351~3366, 3352~3367, 3353~3368, 3354~3369, 3355~3370, 3356~3371, 3357~3372, 3358~3373, 3395~3410, 3396~3411, 3405~3420, 3406~3421, 3408~3423, 340 9~3424, 3410~3425, 3412~3427, 3496~3511, 3497~3512, 3498~3513, 3499~3514, 3598~3613, 3612~3627, 3614~3629, 3615~3630, 3616~3631, 3617~3632, 3618~3633, 3619~3634, 3620~3635, 3622~3637, 3703~3718, 3704~3719, 3715~3730, 3 716~3731, 3723~3738, 3724~3739, 3799~3814, 3801~3816, 3802~3817, 3803~3818, 3804~3819, 3805~3820, 3806~3821, 3807~3822, 3808~3823, 3809~3824, 3811~3826, 3814~3829, 3815~3830, 3816~3831, 3817~3832, 3821~3836, 3823~3838,3830~3845、3831~3846、3848~3863、3849~3864、3850~3865、3851~3866、3861~3876、3863~3878、3864~3879、3869~3884、3871~3886、3976~3991、3977~3992、3978~3993、3980~3995、3981~3996、4116~4131、4159~4174、4204~4219、4207~4222、4208~4223、4209~4224、4210~4225、4211~4226、4212~4227、4214~4229、4221~4236、4231~4246、4232~4247、4233~4248、4234~4249、4235~4250、4236~4251、4238~4253、4252~4267、4253~4268、4266~4281、4348~4363、4349~4364、4350~4365、4367~4382、4373~4388、4374~4389、4375~4390、4510~4525、4511~4526、4513~4528、4515~4530、4516~4531、4517~4532、4518~4533、4519~4534、4530~4545、4537~4552、4539~4554、4540~4555、4541~4556、4542~4557、4543~4558、4544~4559、4545~4560、4562~4577、4614~4629、4617~4632、4619~4634、4620~4635、4621~4636、4622~4637、4623~4638、4624~4639、4638~4653、4640~4655、4641~4656、4642~4657、4643~4658、4665~4680、4672~4687、4693~4708、4694~4709、4695~4710、4696~4711、4697~4712、4750~4765、4751~4766、4752~4767、4753~4768、4774~4789、4802~4817、4804~4819、4805~4820、4806~4821、4807~4822、4823~4838、4825~4840、4826~4841、4828~4843、4860~4875、4862~4877、4869~4884、4872~4887、4874~4889、4878~4893、4881~4896、4883~4898、4884~4899、4942~4957、4943~4958、4945~4960、4946~4961、4957~4972、4958~4973、4960~4975、4961~4976、4964~4979、4965~4980、4966~4981、4968~4983、4969~4984、4971~4986、4972~4987、4974~4989、4984~4999、4985~5000、4987~5002、4988~5003、5024~5039、5127~5142、5133~5148、5134~5149、5158~5173、5159~5174、5160~5175、5163~5178、5294~5309、5341~5356、5359~5374、5394~5409、5399~5414、5400~5415、5401~5416、5402~5417、5404~5419、5411~5426、5413~5428、5414~5429、5415~5430、5416~5431、5417~5432、5418~5433、5419~5434、5421~5436、5427~5442、5428~5443、5489~5504、5494~5509、5495~5510、5497~5512、5498~5513、5498~5515、5498~5517、5499~5514、5499~5515、5499~5516、5499~5518、5500~5515、5500~5516、5500~5517、5501~5516、5501~5514、5501~5517、5502~5517、5502~5515、5503~5518、5504~5519、5505~5520、5506~5521、5511~5526、5532~5547、5533~5548、5534~5549、5547~5562、5557~5572、5558~5573、5559~5574、5560~5575、5562~5577、5563~5578、5565~5580、5599~5614、5673~5688、5674~5689、5675~5690、5676~5691、5677~5692、5678~5693、5679~5694、5694~5709、5695~5710、5696~5711、5697~5712、5698~5713、5774~5789、5827~5842、5845~5860、5847~5862、5848~5863、5850~5865、5851~5866、5855~5870、5859~5874、5924~5939、5925~5940、5926~5941、5927~5942、5929~5944、5930~5945、5931~5946、5932~5947、6008~6023、6009~6024、6039~6054、6053~6068、6054~6069、6055~6070、6059~6074、6066~6081、6069~6084、6070~6085、6076~6091、6092~6107、6098~6113、6112~6127、6114~6129、6117~6132、6118~6133、6119~6134、6124~6139、6125~6140、6126~6141、6147~6162、6154~6169、6155~6170、6156~6171、6157~6172、6176~6191、6177~6192、6185~6200、6186~6201、6187~6202、6188~6203、6202~6217、6209~6224、6243~6258、6249~6264、6267~6282、6268~6283、6274~6289、6275~6290、6291~6306、6338~6353、6352~6367、6353~6368、6354~6369、6365~6380、6366~6381、6368~6383、6369~6384、6403~6418、6405~6420、6406~6421、6407~6422、6408~6423、6409~6424、6410~6425、6411~6426、6413~6428、6468~6483、6471~6486、6502~6517、6546~6561、6554~6569、6555~6570、6556~6571、6557~6572、6569~6584、6574~6589、6575~6590、6576~6591、6577~6592、6578~6593、6579~6594、6644~6659、6646~6661、6647~6662、6664~6679、6665~6680、6666~6681、6667~6682、6676~6691、6677~6692、6746~6761、6804~6819、6806~6821、6825~6840、6826~6841、6827~6842、6828~6843、6831~6846、6833~6848、6834~6849、6875~6890、6877~6892、6879~6894、6880~6895、6881~6896、6893~6908、6896~6911、6898~6913、6899~6914、6900~6915、6901~6916、6903~6918、6904~6919、6906~6921、6907~6922、6908~6923、6920~6935、6921~6936、6922~6937、6923~6938、6927~6942、6928~6943、6930~6945、6937~6952、6939~6954、6940~6955、6941~6956、6942~6957、6943~6958、6944~6959、6945~6960、6947~6962、6965~6980、6966~6981、6967~6982、6968~6983、6972~6987、6975~6990、7029~7044、7042~7057、7047~7062、7050~7065、7073~7088、7082~7097、7083~7098、7102~7117、7106~7121、7107~7122、7108~7123、7120~7135、7122~7137、7123~7138、7124~7139、7125~7140、7126~7141、7128~7143、7129~7144、7130~7145、7131~7146、7279~7294、7280~7295、7282~7297、7283~7298、7284~7299、7285~7300、7286~7301、7287~7302、7320~7335、7341~7356、7342~7357、7344~7359、7353~7368、7354~7369、7356~7371、7357~7372、7358~7373、7359~7374、7360~7375、7361~7376、7362~7377、7377~7392、7378~7393、7392~7407、7393~7408、7411~7426、7425~7440、7436~7451、7457~7472、7458~7473、7459~7474、7460~7475、7461~7476、7463~7478、7464~7479、7470~7485、7516~7531、7518~7533、7519~7534、7520~7535、7521~7536、7522~7537、7546~7561、 7548~7563、7553~7568、7554~7569、7555~7570、7556~7571、7558~7573、7560~7575、7561~7576、7562~7577、7563~7578、7564~7579、7565~7580、7566~7581、7568~7583、7587~7602、7588~7603、7589~7604、7595~7610、7638~7653、7679~7694、7726~7741、7779~7794、7797~7812、7799~7814、7806~7821、7857~7872、7859~7874、7860~7875、7861~7876、7862~7877、7863~7878、7864~7879、7865~7880、7867~7882、7876~7891、7878~7893、7888~7903、7889~7904、7893~7908、7908~7923、7929~7944、7965~7980、7967~7982、7968~7983、8047~8062、8058~8073、8061~8076、8089~8104、8090~8105、8163~8178、8182~8197、8194~8209、8195~8210、8196~8211、8197~8212、8284~8299、8285~8300、8286~8301、8287~8302、8288~8303、8326~8341、8336~8351、8352~8367、8353~8368、8368~8383、8393~8408、8412~8427、8413~8428、8415~8430、8418~8433、8427~8442、8447~8462、8493~8508、8494~8509、8495~8510、8496~8511、8498~8513、8542~8557、8573~8588、8621~8636、8627~8642、8628~8643、8638~8653、8639~8654、8641~8656、8653~8668、8655~8670、8703~8718、8708~8723、8732~8747、8733~8748、8739~8754、8774~8789、8776~8791、8777~8792、8818~8833、8823~8838、8824~8839、8826~8841、8827~8842、8850~8865、8855~8870、8942~8957、8943~8958、8944~8959、8955~8970、8961~8976、8962~8977、8963~8978、8964~8979、9377~9392、9443~9458、9474~9489、9523~9538、9524~9539、9525~9540、9526~9541、9528~9543、9536~9551、9537~9552、9538~9553、9540~9555、9541~9556、9545~9560、9549~9564、9550~9565、9587~9602、9630~9645、9641~9656、9642~9657、9646~9661、9647~9662、9648~9663、9649~9664、9651~9666、9660~9675、9668~9683、9669~9684、9672~9687、9697~9712、9702~9717、9703~9718、9706~9721、9707~9722、9708~9723、9709~9724、9710~9725、9711~9726、9720~9735、9727~9742、9752~9767、9756~9771、9788~9803、9934~9949、9936~9951、9937~9952、9938~9953、9939~9954、9940~9955、10019~10034、10054~10069、10062~10077、10081~10096、10106~10121、10117~10132、10443~10458、10444~10459、10445~10460、10480~10495、10481~10496、10486~10501、10489~10504、10490~10505、10491~10506、10532~10547、10623~10638、10638~10653、10645~10660、10718~10733、10719~10734、10720~10735、10721~10736、10722~10737、10723~10738、10724~10739、10747~10762、10770~10785、11066~11081、11068~11083、11104~11119、11111~11126、11112~11127、11115~11130、11116~11131、11118~11133、11130~11145、11144~11159、11224~11239、11225~11240、11237~11252、11258~11273、11259~11274、11302~11317、11353~11368、11356~11371、11368~11383、11369~11384、11409~11424、11410~11425、11411~11426、11412~11427、11413~11428、11414~11429、11415~11430、11417~11432、11457~11472、11458~11473、11467~11482、11474~11489、11475~11490、11509~11524、11510~11525、11511~11526、11524~11539、11525~11540、11526~11541、11527~11542、11529~11544、11530~11545、11622~11637、11631~11646、11632~11647、11633~11648、11634~11649、11635~11650、11636~11651、11639~11654、11670~11685、11678~11693、11679~11694、11680~11695、11681~11696、11682~11697、11684~11699、11685~11700、11726~11741、11727~11742、11740~11755、11741~11756、11742~11757、11743~11758、11799~11814、11832~11847、11833~11848、11854~11869、11855~11870、11856~11871、11857~11872、11858~11873、11859~11874、11900~11915、11931~11946、11956~11971、11988~12003、11989~12004、11990~12005、11991~12006、11992~12007、11993~12008、11994~12009、11995~12010、11997~12012、11998~12013、11999~12014、12000~12015、12015~12030、12016~12031、12017~12032、12027~12042、12032~12047、12040~12055、12041~12056、12042~12057、12076~12091、12080~12095、12081~12096、12082~12097、12084~12099、12085~12100、12086~12101、12087~12102、12088~12103、12089~12104、12090~12105、12092~12107、12194~12209、12195~12210、12238~12253、12239~12254、12241~12256、12242~12257、12243~12258、12246~12261、12282~12297、12283~12298、12285~12300、12286~12301、12287~12302、12288~12303、12307~12322、12308~12323、12310~12325、12312~12327、12315~12330、12348~12363、12355~12370、12356~12371、12357~12372、12368~12383、12388~12403、12389~12404、12390~12405、12391~12406、12392~12407、12470~12485、12471~12486、12472~12487、12473~12488、12474~12489、12498~12513、12529~12544、12530~12545、12546~12561、12548~12563、12550~12565、12551~12566、12585~12600、12721~12736、12722~12737、12723~12738、12724~12739、12727~12742、12732~12747、12733~12748、12734~12749、12735~12750、12760~12775、12812~12827、12813~12828、12817~12832、12818~12833、12912~12927、12915~12930、12929~12944、12943~12958、12946~12961、13243~13258、13327~13342、13409~13424、13431~13446、13438~13453、13460~13475、13461~13476、13484~13499、13485~13500、13486~13501、13489~13504、13490~13505、13491~13506、13492~13507、13493~13508、13525~13540、13528~13543、13529~13544、13530~13545、13717~13732、13736~13751、13770~13785、13776~13791、13777~13792、13786~13801、13814~13829、13816~13831、13818~13833、13819~13834、13820~13835、13821~13836、13822~13837、13823~13838、13835~13850、13836~13851、13837~13852、13838~13853、13839~13854、13843~13858、13870~13885、13872~13887、13875~13890、13876~13891、13877~13892、13878~13893、13879~13894、13880~13895、13881~13896、13882~13897、13883~13898、13885~13900、13904~13919、13905~13920、13906~13921、13907~13922、13908~13923、13910~13925、13912~13927、13918~13933、13924~13939、13926~13941、13927~13942、13930~13945、13934~13949、13935~13950、13936~13951、13937~13952、13938~13953、13939~13954、13940~13955、13941~13956、13942~13957、13943~13958、13944~13959、13945~13960、13946~13961、13952~13967、13953~13968、13954~13969、13955~13970、13956~13971、13957~13972、13958~13973、13959~13974、13960~13975、13961~13976、13962~13977、13963~13978、13964~13979、13965~13980、13966~13981、13967~13982、13968~13983、13969~13984、13970~13985、13973~13988、13976~13991、 14000~14015、14003~14018、14028~14043、14030~14045、14032~14047、14035~14050、14036~14051、14038~14053、14039~14054、14040~14055、14041~14056、14045~14060、14047~14062、14048~14063、14049~14064、14050~14065、14051~14066、14053~14068、14054~14069、14055~14070、14056~14071、14059~14074、14060~14075、14061~14076、14062~14077、14063~14078、14064~14079、14065~14080、14066~14081、14078~14093、14081~14096、14082~14097、14084~14099、14085~14100、14086~14101、14087~14102、14088~14103、14089~14104、14090~14105、14091~14106、14092~14107、14093~14108、14095~14110、14096~14111、14097~14112、14098~14113、14099~14114、14100~14115、14102~14117、14105~14120、14110~14125、14111~14126、14112~14127、14113~14128、14115~14130、14117~14132、14119~14134、14130~14145、14163~14178、14165~14180、14166~14181、14167~14182、14169~14184、14170~14185、14174~14189、14180~14195、14181~14196、14203~14218、14207~14222、14209~14224、14212~14227、14217~14232、14220~14235、14222~14237、14223~14238、14224~14239、14225~14240、14232~14247、14233~14248、14235~14250、14242~14257、14244~14259、14247~14262、14248~14263、14249~14264、14250~14265、14251~14266、14252~14267、14253~14268、14254~14269、14255~14270、14256~14271、14257~14272、14316~14331、14317~14332、14318~14333、14319~14334、14321~14336、14324~14339、14327~14342、14337~14352、14338~14353、14339~14354、14340~14355、14341~14356、14342~14357、14343~14358、14344~14359、14345~14360、14346~14361、14347~14362、14398~14413、14400~14415、14401~14416、14403~14418、14404~14419、14405~14420、14406~14421、14408~14423、14409~14424、14410~14425、14412~14427、14443~14458、14479~14494、14480~14495、14482~14497、14504~14519、14507~14522、14508~14523、14509~14524、14510~14525、14511~14526、14512~14527、14513~14528、14514~14529、14515~14530、14515~14532、14515~14534、14516~14531、14516~14532、14516~14533、14517~14532、14517~14533、14518~14531、14519~14534、14520~14535、14522~14537、14534~14549、14535~14550、14553~14568、14569~14584、14570~14585、14571~14586、14573~14588、14601~14616、14602~14617、14603~14618、14605~14620、14606~14621、14607~14622、14608~14623、14609~14624、14610~14625、14611~14626、14612~14627、14613~14628、14614~14629、14615~14630、14616~14631、14655~14670、14656~14671、14658~14673、14659~14674、14681~14696、14683~14698、14684~14699、14684~14701、14684~14703、14685~14700、14685~14701、14685~14702、14686~14701、14686~14702、14687~14702、14687~14700、14688~14703、14689~14704、14691~14706、14692~14707、14696~14711、14703~14718、14704~14719、14705~14720、14706~14721、14707~14722、14708~14723、14709~14724、14710~14725、14711~14726、14712~14727、14713~14728、14714~14729、14759~14774、14760~14775、14761~14776、14762~14777、14763~14778、14764~14779、14765~14780、14766~14781、14767~14782、14768~14783、14769~14784、14770~14785、14771~14786、14772~14787、14773~14788、14774~14789、14775~14790、14776~14791、14779~14794、14787~14802、14792~14807、14793~14808、14794~14809、14797~14812、14798~14813、14800~14815、14818~14833、14822~14837、14823~14838、14824~14839、14825~14840、14826~14841、14827~14842、14828~14843、14829~14844、14830~14845、14831~14846、14832~14847、14833~14848、14834~14849、14835~14850、14841~14856、14842~14857、14843~14858、14844~14859、14845~14860、14846~14861、14847~14862、14848~14863、14849~14864、14850~14865、14851~14866、14852~14867、14853~14868、14855~14870、14856~14871、14857~14872、14858~14873、14859~14874、14861~14876、14862~14877、14863~14878、14864~14879、14866~14881、14877~14892、14878~14893、14880~14895、14881~14896、14889~14904、14898~14913、14899~14914、14901~14916、14903~14918、14904~14919、14905~14920、14906~14921、14913~14928、14915~14930、14916~14931、14917~14932、14918~14933、14919~14934、14921~14936、14922~14937、14923~14938、14924~14939、14925~14940、14926~14941、14927~14942、14928~14943、14929~14944、14930~14945、14931~14946、14932~14947、14933~14948、14934~14949、14935~14950、14936~14951、14937~14952、14938~14953、14938~14955、14938~14957、14939~14954、14939~14955、14939~14956、14939~14958、14940~14955、14940~14956、14940~14957、14940~14959、14941~14956、14941~14954、14941~14957、14941~14958、14941~14960、14942~14957、14942~14955、14942~14958、14942~14959、14942~14961、14943~14958、14943~14956、14943~14959、14943~14960、14943~14962、14944~14959、14944~14957、14944~14960、14944~14961、14945~14960、14945~14958、14945~14961、14946~14961、14946~14959、14948~14963、14956~14971、14957~14972、14958~14973、14959~14974、14960~14975、14961~14976、14962~14977、14963~14978、14964~14979、14965~14980、14966~14981、14968~14983、14969~14984、14970~14985、14987~15002、14992~15007、14993~15008、14994~15009、14995~15010、14996~15011、15003~15018、15005~15020、15006~15021、15007~15022、15008~15023、15009~15024、15010~15025、15011~15026、15012~15027、15013~15028、15014~15029、15015~15030、15016~15031、15017~15032、15019~15034、15142~15157、15143~15158、15150~15165、15151~15166、15152~15167、15153~15168、15154~15169、15155~15170、15156~15171、15157~15172、15158~15173、15159~15174、15160~15175、15161~15176、15162~15177、15163~15178、15164~15179、15182~15197、15184~15199、15185~15200、15186~15201、15195~15210、15197~15212、15198~15213、15199~15214、15200~15215、15201~15216、15202~15217、15203~15218、15204~15219、15205~15220、15206~15221、15207~15222、15208~15223、15209~15224、15210~15225、15211~15226、15214~15229、15215~15230、15216~15231、15217~15232、15218~15233、15219~15234、15220~15235、15221~15236、15222~15237、15222~15239、15222~15241、15223~15238、15223~15239、15223~15240、15224~15239、15224~15240、15225~15240、 15225~15238、15227~15242、15228~15243、15229~15244、15230~15245、15231~15246、15232~15247、15233~15248、15234~15249、15235~15250、15236~15251、15237~15252、15238~15253、15239~15254、15247~15262、15248~15263、15249~15264、15250~15265、15251~15266、15252~15267、15253~15268、15254~15269、15255~15270、15256~15271、15257~15272、15258~15273、15259~15274、15260~15275、15261~15276、15293~15308、15299~15314、15301~15316、15302~15317、15303~15318、15304~15319、15305~15320、15320~15335、15321~15336、15323~15338、15411~15426、15414~15429、15415~15430、15416~15431、15417~15432、15496~15511、15501~15516、15504~15519、15505~15520、15506~15521、15507~15522、15508~15523、15509~15524、15510~15525、15511~15526、15512~15527、15513~15528、15515~15530、15556~15571、15558~15573、15559~15574、15560~15575、15562~15577、15569~15584、15571~15586、15574~15589、15593~15608、15594~15609、15595~15610、15596~15611、15598~15613、15599~15614、15600~15615、15601~15616、15602~15617、15603~15618、15604~15619、15605~15620、15627~15642、15629~15644、15630~15645、15631~15646、15632~15647、15633~15648、15635~15650、15636~15651、15639~15654、15640~15655、15641~15656、15642~15657、15658~15673、15659~15674、15660~15675、15661~15676、15665~15680、15666~15681、15667~15682、15668~15683、15671~15686、15673~15688、15674~15689、15675~15690、15681~15696、15682~15697、15683~15698、15684~15699、15685~15700、15686~15701、15687~15702、15740~15755、15741~15756、15753~15768、15757~15772、15758~15773、15761~15776、15762~15777、15763~15778、15765~15780、15788~15803、15812~15827、15813~15828、15814~15829、15815~15830、15816~15831、15826~15841、15827~15842、15833~15848、15858~15873、15861~15876、15863~15878、15864~15879、15865~15880、15866~15881、15867~15882、15868~15883、15869~15884、15870~15885、15871~15886、15872~15887、15873~15888、15874~15889、15875~15890、15876~15891、15877~15892、15878~15893、15882~15897、15883~15898、15910~15925、15911~15926、15912~15927、15913~15928、15914~15929、15943~15958、15947~15962、15949~15964、15950~15965、15951~15966、15955~15970、15973~15988、15974~15989、15979~15994、15980~15995、16000~16015、16008~16023、16010~16025、16026~16041、16027~16042、16030~16045, 16032~16047, 16034~16049, 16036~16051, 16037~16052, 16038~16053, 16039~16054, 16056~16071, 16057~16072, 16080~16095, 16117~16132, 16118~16133, 16216~16231, 16248~16263, 16265~16280, 16266~16281, 16268~16283, 16269~16284, 16273~ At least 80% complementary to an isometric portion within 16288, 16300 to 16315, 16305 to 16320, 16306 to 16321, 16327 to 16342, 16329 to 16344, 16422 to 16437, 16427 to 16442, 16428 to 16443, 16550 to 16565, 16557 to 16572, 16564 to 16579, 16569 to 16584, 16582 to 16597, 16592 to 16607, 16617 to 16632, or 16676 to 16691.

[0249] In certain embodiments, the nucleobase sequence of the modified oligonucleotide is at least 80% complementary to an isometric portion within nucleobases 3341-3368, 4516-4533, 5498-5517, 14337-14357, 14569-14588, 14607-14631, 14683-14703, 14828-14848, 14939-14958, 15222-15243, or 15251-15273 of SEQ ID NO:2. In certain embodiments, the nucleobase sequence of the modified oligonucleotide is at least 80% complementary to an equal-length portion within nucleobases 5499-5514, 5500-5515, 5501-5516, 14686-14701, 14941-14956, 14942-14957, or 15224-15239 of SEQ ID NO: 2. In certain embodiments, the nucleobase sequence of the modified oligonucleotide is at least 85%, at least 90%, at least 95%, or 100% complementary to an equal-length portion of the PLN nucleic acid.

[0250] In certain embodiments, oligomeric compounds are provided comprising a modified oligonucleotide consisting of 8 to 80 linked nucleosides, wherein the nucleobase sequence of the modified oligonucleotide comprises at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, or at least 16 consecutive nucleobases of any of the nucleobase sequences of SEQ ID NOs: 15-1712.

[0251] In certain embodiments, oligomeric compounds are provided comprising a modified oligonucleotide consisting of 16 to 80 linked nucleosides, wherein the nucleobase sequence of the modified oligonucleotide comprises the nucleobase sequence of any of the nucleobase sequences of SEQ ID NOs: 15-1712.

[0252] In certain embodiments, oligomeric compounds are provided comprising a modified oligonucleotide consisting of 16 linked nucleosides, the modified oligonucleotide having a nucleobase sequence consisting of any of the nucleobase sequences of SEQ ID NOs: 15-1712.

[0253] In certain embodiments, oligomeric compounds are provided comprising a modified oligonucleotide consisting of 16 to 80 linked nucleosides, wherein the nucleobase sequence of the modified oligonucleotide comprises at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, or at least 16 consecutive nucleobases of any of the nucleobase sequences of SEQ ID NOs: 45, 120, 185, 609, 675, 737, or 752.

[0254] In certain embodiments, oligomeric compounds are provided comprising a modified oligonucleotide consisting of 16 to 80 linked nucleosides, wherein the nucleobase sequence of the modified oligonucleotide comprises any of the nucleobase sequences of SEQ ID NOs: 45, 120, 185, 609, 675, 737, or 752.

[0255] In certain embodiments, oligomeric compounds are provided comprising a modified oligonucleotide consisting of 16 linked nucleosides, wherein the modified oligonucleotide has a nucleobase sequence consisting of any of the nucleobase sequences of SEQ ID NOs: 45, 120, 185, 609, 675, 737, or 752.

[0256] In any of the oligomeric compounds provided herein, the nucleobase sequence of the modified oligonucleotide may be at least 85%, at least 90%, at least 95%, or 100% complementary to an equal-length portion of a PLN nucleic acid, wherein the PLN nucleic acid has the nucleobase sequence of SEQ ID NO: 1 or 2.

[0257] In any of the oligomeric compounds provided herein, the modified oligonucleotides may be 10-25, 10-30, 10-50, 12-20, 12-25, 12-30, 12-50, 13-20, 13-25, 13-30, 13-50, 14-20, 14-25, 14-30, 14-50, 15-20, 15-25, 15-30, 15-50, 16-18, 16-20, 16-25, 16-50, 16-60, 16-70, 16-80, 16-90, 16-110, 16-120, 16-130, 16-140, 16-150, 16-160, 16-20, 16-25, 16-260, 16-30, 16-40, 16-50, 16-60, 16-70, 16-80, 16-90, 16-170, 16-180, 16-190, 16-210, 16-220, 16-230, 16-240, 16-250, 16-310, 16-320, 16-330, 16-340, 16-350, 16-410, 16-420, 16-430, 16-440, 16-450, 16-510, 16-520, 16-530, 16-640, 16-650, 1 20-25, 20-30, 20-50, 21-25, 21-30, 21-50, 22-25, 22-30, 22-50, 23-25, 23-30, or 23-50 linked nucleosides.

[0258] In any of the oligomeric compounds provided herein, at least one nucleoside of the modified oligonucleotide can comprise a modified sugar moiety. In certain embodiments, the modified sugar moiety comprises a bicyclic sugar moiety, e.g., a 2'-4' bridge selected from -O-CH2- and -O-CH(CH3)-. In certain embodiments, the modified sugar moiety comprises a non-bicyclic modified sugar moiety, e.g., a 2'-MOE sugar moiety or a 2'-OMe sugar moiety.

[0259] In any of the oligomeric compounds provided herein, at least one nucleoside of the modified oligonucleotide compound can comprise a sugar surrogate.

[0260] In any of the oligomeric compounds provided herein, at least one internucleoside bond of the modified oligonucleotide can comprise a modified internucleoside bond, for example, a phosphorothioate internucleoside bond.In certain embodiments, each internucleoside bond of the modified oligonucleotide can be a modified internucleoside bond, or each internucleoside bond of the modified oligonucleotide can be a phosphorothioate internucleoside bond.In certain embodiments, at least one internucleoside bond of the modified oligonucleotide can be a phosphodiester internucleoside bond.In certain embodiments, each internucleoside bond of the modified oligonucleotide can be independently selected from phosphodiester or phosphorothioate internucleoside bond.In certain embodiments, at least 2, at least 3, at least 4, at least 5, or at least 6 internucleoside bonds of the modified oligonucleotide can be phosphodiester internucleoside bond. In certain embodiments, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, or at least 18 internucleoside linkages of the modified oligonucleotide can be phosphorothioate internucleoside linkages.

[0261] In any of the oligomeric compounds provided herein, at least one nucleobase of the modified oligonucleotide can be a modified nucleobase, such as 5-methylcytosine. In certain embodiments, each cytosine is a 5-methylcytosine.

[0262] In any of the oligomeric compounds provided herein, the modified oligonucleotide can comprise a deoxy region consisting of 5 to 12 consecutive 2'-deoxynucleosides. In certain embodiments, each nucleoside in the deoxy region is a 2'-β-D-deoxynucleoside. In certain embodiments, the deoxy region consists of 7, 8, 9, 10, or 7 to 10 linked nucleosides. In certain embodiments, each nucleoside immediately adjacent to the deoxy region comprises a modified sugar moiety. In certain embodiments, the deoxy region is flanked on its 5' side by a 5' region consisting of 1 to 6 linked 5' region nucleosides and on its 3' side by a 3' region consisting of 1 to 6 linked 3' region nucleosides, wherein the 3'-most nucleoside of the 5' region comprises a modified sugar moiety and the 5'-most nucleoside of the 3' region comprises a modified sugar moiety. In certain embodiments, each nucleoside of the 3' region comprises a modified sugar moiety. In certain embodiments, each nucleoside of the 5' region comprises a modified sugar moiety.

[0263] In certain embodiments, a compound comprises or consists of a modified oligonucleotide of 16 to 80 linked nucleobases having a nucleobase sequence comprising a nucleobase sequence set forth in any one of SEQ ID NOs: 185, 609, or 752, wherein the modified oligonucleotide is a gap segment consisting of 10 linked 2'-deoxynucleosides; a 5' wing segment consisting of three linked nucleosides, and having a 3' wing segment consisting of three linked nucleosides; The gap segment is disposed between the 5' wing segment and the 3' wing segment, each nucleoside of each wing segment comprises a cEt nucleoside, each internucleoside linkage is a phosphorothioate linkage, and each cytosine is a 5-methylcytosine. In certain embodiments, the modified oligonucleotide consists of 16 to 30 linked nucleosides. In certain embodiments, the modified oligonucleotide consists of 16 linked nucleosides.

[0264] In certain embodiments, the oligomeric compound comprises a modified oligonucleotide according to the following chemical designation: m C ks m C ks A ks T ds A ds m C ds T ds T ds G ds A ds T ds T ds m C ds T ks m C ks A k (SEQ ID NO: 185), wherein A = adenine nucleobase, m C=5-methylcytosine nucleobase, G = guanine nucleobase; T=thymine nucleobase, k=cEt modified sugar moiety, d=2'-β-D-deoxyribosyl sugar moiety, and s = phosphorothioate internucleoside linkage.

[0265] In certain embodiments, the oligomeric compound comprises a modified oligonucleotide according to the following chemical designation: G ks T ks A ks G ds T ds Tds A ds A ds G ds A ds T ds T ds T ds T ks G ks m C k (SEQ ID NO: 752), wherein: A = adenine nucleobase, m C=5-methylcytosine nucleobase, G = guanine nucleobase; T=thymine nucleobase, k=cEt modified sugar moiety, d=2'-β-D-deoxyribosyl sugar moiety, and s = phosphorothioate internucleoside linkage.

[0266] In certain embodiments, the oligomeric compound comprises a modified oligonucleotide according to the following chemical designation: A ks m C ks A ks m C ds G ds A ds G ds T ds A ds T ds A ds T ds T ds A ks G ks G k (SEQ ID NO: 609), wherein A = adenine nucleobase, m C=5-methylcytosine nucleobase, G = guanine nucleobase; T=thymine nucleobase, k=cEt modified sugar moiety, d=2'-β-D-deoxyribosyl sugar moiety, and s = phosphorothioate internucleoside linkage.

[0267] In certain embodiments, the oligomeric compound comprises a modified oligonucleotide according to the following chemical designation: A ks A ks G ds A ds T ds A ds T ds A ds G ds T ds A ds T ks G es G ks T es A k (SEQ ID NO: 45), wherein A = adenine nucleobase, G = guanine nucleobase; T=thymine nucleobase, e=2'-MOE sugar moiety, k=cEt modified sugar moiety, d=2'-β-D-deoxyribosyl sugar moiety, and s = phosphorothioate internucleoside linkage.

[0268] In certain embodiments, the oligomeric compound comprises a modified oligonucleotide according to the following chemical designation: A ks m C ks G ds A ds G ds T ds A ds T ds A ds T ds T ds A ks G es G ks A es A k (SEQ ID NO: 737), wherein: A = adenine nucleobase, m C=5-methylcytosine nucleobase, G = guanine nucleobase; T=thymine nucleobase, e=2'-MOE sugar moiety, k=cEt modified sugar moiety, d=2'-β-D-deoxyribosyl sugar moiety, and s = phosphorothioate internucleoside linkage.

[0269] In certain embodiments, the oligomeric compound comprises a modified oligonucleotide according to the following chemical designation: A ks A ks A ds G ds A ds T ds A ds T ds A ds G ds T ds A ks T es G ks G es T k (SEQ ID NO: 120), wherein A = adenine nucleobase, G = guanine nucleobase; T=thymine nucleobase, e=2'-MOE sugar moiety, k=cEt modified sugar moiety, d=2'-β-D-deoxyribosyl sugar moiety, and s = phosphorothioate internucleoside linkage.

[0270] In certain embodiments, the oligomeric compound comprises a modified oligonucleotide according to the following chemical designation: m C ks A ks m C ks G ds A ds G ds T ds A ds T ds A ds T ds T ds A ks G ks G ks A e (SEQ ID NO: 675), wherein A = adenine nucleobase, m C=5-methylcytosine nucleobase, G = guanine nucleobase; T=thymine nucleobase, e=2'-MOE sugar moiety, k=cEt modified sugar moiety, d=2'-β-D-deoxyribosyl sugar moiety, and s = phosphorothioate internucleoside linkage.

[0271] In certain embodiments, an oligomeric compound comprises a conjugate group. In certain embodiments, the conjugate group comprises a conjugate linker and a conjugate moiety. In certain embodiments, the conjugate linker consists of a single bond, the conjugate linker is cleavable, the conjugate linker comprises 1 to 3 linker nucleosides, the conjugate linker does not comprise a linker nucleoside, the conjugate group is attached to the modified oligonucleotide at the 5'-end of the modified oligonucleotide, or the conjugate group is attached to the modified oligonucleotide at the 3'-end of the modified oligonucleotide.

[0272] In certain embodiments, the conjugate group comprises a cell targeting moiety having affinity for transferrin receptor (TfR), also known as TfR1, and CD71. In certain embodiments, the conjugate group comprises an anti-TfR1 antibody or a fragment thereof. In certain embodiments, the conjugate group comprises a protein or peptide capable of binding TfR1. In certain embodiments, the conjugate group comprises an aptamer capable of binding TfR1. In certain embodiments, the conjugate group can be selected from any of C22 alkyl, C20 alkyl, C16 alkyl, C10 alkyl, C21 alkyl, C19 alkyl, C18 alkyl, C15 alkyl, C14 alkyl, C13 alkyl, C12 alkyl, C11 alkyl, C9 alkyl, C8 alkyl, C7 alkyl, C6 alkyl, C5 alkyl, C22 alkenyl, C20 alkenyl, C16 alkenyl, C10 alkenyl, C21 alkenyl, C19 alkenyl, C18 alkenyl, C15 alkenyl, C14 alkenyl, C13 alkenyl, C12 alkenyl, C11 alkenyl, C9 alkenyl, C8 alkenyl, C7 alkenyl, C6 alkenyl, or C5 alkenyl. In certain embodiments, the conjugate group may be selected from any of C22 alkyl, C20 alkyl, C16 alkyl, C10 alkyl, C21 alkyl, C19 alkyl, C18 alkyl, C15 alkyl, C14 alkyl, C13 alkyl, C12 alkyl, C11 alkyl, C9 alkyl, C8 alkyl, C7 alkyl, C6 alkyl, and C5 alkyl, whose alkyl chain has one or more unsaturated bonds.

[0273] In certain embodiments, the conjugate group has the following structure: [ka]

[0274] In certain embodiments, the conjugate group is 6-palmitamidohexyl phosphate. In certain embodiments, the oligomeric compound comprises a 6-palmitamidohexyl phosphate conjugate group attached to the 5'-terminal OH of a modified oligonucleotide.

[0275] In certain embodiments, the oligomeric compound comprises a modified oligonucleotide according to the following chemical designation: [C16-HA] o A ks A ks G ds A ds T ds A ds T ds A ds G ds T ds A ds T ks G es G ks T es A k (SEQ ID NO: 45), wherein A = adenine nucleobase, G = guanine nucleobase; T=thymine nucleobase, e=2'-MOE sugar moiety, k=cEt modified sugar moiety, d=2'-β-D-deoxyribosyl sugar moiety, o = phosphodiester internucleoside linkage; s = phosphorothioate internucleoside linkage, and [C16-HA] = [ka] is.

[0276] In certain embodiments, the oligomeric compound comprises a modified oligonucleotide according to the following chemical designation: [C16-HA] o A ks m C ks A ks m C ds Gds A ds G ds T ds A ds T ds A ds T ds T ds A ks G ks G k (SEQ ID NO: 609), wherein A = adenine nucleobase, m C=5-methylcytosine nucleobase, G = guanine nucleobase; T=thymine nucleobase, k=cEt modified sugar moiety, d=2'-β-D-deoxyribosyl sugar moiety, o = phosphodiester internucleoside linkage; s = phosphorothioate internucleoside linkage, and [C16-HA] = [ka] is.

[0277] In certain embodiments, the oligomeric compound comprises a modified oligonucleotide according to the following chemical designation: [C16-HA] o G ks T ks A ks G ds T ds T ds A ds A ds G ds A ds T ds T ds T ds T ks G ks m C k (SEQ ID NO: 752), wherein: A = adenine nucleobase, m C=5-methylcytosine nucleobase, G = guanine nucleobase; T=thymine nucleobase, k=cEt modified sugar moiety, d=2'-β-D-deoxyribosyl sugar moiety, o = phosphodiester internucleoside linkage; s = phosphorothioate internucleoside linkage, and [C16-HA] = [ka] is.

[0278] In certain embodiments, the oligomeric compound comprises a modified oligonucleotide according to the following chemical designation: [C16-HA] o A ks A ks A ds G ds A ds T ds A ds T ds A ds G ds T ds A ks T es G ks G es T k (SEQ ID NO: 120), wherein A = adenine nucleobase, G = guanine nucleobase; T=thymine nucleobase, e=2'-MOE sugar moiety, k=cEt modified sugar moiety, d=2'-β-D-deoxyribosyl sugar moiety, o = phosphodiester internucleoside linkage; s = phosphorothioate internucleoside linkage, and [C16-HA] = [ka] is.

[0279] Certain oligomeric compounds A conjugate group and the following chemical structure: [ka] (SEQ ID NO: 185), or a salt thereof. In certain embodiments, the oligomeric compound is a sodium salt or a potassium salt. In certain embodiments, the conjugate group comprises a cell targeting moiety having affinity for transferrin receptor (TfR), also known as TfR1, and CD71. In certain embodiments, the conjugate group comprises an anti-TfR1 antibody or a fragment thereof. In certain embodiments, the conjugate group comprises a protein or peptide capable of binding TfR1. In certain embodiments, the conjugate group comprises an aptamer capable of binding TfR1.

[0280] A conjugate group and the following chemical structure: [ka] (SEQ ID NO: 752), or a salt thereof. In certain embodiments, the oligomeric compound is a sodium salt or a potassium salt. In certain embodiments, the conjugate group comprises a cell targeting moiety having affinity for transferrin receptor (TfR), also known as TfR1, and CD71. In certain embodiments, the conjugate group comprises an anti-TfR1 antibody or a fragment thereof. In certain embodiments, the conjugate group comprises a protein or peptide capable of binding TfR1. In certain embodiments, the conjugate group comprises an aptamer capable of binding TfR1.

[0281] A conjugate group and the following chemical structure: [ka] (SEQ ID NO: 609), or a salt thereof. In certain embodiments, the oligomeric compound is a sodium salt or a potassium salt. In certain embodiments, the conjugate group comprises a cell targeting moiety having affinity for transferrin receptor (TfR), also known as TfR1, and CD71. In certain embodiments, the conjugate group comprises an anti-TfR1 antibody or a fragment thereof. In certain embodiments, the conjugate group comprises a protein or peptide capable of binding TfR1. In certain embodiments, the conjugate group comprises an aptamer capable of binding TfR1.

[0282] A conjugate group and the following chemical structure: [ka] (SEQ ID NO: 45), or a salt thereof. In certain embodiments, the oligomeric compound is a sodium salt or a potassium salt. In certain embodiments, the conjugate group comprises a cell targeting moiety having affinity for transferrin receptor (TfR), also known as TfR1, and CD71. In certain embodiments, the conjugate group comprises an anti-TfR1 antibody or a fragment thereof. In certain embodiments, the conjugate group comprises a protein or peptide capable of binding TfR1. In certain embodiments, the conjugate group comprises an aptamer capable of binding TfR1.

[0283] A conjugate group and the following chemical structure: [ka] (SEQ ID NO: 737), or a salt thereof. In certain embodiments, the oligomeric compound is a sodium salt or a potassium salt. In certain embodiments, the conjugate group comprises a cell targeting moiety having affinity for transferrin receptor (TfR), also known as TfR1, and CD71. In certain embodiments, the conjugate group comprises an anti-TfR1 antibody or a fragment thereof. In certain embodiments, the conjugate group comprises a protein or peptide capable of binding TfR1. In certain embodiments, the conjugate group comprises an aptamer capable of binding TfR1.

[0284] A conjugate group and the following chemical structure: [ka] (SEQ ID NO: 120), or a salt thereof. In certain embodiments, the oligomeric compound is a sodium salt or a potassium salt. In certain embodiments, the conjugate group comprises a cell-targeting moiety having affinity for transferrin receptor (TfR), also known as TfR1, and CD71. In certain embodiments, the conjugate group comprises an anti-TfR1 antibody or a fragment thereof. In certain embodiments, the conjugate group comprises a protein or peptide capable of binding TfR1. In certain embodiments, the conjugate group comprises an aptamer capable of binding TfR1.

[0285] A conjugate group and the following chemical structure: [ka] (SEQ ID NO: 675), or a salt thereof. In certain embodiments, the oligomeric compound is a sodium salt or a potassium salt. In certain embodiments, the conjugate group comprises a cell targeting moiety having affinity for transferrin receptor (TfR), also known as TfR1, and CD71. In certain embodiments, the conjugate group comprises an anti-TfR1 antibody or a fragment thereof. In certain embodiments, the conjugate group comprises a protein or peptide capable of binding TfR1. In certain embodiments, the conjugate group comprises an aptamer capable of binding TfR1.

[0286] Specific oligomeric duplexes Certain embodiments are directed to oligomeric duplexes comprising a first oligomeric compound and a second oligomeric compound.

[0287] In certain embodiments, the oligomeric duplex comprises: A first oligomeric compound comprising a first modified oligonucleotide consisting of 8 to 80 linked nucleosides, wherein the nucleic acid base sequence of the first modified oligonucleotide is selected from the group consisting of nucleic acid bases 3278 to 3293, 3281 to 3296, 3282 to 3297, 3284 to 3299, 3286 to 3301, 3287 to 3302, 3288 to 3303, 3327 to 3342, 3329 to 3344, 3332 to 3347, 3333 to 3348, 3336 to 3351, 3337 to 3352, 3338 to 3353, 3339 to 3354, 3340 to 3342 of SEQ ID NO: 2. ~3355, 3341~3356, 3343~3358, 3345~3360, 3348~3363, 3349~3364, 3350~3365, 3351~3366, 3352~3367, 3353~3368, 3354~3369, 3355~3370, 3356~337 1, 3357~3372, 3358~3373, 3395~3410, 3396~3411, 3405~3420, 3406~3421, 3408~3423, 3409~3424, 3410~3425, 3412~3427, 3496~3511, 3497~3512, 349 8~3513, 3499~3514, 3598~3613, 3612~3627, 3614~3629, 3615~3630, 3616~3631, 3617~3632, 3618~3633, 3619~3634, 3620~3635, 3622~3637, 3703~37 18, 3704~3719, 3715~3730, 3716~3731, 3723~3738, 3724~3739, 3799~3814, 3801~3816, 3802~3817, 3803~3818, 3804~3819, 3805~3820, 3806~3821, 3 807~3822, 3808~3823, 3809~3824, 3811~3826, 3814~3829, 3815~3830, 3816~3831, 3817~3832, 3821~3836, 3823~3838, 3830~3845, 3831~3846, 3848~ 3863, 3849~3864, 3850~3865, 3851~3866, 3861~3876, 3863~3878, 3864~3879, 3869~3884, 3871~3886, 3976~3991, 3977~3992, 3978~3993, 3980~3995,3981~3996、4116~4131、4159~4174、4204~4219、4207~4222、4208~4223、4209~4224、4210~4225、4211~4226、4212~4227、4214~4229、4221~4236、4231~4246、4232~4247、4233~4248、4234~4249、4235~4250、4236~4251、4238~4253、4252~4267、4253~4268、4266~4281、4348~4363、4349~4364、4350~4365、4367~4382、4373~4388、4374~4389、4375~4390、4510~4525、4511~4526、4513~4528、4515~4530、4516~4531、4517~4532、4518~4533、4519~4534、4530~4545、4537~4552、4539~4554、4540~4555、4541~4556、4542~4557、4543~4558、4544~4559、4545~4560、4562~4577、4614~4629、4617~4632、4619~4634、4620~4635、4621~4636、4622~4637、4623~4638、4624~4639、4638~4653、4640~4655、4641~4656、4642~4657、4643~4658、4665~4680、4672~4687、4693~4708、4694~4709、4695~4710、4696~4711、4697~4712、4750~4765、4751~4766、4752~4767、4753~4768、4774~4789、4802~4817、4804~4819、4805~4820、4806~4821、4807~4822、4823~4838、4825~4840、4826~4841、4828~4843、4860~4875、4862~4877、4869~4884、4872~4887、4874~4889、4878~4893、4881~4896、4883~4898、4884~4899、4942~4957、4943~4958、4945~4960、4946~4961、4957~4972、4958~4973、4960~4975、4961~4976、4964~4979、4965~4980、4966~4981、4968~4983、4969~4984、4971~4986、4972~4987、4974~4989、4984~4999、4985~5000、4987~5002、4988~5003、5024~5039、5127~5142、5133~5148、5134~5149、5158~5173、5159~5174、5160~5175、5163~5178、5294~5309、5341~5356、5359~5374、5394~5409、5399~5414、5400~5415、5401~5416、5402~5417、5404~5419、5411~5426、5413~5428、5414~5429、5415~5430、5416~5431、5417~5432、5418~5433、5419~5434、5421~5436、5427~5442、5428~5443、5489~5504、5494~5509、5495~5510、5497~5512、5498~5513、5498~5515、5498~5517、5499~5514、5499~5515、5499~5516、5499~5518、5500~5515、5500~5516、5500~5517、5501~5516、5501~5514、5501~5517、5502~5517、5502~5515、5503~5518、5504~5519、5505~5520、5506~5521、5511~5526、5532~5547、5533~5548、5534~5549、5547~5562、5557~5572、5558~5573、5559~5574、5560~5575、5562~5577、5563~5578、5565~5580、5599~5614、5673~5688、5674~5689、5675~5690、5676~5691、5677~5692、5678~5693、5679~5694、5694~5709、5695~5710、5696~5711、5697~5712、5698~5713、5774~5789、5827~5842、5845~5860、5847~5862、5848~5863、5850~5865、5851~5866、5855~5870、5859~5874、5924~5939、5925~5940、5926~5941、5927~5942、5929~5944、5930~5945、5931~5946、5932~5947、6008~6023、6009~6024、6039~6054、6053~6068、6054~6069、6055~6070、6059~6074、6066~6081、6069~6084、6070~6085、6076~6091、6092~6107、6098~6113、6112~6127、6114~6129、6117~6132、6118~6133、6119~6134、6124~6139、6125~6140、6126~6141、6147~6162、6154~6169、6155~6170、6156~6171、6157~6172、6176~6191、6177~6192、6185~6200、6186~6201、6187~6202、6188~6203、6202~6217、6209~6224、6243~6258、6249~6264、6267~6282、6268~6283、6274~6289、6275~6290、6291~6306、6338~6353、6352~6367、6353~6368、6354~6369、6365~6380、6366~6381、6368~6383、6369~6384、6403~6418、6405~6420、6406~6421、6407~6422、6408~6423、6409~6424、6410~6425、6411~6426、6413~6428、6468~6483、6471~6486、6502~6517、6546~6561、6554~6569、6555~6570、6556~6571、6557~6572、6569~6584、6574~6589、6575~6590、6576~6591、6577~6592、6578~6593、6579~6594、6644~6659、6646~6661、6647~6662、6664~6679、6665~6680、6666~6681、6667~6682、6676~6691、6677~6692、6746~6761、6804~6819、6806~6821、6825~6840、6826~6841、6827~6842、6828~6843、6831~6846、6833~6848、6834~6849、6875~6890、6877~6892、6879~6894、6880~6895、6881~6896、6893~6908、6896~6911、6898~6913、6899~6914、6900~6915、6901~6916、6903~6918、6904~6919、6906~6921、6907~6922、6908~6923、6920~6935、6921~6936、6922~6937、6923~6938、6927~6942、6928~6943、6930~6945、6937~6952、6939~6954、6940~6955、6941~6956、6942~6957、6943~6958、6944~6959、6945~6960、6947~6962、6965~6980、6966~6981、6967~6982、6968~6983、6972~6987、6975~6990、7029~7044、7042~7057、7047~7062、7050~7065、7073~7088、7082~7097、7083~7098、7102~7117、7106~7121、7107~7122、7108~7123、7120~7135、7122~7137、7123~7138、7124~7139、7125~7140、7126~7141、7128~7143、7129~7144、7130~7145、7131~7146、7279~7294、7280~7295、7282~7297、7283~7298、7284~7299、7285~7300、7286~7301、7287~7302、7320~7335、7341~7356、7342~7357、7344~7359、7353~7368、7354~7369、7356~7371、7357~7372、7358~7373、7359~7374、7360~7375、7361~7376、7362~7377、7377~7392、7378~7393、7392~7407、7393~7408、7411~7426、7425~7440、7436~7451、7457~7472、7458~7473、7459~7474、7460~7475、7461~7476、7463~7478、7464~7479、7470~7485、7516~7531、7518~7533、7519~7534、7520~7535、7521~7536、7522~7537、7546~7561、7548~7563、7553~7568、7554~7569、7555~7570、7556~7571、7558~7573、7560~7575、7561~7576、7562~7577、7563~7578、7564~7579、7565~7580、7566~7581、7568~7583、7587~7602、 7588~7603、7589~7604、7595~7610、7638~7653、7679~7694、7726~7741、7779~7794、7797~7812、7799~7814、7806~7821、7857~7872、7859~7874、7860~7875、7861~7876、7862~7877、7863~7878、7864~7879、7865~7880、7867~7882、7876~7891、7878~7893、7888~7903、7889~7904、7893~7908、7908~7923、7929~7944、7965~7980、7967~7982、7968~7983、8047~8062、8058~8073、8061~8076、8089~8104、8090~8105、8163~8178、8182~8197、8194~8209、8195~8210、8196~8211、8197~8212、8284~8299、8285~8300、8286~8301、8287~8302、8288~8303、8326~8341、8336~8351、8352~8367、8353~8368、8368~8383、8393~8408、8412~8427、8413~8428、8415~8430、8418~8433、8427~8442、8447~8462、8493~8508、8494~8509、8495~8510、8496~8511、8498~8513、8542~8557、8573~8588、8621~8636、8627~8642、8628~8643、8638~8653、8639~8654、8641~8656、8653~8668、8655~8670、8703~8718、8708~8723、8732~8747、8733~8748、8739~8754、8774~8789、8776~8791、8777~8792、8818~8833、8823~8838、8824~8839、8826~8841、8827~8842、8850~8865、8855~8870、8942~8957、8943~8958、8944~8959、8955~8970、8961~8976、8962~8977、8963~8978、8964~8979、9377~9392、9443~9458、9474~9489、9523~9538、9524~9539、9525~9540、9526~9541、9528~9543、9536~9551、9537~9552、9538~9553、9540~9555、9541~9556、9545~9560、9549~9564、9550~9565、9587~9602、9630~9645、9641~9656、9642~9657、9646~9661、9647~9662、9648~9663、9649~9664、9651~9666、9660~9675、9668~9683、9669~9684、9672~9687、9697~9712、9702~9717、9703~9718、9706~9721、9707~9722、9708~9723、9709~9724、9710~9725、9711~9726、9720~9735、9727~9742、9752~9767、9756~9771、9788~9803、9934~9949、9936~9951、9937~9952、9938~9953、9939~9954、9940~9955、10019~10034、10054~10069、10062~10077、10081~10096、10106~10121、10117~10132、10443~10458、10444~10459、10445~10460、10480~10495、10481~10496、10486~10501、10489~10504、10490~10505、10491~10506、10532~10547、10623~10638、10638~10653、10645~10660、10718~10733、10719~10734、10720~10735、10721~10736、10722~10737、10723~10738、10724~10739、10747~10762、10770~10785、11066~11081、11068~11083、11104~11119、11111~11126、11112~11127、11115~11130、11116~11131、11118~11133、11130~11145、11144~11159、11224~11239、11225~11240、11237~11252、11258~11273、11259~11274、11302~11317、11353~11368、11356~11371、11368~11383、11369~11384、11409~11424、11410~11425、11411~11426、11412~11427、11413~11428、11414~11429、11415~11430、11417~11432、11457~11472、11458~11473、11467~11482、11474~11489、11475~11490、11509~11524、11510~11525、11511~11526、11524~11539、11525~11540、11526~11541、11527~11542、11529~11544、11530~11545、11622~11637、11631~11646、11632~11647、11633~11648、11634~11649、11635~11650、11636~11651、11639~11654、11670~11685、11678~11693、11679~11694、11680~11695、11681~11696、11682~11697、11684~11699、11685~11700、11726~11741、11727~11742、11740~11755、11741~11756、11742~11757、11743~11758、11799~11814、11832~11847、11833~11848、11854~11869、11855~11870、11856~11871、11857~11872、11858~11873、11859~11874、11900~11915、11931~11946、11956~11971、11988~12003、11989~12004、11990~12005、11991~12006、11992~12007、11993~12008、11994~12009、11995~12010、11997~12012、11998~12013、11999~12014、12000~12015、12015~12030、12016~12031、12017~12032、12027~12042、12032~12047、12040~12055、12041~12056、12042~12057、12076~12091、12080~12095、12081~12096、12082~12097、12084~12099、12085~12100、12086~12101、12087~12102、12088~12103、12089~12104、12090~12105、12092~12107、12194~12209、12195~12210、12238~12253、12239~12254、12241~12256、12242~12257、12243~12258、12246~12261、12282~12297、12283~12298、12285~12300、12286~12301、12287~12302、12288~12303、12307~12322、12308~12323、12310~12325、12312~12327、12315~12330、12348~12363、12355~12370、12356~12371、12357~12372、12368~12383、12388~12403、12389~12404、12390~12405、12391~12406、12392~12407、12470~12485、12471~12486、12472~12487、12473~12488、12474~12489、12498~12513、12529~12544、12530~12545、12546~12561、12548~12563、12550~12565、12551~12566、12585~12600、12721~12736、12722~12737、12723~12738、12724~12739、12727~12742、12732~12747、12733~12748、12734~12749、12735~12750、12760~12775、12812~12827、12813~12828、12817~12832、12818~12833、12912~12927、12915~12930、12929~12944、12943~12958、12946~12961、13243~13258、13327~13342、13409~13424、13431~13446、13438~13453、13460~13475、13461~13476、13484~13499、13485~13500、13486~13501、13489~13504、13490~13505、13491~13506、13492~13507、13493~13508、13525~13540、13528~13543、13529~13544、13530~13545、13717~13732、13736~13751、13770~13785、13776~13791、13777~13792、13786~13801、13814~13829、13816~13831、13818~13833、13819~13834、13820~13835、13821~13836、13822~13837、13823~13838、13835~13850、13836~13851、13837~13852、13838~13853、13839~13854、13843~13858、13870~13885、13872~13887、13875~13890、13876~13891、13877~13892、13878~13893、13879~13894、13880~13895、13881~13896、13882~13897、13883~13898、13885~13900、13904~13919、13905~13920、13906~13921、13907~13922、13908~13923、13910~13925、13912~13927、13918~13933、13924~13939、13926~13941、13927~13942、13930~13945、13934~13949、13935~13950、13936~13951、13937~13952、13938~13953、13939~13954、13940~13955、13941~13956、13942~13957、13943~13958、13944~13959、13945~13960、13946~13961、13952~13967、13953~13968、13954~13969、13955~13970、13956~13971、13957~13972、13958~13973、13959~13974、13960~13975、13961~13976、13962~13977、13963~13978、13964~13979、13965~13980、13966~13981、13967~13982、13968~13983、13969~13984、13970~13985、13973~13988、13976~13991、14000~14015、14003~14018、14028~14043、14030~14045、14032~14047、14035~14050、14036~14051、14038~14053、14039~14054、14040~14055、14041~14056、14045~14060、 14047~14062、14048~14063、14049~14064、14050~14065、14051~14066、14053~14068、14054~14069、14055~14070、14056~14071、14059~14074、14060~14075、14061~14076、14062~14077、14063~14078、14064~14079、14065~14080、14066~14081、14078~14093、14081~14096、14082~14097、14084~14099、14085~14100、14086~14101、14087~14102、14088~14103、14089~14104、14090~14105、14091~14106、14092~14107、14093~14108、14095~14110、14096~14111、14097~14112、14098~14113、14099~14114、14100~14115、14102~14117、14105~14120、14110~14125、14111~14126、14112~14127、14113~14128、14115~14130、14117~14132、14119~14134、14130~14145、14163~14178、14165~14180、14166~14181、14167~14182、14169~14184、14170~14185、14174~14189、14180~14195、14181~14196、14203~14218、14207~14222、14209~14224、14212~14227、14217~14232、14220~14235、14222~14237、14223~14238、14224~14239、14225~14240、14232~14247、14233~14248、14235~14250、14242~14257、14244~14259、14247~14262、14248~14263、14249~14264、14250~14265、14251~14266、14252~14267、14253~14268、14254~14269、14255~14270、14256~14271、14257~14272、14316~14331、14317~14332、14318~14333、14319~14334、14321~14336、14324~14339、14327~14342、14337~14352、14338~14353、14339~14354、14340~14355、14341~14356、14342~14357、14343~14358、14344~14359、14345~14360、14346~14361、14347~14362、14398~14413、14400~14415、14401~14416、14403~14418、14404~14419、14405~14420、14406~14421、14408~14423、14409~14424、14410~14425、14412~14427、14443~14458、14479~14494、14480~14495、14482~14497、14504~14519、14507~14522、14508~14523、14509~14524、14510~14525、14511~14526、14512~14527、14513~14528、14514~14529、14515~14530、14515~14532、14515~14534、14516~14531、14516~14532、14516~14533、14517~14532、14517~14533、14518~14531、14519~14534、14520~14535、14522~14537、14534~14549、14535~14550、14553~14568、14569~14584、14570~14585、14571~14586、14573~14588、14601~14616、14602~14617、14603~14618、14605~14620、14606~14621、14607~14622、14608~14623、14609~14624、14610~14625、14611~14626、14612~14627、14613~14628、14614~14629、14615~14630、14616~14631、14655~14670、14656~14671、14658~14673、14659~14674、14681~14696、14683~14698、14684~14699、14684~14701、14684~14703、14685~14700、14685~14701、14685~14702、14686~14701、14686~14702、14687~14702、14687~14700、14688~14703、14689~14704、14691~14706、14692~14707、14696~14711、14703~14718、14704~14719、14705~14720、14706~14721、14707~14722、14708~14723、14709~14724、14710~14725、14711~14726、14712~14727、14713~14728、14714~14729、14759~14774、14760~14775、14761~14776、14762~14777、14763~14778、14764~14779、14765~14780、14766~14781、14767~14782、14768~14783、14769~14784、14770~14785、14771~14786、14772~14787、14773~14788、14774~14789、14775~14790、14776~14791、14779~14794、14787~14802、14792~14807、14793~14808、14794~14809、14797~14812、14798~14813、14800~14815、14818~14833、14822~14837、14823~14838、14824~14839、14825~14840、14826~14841、14827~14842、14828~14843、14829~14844、14830~14845、14831~14846、14832~14847、14833~14848、14834~14849、14835~14850、14841~14856、14842~14857、14843~14858、14844~14859、14845~14860、14846~14861、14847~14862、14848~14863、14849~14864、14850~14865、14851~14866、14852~14867、14853~14868、14855~14870、14856~14871、14857~14872、14858~14873、14859~14874、14861~14876、14862~14877、14863~14878、14864~14879、14866~14881、14877~14892、14878~14893、14880~14895、14881~14896、14889~14904、14898~14913、14899~14914、14901~14916、14903~14918、14904~14919、14905~14920、14906~14921、14913~14928、14915~14930、14916~14931、14917~14932、14918~14933、14919~14934、14921~14936、14922~14937、14923~14938、14924~14939、14925~14940、14926~14941、14927~14942、14928~14943、14929~14944、14930~14945、14931~14946、14932~14947、14933~14948、14934~14949、14935~14950、14936~14951、14937~14952、14938~14953、14938~14955、14938~14957、14939~14954、14939~14955、14939~14956、14939~14958、14940~14955、14940~14956、14940~14957、14940~14959、14941~14956、14941~14954、14941~14957、14941~14958、14941~14960、14942~14957、14942~14955、14942~14958、14942~14959、14942~14961、14943~14958、14943~14956、14943~14959、14943~14960、14943~14962、14944~14959、14944~14957、14944~14960、14944~14961、14945~14960、14945~14958、14945~14961、14946~14961、14946~14959、14948~14963、14956~14971、14957~14972、14958~14973、14959~14974、14960~14975、14961~14976、14962~14977、14963~14978、14964~14979、14965~14980、14966~14981、14968~14983、14969~14984、14970~14985、14987~15002、14992~15007、14993~15008、14994~15009、14995~15010、14996~15011、15003~15018、15005~15020、15006~15021、15007~15022、15008~15023、15009~15024、15010~15025、15011~15026、15012~15027、15013~15028、15014~15029、15015~15030、15016~15031、15017~15032、15019~15034、15142~15157、15143~15158、15150~15165、15151~15166、15152~15167、15153~15168、15154~15169、15155~15170、15156~15171、15157~15172、15158~15173、15159~15174、15160~15175、15161~15176、15162~15177、15163~15178、15164~15179、15182~15197、15184~15199、15185~15200、15186~15201、15195~15210、15197~15212、15198~15213、15199~15214、15200~15215、15201~15216、15202~15217、15203~15218、15204~15219、15205~15220、15206~15221、15207~15222、15208~15223、15209~15224、15210~15225、15211~15226、15214~15229、15215~15230、15216~15231、15217~15232、15218~15233、15219~15234、15220~15235、15221~15236、15222~15237、15222~15239、15222~15241、15223~15238、15223~15239、15223~15240、15224~15239、15224~15240、15225~15240、15225~15238、15227~15242、15228~15243、15229~15244、15230~15245、15231~15246、15232~15247、15233~15248、15234~15249、15235~15250、15236~15251、 15237~15252、15238~15253、15239~15254、15247~15262、15248~15263、15249~15264、15250~15265、15251~15266、15252~15267、15253~15268、15254~15269、15255~15270、15256~15271、15257~15272、15258~15273、15259~15274、15260~15275、15261~15276、15293~15308、15299~15314、15301~15316、15302~15317、15303~15318、15304~15319、15305~15320、15320~15335、15321~15336、15323~15338、15411~15426、15414~15429、15415~15430、15416~15431、15417~15432、15496~15511、15501~15516、15504~15519、15505~15520、15506~15521、15507~15522、15508~15523、15509~15524、15510~15525、15511~15526、15512~15527、15513~15528、15515~15530、15556~15571、15558~15573、15559~15574、15560~15575、15562~15577、15569~15584、15571~15586、15574~15589、15593~15608、15594~15609、15595~15610、15596~15611、15598~15613、15599~15614、15600~15615、15601~15616、15602~15617、15603~15618、15604~15619、15605~15620、15627~15642、15629~15644、15630~15645、15631~15646、15632~15647、15633~15648、15635~15650、15636~15651、15639~15654、15640~15655、15641~15656、15642~15657、15658~15673、15659~15674、15660~15675、15661~15676、15665~15680、15666~15681、15667~15682、15668~15683、15671~15686、15673~15688、15674~15689、15675~15690、15681~15696、15682~15697、15683~15698、15684~15699、15685~15700、15686~15701、15687~15702、15740~15755、15741~15756、15753~15768、15757~15772、15758~15773、15761~15776、15762~15777、15763~15778、15765~15780、15788~15803、15812~15827、15813~15828、15814~15829、15815~15830、15816~15831、15826~15841、15827~15842、15833~15848、15858~15873、15861~15876、15863~15878、15864~15879、15865~15880、15866~15881、15867~15882、15868~15883、15869~15884、15870~15885、15871~15886、15872~15887、15873~15888、15874~15889、15875~15890、15876~15891、15877~15892、15878~15893、15882~15897、15883~15898、15910~15925、15911~15926、15912~15927、15913~15928、15914~15929、15943~15958、15947~15962、15949~15964、15950~15965、15951~15966、15955~15970、15973~15988、15974~15989、15979~15994、15980~15995、16000~16015、16008~16023、16010~16025、16026~16041、16027~16042、16030~16045、16032~16047、16034~16049、16036~16051、16037~16052、16038~16053、16039~16054、16056~16071、16057~16072、16080~16095、16117~16132、16118~16133, 16216~16231, 16248~16263, 16265~16280, 16266~16281, 16268~16283, 16269~16284, 16273~16288, 16300~16315, 16305~16320, 16306~16321, 16327~16342, 16329~16344, 16 at least 80% complementary to an equal length portion within 422-16437, 16427-16442, 16428-16443, 16550-16565, 16557-16572, 16564-16579, 16569-16584, 16582-16597, 16592-16607, 16617-16632, or 16676-16691; and A second oligomeric compound comprising a second modified oligonucleotide consisting of 8 to 80 linked nucleosides, wherein the nucleic acid base sequence of the second modified oligonucleotide comprises a complementary region of at least 8 nucleic acid bases that is at least 90% complementary to an equal-length portion of the first modified oligonucleotide.

[0288] In certain embodiments, the oligomeric duplex comprises: a first oligomeric compound comprising a first modified oligonucleotide consisting of 8 to 80 linked nucleosides, wherein the nucleobase sequence of the first modified oligonucleotide is at least 80% complementary to an isometric portion within nucleobases 3341 to 3368, 4516 to 4533, 5498 to 5517, 14337 to 14357, 14569 to 14588, 14607 to 14631, 14683 to 14703, 14828 to 14848, 14939 to 14958, 15222 to 15243, or 15251 to 15273 of SEQ ID NO: 2; and A second oligomeric compound comprising a second modified oligonucleotide consisting of 8 to 80 linked nucleosides, wherein the nucleic acid base sequence of the second modified oligonucleotide comprises a complementary region of at least 8 nucleic acid bases that is at least 90% complementary to an equal-length portion of the first modified oligonucleotide.

[0289] In certain embodiments, the oligomeric duplex comprises: a first oligomeric compound comprising a first modified oligonucleotide consisting of 8 to 80 linked nucleosides, wherein the nucleobase sequence of said first modified oligonucleotide comprises at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, or at least 16 contiguous nucleobases of the nucleobase sequence of any of SEQ ID NOs: 15-1712, wherein each thymine is replaced with uracil; and A second oligomeric compound comprising a second modified oligonucleotide consisting of 8 to 80 linked nucleosides, wherein the nucleic acid base sequence of the second modified oligonucleotide comprises a complementary region of at least 8 nucleic acid bases that is at least 90% complementary to an equal-length portion of the first modified oligonucleotide.

[0290] In certain embodiments, the first oligomeric compound is an antisense compound.In certain embodiments, the first modified oligonucleotide is an antisense oligonucleotide.In certain embodiments, the second oligomeric compound is a sense compound.In certain embodiments, the second modified oligonucleotide is a sense oligonucleotide.

[0291] In certain embodiments, the oligomeric duplex comprises: a first oligomeric compound comprising a first modified oligonucleotide consisting of 14 to 80 linked nucleosides, wherein the nucleobase sequence of the first modified oligonucleotide comprises the nucleobase sequence of any of SEQ ID NOs: 15 to 1712, wherein each thymine is replaced with uracil; and A second oligomeric compound comprising a second modified oligonucleotide consisting of 14 to 80 linked nucleosides, wherein the nucleic acid base sequence of the second modified oligonucleotide comprises a complementary region of at least 16 nucleic acid bases that is at least 90% complementary to an equal-length portion of the first modified oligonucleotide.

[0292] In certain embodiments, the first oligomeric compound is an antisense compound.In certain embodiments, the first modified oligonucleotide is an antisense oligonucleotide.In certain embodiments, the second oligomeric compound is a sense compound.In certain embodiments, the second modified oligonucleotide is a sense oligonucleotide.

[0293] In certain embodiments, the oligomeric duplex comprises: a first oligomeric compound comprising a first modified oligonucleotide consisting of 19 to 29 linked nucleosides, wherein the nucleobase sequence of the first modified oligonucleotide comprises at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 consecutive nucleobases of the nucleobase sequence of any of SEQ ID NOs: 1713-2024; and A second oligomeric compound comprising a second modified oligonucleotide consisting of 15 to 29 linked nucleosides, wherein the nucleic acid base sequence of the second modified oligonucleotide comprises a complementary region of at least 8 nucleic acid bases that is at least 90% complementary to an equal-length portion of the first modified oligonucleotide.

[0294] In certain embodiments, the first oligomeric compound is an antisense compound.In certain embodiments, the first modified oligonucleotide is an antisense oligonucleotide.In certain embodiments, the second oligomeric compound is a sense compound.In certain embodiments, the second modified oligonucleotide is a sense oligonucleotide.

[0295] In certain embodiments, the oligomeric duplex comprises: a first oligomeric compound comprising a first modified oligonucleotide consisting of 19 to 29 linked nucleosides, wherein the nucleobase sequence of the first modified oligonucleotide comprises at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 consecutive nucleobases of the nucleobase sequence of any of SEQ ID NOs: 1713-2024; and A second oligomeric compound comprising a second modified oligonucleotide consisting of 15 to 29 linked nucleosides, wherein the nucleobase sequence of the second modified oligonucleotide comprises at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, or at least 21 consecutive nucleobases of the nucleobase sequence of any of SEQ ID NOs: 2025 to 2336, and the nucleobase sequence of the second modified oligonucleotide is at least 90% complementary to an equal-length portion of the first modified oligonucleotide.

[0296] In certain embodiments, the first oligomeric compound is an antisense compound.In certain embodiments, the first modified oligonucleotide is an antisense oligonucleotide.In certain embodiments, the second oligomeric compound is a sense compound.In certain embodiments, the second modified oligonucleotide is a sense oligonucleotide.

[0297] In certain embodiments, the oligomeric duplex comprises: A first oligomeric compound comprising a first modified oligonucleotide consisting of 23 linked nucleosides, wherein the nucleic acid base sequence of the first modified oligonucleotide consists of any of the nucleic acid base sequences of SEQ ID NOs: 1713 to 2024; and A second oligomeric compound comprising a second modified oligonucleotide consisting of 21 linked nucleosides, wherein the nucleic acid base sequence of the second modified oligonucleotide consists of any of the nucleic acid base sequences of SEQ ID NOs: 2025 to 2336, and the nucleic acid base sequence of the second modified oligonucleotide is at least 90% complementary to an equal-length portion of the first modified oligonucleotide.

[0298] In certain embodiments, the first oligomeric compound is an antisense compound.In certain embodiments, the first modified oligonucleotide is an antisense oligonucleotide.In certain embodiments, the second oligomeric compound is a sense compound.In certain embodiments, the second modified oligonucleotide is a sense oligonucleotide.

[0299] In certain embodiments, the oligomeric duplex comprises a first oligomeric compound comprising a first modified oligonucleotide, wherein the nucleobase sequence of the modified oligonucleotide is selected from the group consisting of nucleobases 34-56, 44-66, 54-76, 64-86, 74-96, 84-106, 94-116, 104-126, 114-136, 124-146, 134-156, 144-166, 154-176, 164-186, 174-196, 184-206, 194-216, 204-226, 214-236, 224-246, 234-256, 244-266, 254-266, 264-276, 274-286, 284-296, 304-316, 314-326, 324-336, 334-346, 344-356, 354-366, 364-376, 374-386, 384-396, 404-416, 424-436, 444-456, 464-476, 484-496, 494-506, 504-516, 514-526, 524-536, 534-546, 544-556, 554-566, 564-576, 574-586, 584-596, 604-616, 614-626, 624-63 54~276, 264~286, 274~296, 284~306, 294~316, 304~326, 314~336, 324~346, 334~356, 344~366, 354~376, 364~386, 374~396, 384~406, 394~416, 404~42 6, 414-436, 424-446, 434-456, 444-466, 454-476, 464-486, 474-496, 484-506, 494-516, 504-526, 514-536, 524-546, 534-556, 544-566, 554-576, 564 ~586, 574~596, 584~606, 594~616, 604~626, 614~636, 624~646, 634~656, 644~666, 654~676, 664~686, 674~696, 684~706, 694~716, 704~726, 714~736, 724~746, 734~756, 744~766, 754~776, 764~786, 774~796, 784~806, 794~816, 804~826, 814~836, 819~841, 834~856, 844~866, 854~876, 864~886, 874~8 96, 884~906, 894~916, 904~926, 914~936, 924~946, 934~956, 944~966, 954~976, 964~986, 974~996, 984~1006, 994~1016, 1004~1026, 1014~1036, 1024 ~1046, 1034~1056, 1044~1066, 1054~1076, 1064~1086, 1074~1096, 1084~1106, 1094~1116, 1104~1126, 1114~1136, 1124~1146, 1134~1156, 1144~1166,1154~1176、1164~1186、1174~1196、1184~1206、1194~1216、1204~1226、1214~1236、1224~1246、1234~1256、1238~1260、1243~1265、1248~1270、1254~1276、1264~1286、1274~1296、1279~1301、1284~1306、1294~1316、1304~1326、1314~1336、1324~1346、1334~1356、1344~1366、1354~1376、1364~1386、1374~1396、1384~1406、1394~1416、1404~1426、1414~1436、1424~1446、1434~1456、1444~1466、1454~1476、1464~1486、1474~1496、1484~1506、1494~1516、1499~1521、1504~1526、1514~1536、1522~1544、1534~1556、1544~1566、1554~1576、1564~1586、1574~1596、1584~1606、1594~1616、1604~1626、1614~1636、1624~1646、1634~1656、1644~1666、1654~1676、1664~1686、1674~1696、1684~1706、1694~1716、1704~1726、1714~1736、1724~1746、1734~1756、1744~1766、1754~1776、1764~1786、1774~1796、1784~1806、1794~1816、1804~1826、1814~1836、1824~1846、1834~1856、1844~1866、1854~1876、1864~1886、1874~1896、1884~1906、1894~1916、1904~1926、1914~1936、1924~1946、1934~1956、1944~1966、1954~1976、1964~1986、1974~1996、1984~2006、1994~2016、2004~2026、2014~2036、2019~2041、2024~2046、2034~2056、2044~2066、2054~2076、2064~2086、2074~2096、2084~2106、2094~2116、2104~2126、2114~2136、2124~2146、2134~2156、2144~2166、2154~2176、2164~2186、2174~2196、2184~2206、2194~2216、2204~2226、2214~2236、2219~2241、2224~2246、2234~2256、2244~2266、2254~2276、2264~2286、2274~2296、2284~2306、2294~2316、2304~2326、2314~2336、2324~2346、2334~2356、2344~2366、2354~2376、2364~2386、2374~2396、2379~2401、2384~2406、2394~2416、2404~2426、2414~2436、2424~2446、2434~2456、2444~2466、2454~2476、2464~2486、2474~2496、2479~2501、2484~2506、2494~2516、2504~2526、2514~2536、2524~2546、2534~2556、2544~2566、2554~2576、2564~2586、2574~2596、2584~2606、2594~2616、2604~2626、2614~2636、2619~2641、2624~2646、2634~2656、2644~2666、2654~2676、2664~2686、2674~2696、2684~2706、2694~2716、2699~2721、2704~2726、2714~2736、2724~2746、2734~2756、2744~2766、2754~2776、2759~2781、2764~2786、2774~2796、2784~2806、2794~2816、2804~2826、2814~2836、2824~2846、2834~2856、2844~2866、2854~2876、2864~2886、2874~2896、2879~2901、2884~2906、2894~2916、2904~2926、2914~2936、2919~2941、2924~2946、2934~2956、2944~2966、2954~2976、2964~2986、2974~2996、2981~3003、2987~3009、Or at least 80% complementary to an isometric portion within 2994 to 3016, e.g., at least 80%, at least 85%, at least 90%, or at least 95%.

[0300] In certain embodiments, the oligomeric duplex comprises a first oligomeric compound comprising a first modified oligonucleotide consisting of 19 to 29 linked nucleosides, and a second oligomeric compound comprising a second modified oligonucleotide consisting of 15 to 29 linked nucleosides, wherein the nucleobase sequences of the first modified oligonucleotide and the second modified oligonucleotide are set forth in the following SEQ ID NOs: 1713 / 2025, 1714 / 2026, 1715 / 2027, 1716 / 2028, 1717 / 2029, 1718 / 2030, 1719 / 2031, 1720 / 2032, 1721 / 2033, 1722 / 2034, 1723 / 2035, 1724 / 2036, 1725 / 2037, 1726 / 2038, 1727 / 2039, 1728 / 2040, 1729 / 2041, 1730 / 2042, 1731 / 2043 3, 1732 / 2044, 1733 / 2045, 1734 / 2046, 1735 / 2047, 1736 / 2048, 1737 / 2049, 1738 / 2050, 1739 / 2051, 1740 / 2052, 1741 / 2053, 1742 / 2054, 1743 / 2055, 1744 4 / 2056, 1745 / 2057, 1746 / 2058, 1747 / 2059, 1748 / 2060, 1749 / 2061, 1750 / 2062, 1751 / 2063, 1752 / 2064, 1753 / 2065, 1754 / 2066, 1755 / 2067, 1756 / 2068, 1757 / 2069, 1758 / 2070, 1759 / 2071, 1760 / 2072, 1761 / 2073, 1762 / 2074, 1763 / 2075, 1764 / 2076, 1765 / 2077, 1766 / 2078, 1767 68, 1757 / 2069, 1758 / 2070, 1759 / 2071, 1760 / 2072, 1761 / 2073, 1762 / 2074, 1763 / 2075, 1764 / 2076, 1765 / 2077, 1766 / 2078, 1767 / 2079, 1768 / 2080, 1 769 / 2081, 1770 / 2082, 1771 / 2083, 1772 / 2084, 1773 / 2085, 1774 / 2086, 1775 / 2087, 1776 / 2088, 1777 / 2089, 1778 / 2090, 1779 / 2091, 1780 / 2092, 1781 / 2093, 1782 / 2094, 1783 / 2095, 1784 / 2096, 1785 / 2097, 1786 / 2098, 1787 / 2099, 1788 / 2100, 1789 / 2101, 1790 / 2102, 1791 / 2103, 1792 / 2104, 1793 / 2105,1794 / 2106、1795 / 2107、1796 / 2108、1797 / 2109、1798 / 2110、1799 / 2111、1800 / 2112、1801 / 2113、1802 / 2114、1803 / 2115、1804 / 2116、1805 / 2117、1806 / 2118、1807 / 2119、1808 / 2120、1809 / 2121、1810 / 2122、1811 / 2123、1812 / 2124、1813 / 2125、1814 / 2126、1815 / 2127、1816 / 2128、1817 / 2129、1818 / 2130、1819 / 2131、1820 / 2132、1821 / 2133、1822 / 2134、1823 / 2135、1824 / 2136、1825 / 2137、1826 / 2138、1827 / 2139、1828 / 2140、1829 / 2141、1830 / 2142、1831 / 2143、1832 / 2144、1833 / 2145、1834 / 2146、1835 / 2147、1836 / 2148、1837 / 2149、1838 / 2150、1839 / 2151、1840 / 2152、1841 / 2153、1842 / 2154、1843 / 2155、1844 / 2156、1845 / 2157、1846 / 2158、1847 / 2159、1848 / 2160、1849 / 2161、1850 / 2162、1851 / 2163、1852 / 2164、1853 / 2165、1854 / 2166、1855 / 2167、1856 / 2168、1857 / 2169、1858 / 2170、1859 / 2171、1860 / 2172、1861 / 2173、1862 / 2174、1863 / 2175、1864 / 2176、1865 / 2177、1866 / 2178、1867 / 2179、1868 / 2180、1869 / 2181、1870 / 2182、1871 / 2183、1872 / 2184、1873 / 2185、1874 / 2186、1875 / 2187、1876 / 2188、1877 / 2189、1878 / 2190、1879 / 2191、1880 / 2192、1881 / 2193、1882 / 2194、1883 / 2195、1884 / 2196、1885 / 2197、1886 / 2198、1887 / 2199、1888 / 2200、1889 / 2201、1890 / 2202、1891 / 2203、1892 / 2204、1893 / 2205、1894 / 2206、1895 / 2207、1896 / 2208、1897 / 2209、1898 / 2210、1899 / 2211、1900 / 2212、1901 / 2213、1902 / 2214、1903 / 2215、1904 / 2216、1905 / 2217、1906 / 2218、1907 / 2219、1908 / 2220、1909 / 2221、1910 / 2222、1911 / 2223、1912 / 2224、1913 / 2225、1914 / 2226、1915 / 2227、1916 / 2228、1917 / 2229、1918 / 2230、1919 / 2231、1920 / 2232、1921 / 2233、1922 / 2234、1923 / 2235、1924 / 2236、1925 / 2237、1926 / 2238、1927 / 2239、1928 / 2240、1929 / 2241、1930 / 2242、1931 / 2243、1932 / 2244、1933 / 2245、1934 / 2246、1935 / 2247、1936 / 2248、1937 / 2249、1938 / 2250、1939 / 2251、1940 / 2252、1941 / 2253、1942 / 2254、1943 / 2255、1944 / 2256、1945 / 2257、1946 / 2258、1947 / 2259、1948 / 2260、1949 / 2261、1950 / 2262、1951 / 2263、1952 / 2264、1953 / 2265、1954 / 2266、1955 / 2267、1956 / 2268、1957 / 2269、1958 / 2270、1959 / 2271、1960 / 2272、1961 / 2273、1962 / 2274、1963 / 2275、1964 / 2276、1965 / 2277、1966 / 2278、1967 / 2279、1968 / 2280、1969 / 2281、1970 / 2282、1971 / 2283、1972 / 2284、1973 / 2285、1974 / 2286、1975 / 2287、1976 / 2288、1977 / 2289、1978 / 2290、1979 / 2291、1980 / 2292、1981 / 2293、1982 / 2294、1983 / 2295、1984 / 2296、1985 / 2297、1986 / 2298、1987 / 2299、1988 / 2300、1989 / 2301、1990 / 2302、1991 / 2303、1992 / 2304、1993 / 2305、1994 / 2306, 1995 / 2307, 1996 / 2308, 1997 / 2309, 1998 / 2310, 1999 / 2311, 2000 / 2312, 2001 / 2313, 2002 / 2314, 2003 / 2315, 2004 / 2316, 2005 / 2317, 2006 / 2318, 2007 / 2319, 2008 / 2320, 2009 / 2321, 2010 / 2322, 2011 / 2323, 2012 / 2324, 2013 / 2325, 2014 / 2326, 2015 / 2327, 2016 / 2328, 2017 / 2329, 2018 / 2330, 2019 / 2331, 2020 / 2332, 2021 / 2333, 2022 / 2334, 2023 / 2335, 2024 / 2336, 2025 / 2337, 2026 / 2338, 2027 / 2339, 2028 / 2340, 2029 / 2351, 2030 / 2341, 2031 / 2342, 2032 / 2343, 2033 / 2344, 2034 / 2345, 2035 / 2346, 2036 / 2347, 2037 / 2348, 2038 / 2349, 2039 / 2350, 2040 8 / 2320, 2009 / 2321, 2010 / 2322, 2011 / 2323, 2012 / 2324, 2013 / 2325, 2014 / 2326, 2015 / 2327, 2016 / 2328, 2017 / 2329, 2018 / 2330, 2019 / 2331, 2020 / 2332, 2021 / 2333, 2022 / 2334 The modified oligonucleotide may comprise at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 consecutive nucleobases of any of the pairs of nucleobase sequences listed in SEQ ID NO: 34, 2023 / 2335, or 2024 / 2336, wherein the nucleobase sequence of the first modified oligonucleotide comprises the nucleobase sequence of the first SEQ ID NO: listed in the pair, and the nucleobase sequence of the second modified oligonucleotide comprises the nucleobase sequence of the second SEQ ID NO: listed in the pair. In certain embodiments, the first oligomeric compound is an antisense compound. In certain embodiments, the first modified oligonucleotide is an antisense oligonucleotide. In certain embodiments, the second oligomeric compound is a sense compound. In certain embodiments, the second modified oligonucleotide is a sense oligonucleotide.

[0301] In certain embodiments, the oligomeric duplex comprises a first oligomeric compound comprising a first modified oligonucleotide consisting of 19 to 29 linked nucleosides and a second oligomeric compound comprising a second modified oligonucleotide consisting of 15 to 29 linked nucleosides, wherein the nucleobase sequences of the first modified oligonucleotide and the second modified oligonucleotide are set forth in the following SEQ ID NOs: 1713 / 2025, 1714 / 2026, 1715 / 2027, 1716 / 2028, 1717 / 2029, 1718 / 2030, 1719 / 2031, 1720 / 2032, 1721 / 2033, 1722 / 2034, 1723 / 2035, 1724 / 2036, 1725 / 2037, 1726 / 2038, 1727 / 2039, 1728 / 2040, 1729 / 2041, 1730 / 2042, 1731 / 2043, 1732 / 2044 4, 1733 / 2045, 1734 / 2046, 1735 / 2047, 1736 / 2048, 1737 / 2049, 1738 / 2050, 1739 / 2051, 1740 / 2052, 1741 / 2053, 1742 / 2054, 1743 / 2055, 1744 / 2056, 174 5 / 2057, 1746 / 2058, 1747 / 2059, 1748 / 2060, 1749 / 2061, 1750 / 2062, 1751 / 2063, 1752 / 2064, 1753 / 2065, 1754 / 2066, 1755 / 2067, 1756 / 2068, 1757 / 2069 69, 1758 / 2070, 1759 / 2071, 1760 / 2072, 1761 / 2073, 1762 / 2074, 1763 / 2075, 1764 / 2076, 1765 / 2077, 1766 / 2078, 1767 / 2079, 1768 / 2080, 1769 / 2081, 1 770 / 2082, 1771 / 2083, 1772 / 2084, 1773 / 2085, 1774 / 2086, 1775 / 2087, 1776 / 2088, 1777 / 2089, 1778 / 2090, 1779 / 2091, 1780 / 2092, 1781 / 2093, 1782 / 2094, 1783 / 2095, 1784 / 2096, 1785 / 2097, 1786 / 2098, 1787 / 2099, 1788 / 2100, 1789 / 2101, 1790 / 2102, 1791 / 2103, 1792 / 2104, 1793 / 2105, 1794 / 2106,1795 / 2107、1796 / 2108、1797 / 2109、1798 / 2110、1799 / 2111、1800 / 2112、1801 / 2113、1802 / 2114、1803 / 2115、1804 / 2116、1805 / 2117、1806 / 2118、1807 / 2119、1808 / 2120、1809 / 2121、1810 / 2122、1811 / 2123、1812 / 2124、1813 / 2125、1814 / 2126、1815 / 2127、1816 / 2128、1817 / 2129、1818 / 2130、1819 / 2131、1820 / 2132、1821 / 2133、1822 / 2134、1823 / 2135、1824 / 2136、1825 / 2137、1826 / 2138、1827 / 2139、1828 / 2140、1829 / 2141、1830 / 2142、1831 / 2143、1832 / 2144、1833 / 2145、1834 / 2146、1835 / 2147、1836 / 2148、1837 / 2149、1838 / 2150、1839 / 2151、1840 / 2152、1841 / 2153、1842 / 2154、1843 / 2155、1844 / 2156、1845 / 2157、1846 / 2158、1847 / 2159、1848 / 2160、1849 / 2161、1850 / 2162、1851 / 2163、1852 / 2164、1853 / 2165、1854 / 2166、1855 / 2167、1856 / 2168、1857 / 2169、1858 / 2170、1859 / 2171、1860 / 2172、1861 / 2173、1862 / 2174、1863 / 2175、1864 / 2176、1865 / 2177、1866 / 2178、1867 / 2179、1868 / 2180、1869 / 2181、1870 / 2182、1871 / 2183、1872 / 2184、1873 / 2185、1874 / 2186、1875 / 2187、1876 / 2188、1877 / 2189、1878 / 2190、1879 / 2191、1880 / 2192、1881 / 2193、1882 / 2194、1883 / 2195、1884 / 2196、1885 / 2197、1886 / 2198、1887 / 2199、1888 / 2200、1889 / 2201、1890 / 2202、1891 / 2203、1892 / 2204、1893 / 2205、1894 / 2206、1895 / 2207、1896 / 2208、1897 / 2209、1898 / 2210、1899 / 2211、1900 / 2212、1901 / 2213、1902 / 2214、1903 / 2215、1904 / 2216、1905 / 2217、1906 / 2218、1907 / 2219、1908 / 2220、1909 / 2221、1910 / 2222、1911 / 2223、1912 / 2224、1913 / 2225、1914 / 2226、1915 / 2227、1916 / 2228、1917 / 2229、1918 / 2230、1919 / 2231、1920 / 2232、1921 / 2233、1922 / 2234、1923 / 2235、1924 / 2236、1925 / 2237、1926 / 2238、1927 / 2239、1928 / 2240、1929 / 2241、1930 / 2242、1931 / 2243、1932 / 2244、1933 / 2245、1934 / 2246、1935 / 2247、1936 / 2248、1937 / 2249、1938 / 2250、1939 / 2251、1940 / 2252、1941 / 2253、1942 / 2254、1943 / 2255、1944 / 2256、1945 / 2257、1946 / 2258、1947 / 2259、1948 / 2260、1949 / 2261、1950 / 2262、1951 / 2263、1952 / 2264、1953 / 2265、1954 / 2266、1955 / 2267、1956 / 2268、1957 / 2269、1958 / 2270、1959 / 2271、1960 / 2272、1961 / 2273、1962 / 2274、1963 / 2275、1964 / 2276、1965 / 2277、1966 / 2278、1967 / 2279、1968 / 2280、1969 / 2281、1970 / 2282、1971 / 2283、1972 / 2284、1973 / 2285、1974 / 2286、1975 / 2287、1976 / 2288、1977 / 2289、1978 / 2290、1979 / 2291、1980 / 2292、1981 / 2293、1982 / 2294、1983 / 2295、1984 / 2296、1985 / 2297、1986 / 2298、1987 / 2299、1988 / 2300、1989 / 2301、1990 / 2302、1991 / 2303、1992 / 2304、1993 / 2305、1994 / 2306、1995 / 2307, 1996 / 2308, 1997 / 2309, 1998 / 2310, 1999 / 2311, 2000 / 2312, 2001 / 2313, 2002 / 2314, 2003 / 2315, 2004 / 2316, 2005 / 2317, 2006 / 2318, 2007 / 2319, 2008 / 2320, 2009 / 2321, 2010 / 2322, 2011 / 2323, 2012 / 2324, 2013 / 2325, 2014 / 2326, 2015 / 2327, 2016 / 2328, 2017 / 2329, 2020 / 2330, 2021 / 2331, 2022 / 2332, 2023 / 2333, 2024 / 2334, 2025 / 2335, 2026 / 2336, 2027 / 2337, 2028 / 2338, 2029 / 2340, 2030 / 2341, 2031 / 2342, 2032 / 2343, 2033 / 2344, 2034 / 2345, 2035 / 2346, 2036 / 2347, 2037 / 2348, 2038 / 2349, 2040 / 2350, 2041 / 2351, 2042 / 2352, 2043 / 2353, 2044 16 / 2328, 2017 / 2329, 2018 / 2330, 2019 / 2331, 2020 / 2332, 2021 / 2333, 2022 / 2334, 2023 / 2335, or 2024 / 2336, wherein the nucleobase sequence of the first modified oligonucleotide comprises the nucleobase sequence of the first SEQ ID NO: listed in the pair, and the nucleobase sequence of the second modified oligonucleotide comprises the nucleobase sequence of the second SEQ ID NO: listed in the pair. In certain embodiments, the first oligomeric compound is an antisense compound. In certain embodiments, the first modified oligonucleotide is an antisense oligonucleotide. In certain embodiments, the second oligomeric compound is a sense compound. In certain embodiments, the second modified oligonucleotide is a sense oligonucleotide.

[0302] In certain embodiments, the oligomeric duplex comprises a first oligomeric compound comprising a first modified oligonucleotide consisting of 23 linked nucleosides and a second oligomeric compound comprising a second modified oligonucleotide consisting of 21 linked nucleosides, wherein the nucleobase sequences of the first modified oligonucleotide and the second modified oligonucleotide are set forth in the following SEQ ID NOs: 1713 / 2025, 1714 / 2026, 1715 / 2027, 1716 / 2028, 1717 / 2029, 1718 / 2030, 1719 / 2031, 1720 / 2032, 1721 / 2033, 1722 / 2034, 1723 / 2035, 1724 / 2036, 1725 / 2037, 1726 / 2038, 1727 / 2039, 1730 / 2040, 1731 / 2041, 1732 / 2042, 1733 / 2043, 1734 / 2044, 1735 / 2045, 1736 / 2046, 1737 / 2047, 1738 / 2048, 1739 / 2050, 1740 / 2051, 1741 / 2052, 1742 / 2053, 1743 / 2054, 1744 / 2055, 1745 / 2056, 1746 / 2057, 1747 / 2058, 1748 / 2059, 1750 / 2060, 1751 / 2061, 1752 / 2062, 1753 / 2063, 1754 721 / 2033, 1722 / 2034, 1723 / 2035, 1724 / 2036, 1725 / 2037, 1726 / 2038, 1727 / 2039, 1728 / 2040, 1729 / 2041, 1730 / 2042, 1731 / 2043, 1732 / 2044, 1733 / 2045 045, 1734 / 2046, 1735 / 2047, 1736 / 2048, 1737 / 2049, 1738 / 2050, 1739 / 2051, 1740 / 2052, 1741 / 2053, 1742 / 2054, 1743 / 2055, 1744 / 2056, 1745 / 2057, 1 746 / 2058, 1747 / 2059, 1748 / 2060, 1749 / 2061, 1750 / 2062, 1751 / 2063, 1752 / 2064, 1753 / 2065, 1754 / 2066, 1755 / 2067, 1756 / 2068, 1757 / 2069, 1758 / 2070, 1759 / 2071, 1760 / 2072, 1761 / 2073, 1762 / 2074, 1763 / 2075, 1764 / 2076, 1765 / 2077, 1766 / 2078, 1767 / 2079, 1768 / 2080, 1769 / 2081, 1770 / 2082, 1771 / 2083, 1772 / 2084, 1773 / 2085, 1774 / 2086, 1775 / 2087, 1776 / 2088, 1777 / 2089, 1778 / 2090, 1779 / 2091, 1780 / 2092, 1781 / 2093, 1782 / 2094, 1783 / 2095, 1784 / 2096, 1785 / 2097, 1786 / 2098, 1787 / 2099, 1788 / 2100, 1789 / 2101, 1790 / 2102, 1791 / 2103, 1792 / 2104, 1793 / 2105, 1794 / 2106, 1795 / 2107,1796 / 2108、1797 / 2109、1798 / 2110、1799 / 2111、1800 / 2112、1801 / 2113、1802 / 2114、1803 / 2115、1804 / 2116、1805 / 2117、1806 / 2118、1807 / 2119、1808 / 2120、1809 / 2121、1810 / 2122、1811 / 2123、1812 / 2124、1813 / 2125、1814 / 2126、1815 / 2127、1816 / 2128、1817 / 2129、1818 / 2130、1819 / 2131、1820 / 2132、1821 / 2133、1822 / 2134、1823 / 2135、1824 / 2136、1825 / 2137、1826 / 2138、1827 / 2139、1828 / 2140、1829 / 2141、1830 / 2142、1831 / 2143、1832 / 2144、1833 / 2145、1834 / 2146、1835 / 2147、1836 / 2148、1837 / 2149、1838 / 2150、1839 / 2151、1840 / 2152、1841 / 2153、1842 / 2154、1843 / 2155、1844 / 2156、1845 / 2157、1846 / 2158、1847 / 2159、1848 / 2160、1849 / 2161、1850 / 2162、1851 / 2163、1852 / 2164、1853 / 2165、1854 / 2166、1855 / 2167、1856 / 2168、1857 / 2169、1858 / 2170、1859 / 2171、1860 / 2172、1861 / 2173、1862 / 2174、1863 / 2175、1864 / 2176、1865 / 2177、1866 / 2178、1867 / 2179、1868 / 2180、1869 / 2181、1870 / 2182、1871 / 2183、1872 / 2184、1873 / 2185、1874 / 2186、1875 / 2187、1876 / 2188、1877 / 2189、1878 / 2190、1879 / 2191、1880 / 2192、1881 / 2193、1882 / 2194、1883 / 2195、1884 / 2196、1885 / 2197、1886 / 2198、1887 / 2199、1888 / 2200、1889 / 2201、1890 / 2202、1891 / 2203、1892 / 2204、1893 / 2205、1894 / 2206、1895 / 2207、1896 / 2208、1897 / 2209、1898 / 2210、1899 / 2211、1900 / 2212、1901 / 2213、1902 / 2214、1903 / 2215、1904 / 2216、1905 / 2217、1906 / 2218、1907 / 2219、1908 / 2220、1909 / 2221、1910 / 2222、1911 / 2223、1912 / 2224、1913 / 2225、1914 / 2226、1915 / 2227、1916 / 2228、1917 / 2229、1918 / 2230、1919 / 2231、1920 / 2232、1921 / 2233、1922 / 2234、1923 / 2235、1924 / 2236、1925 / 2237、1926 / 2238、1927 / 2239、1928 / 2240、1929 / 2241、1930 / 2242、1931 / 2243、1932 / 2244、1933 / 2245、1934 / 2246、1935 / 2247、1936 / 2248、1937 / 2249、1938 / 2250、1939 / 2251、1940 / 2252、1941 / 2253、1942 / 2254、1943 / 2255、1944 / 2256、1945 / 2257、1946 / 2258、1947 / 2259、1948 / 2260、1949 / 2261、1950 / 2262、1951 / 2263、1952 / 2264、1953 / 2265、1954 / 2266、1955 / 2267、1956 / 2268、1957 / 2269、1958 / 2270、1959 / 2271、1960 / 2272、1961 / 2273、1962 / 2274、1963 / 2275、1964 / 2276、1965 / 2277、1966 / 2278、1967 / 2279、1968 / 2280、1969 / 2281、1970 / 2282、1971 / 2283、1972 / 2284、1973 / 2285、1974 / 2286、1975 / 2287、1976 / 2288、1977 / 2289、1978 / 2290、1979 / 2291、1980 / 2292、1981 / 2293、1982 / 2294、1983 / 2295、1984 / 2296、1985 / 2297、1986 / 2298、1987 / 2299、1988 / 2300、1989 / 2301、1990 / 2302、1991 / 2303、1992 / 2304、1993 / 2305、1994 / 2306、1995 / 2307、1996 / 2308, 1997 / 2309, 1998 / 2310, 1999 / 2311, 2000 / 2312, 2001 / 2313, 2002 / 2314, 2003 / 2315, 2004 / 2316, 2005 / 2317, 2006 / 2318, 2007 / 2319, 2008 / 2320, 2009 / 2321, 2010 / 2322, 2011 / 2323, 2012 / 2324, 2013 / 2325, 2014 / 2326, 2015 / 2327, 2016 / 232 8, 2017 / 2329, 2018 / 2330, 2019 / 2331, 2020 / 2332, 2021 / 2333, 2022 / 2334, 2023 / 2335, or 2024 / 2336, wherein the nucleobase sequence of the first modified oligonucleotide comprises the nucleobase sequence of the first SEQ ID NO: listed in the pair, and the nucleobase sequence of the second modified oligonucleotide comprises the nucleobase sequence of the second SEQ ID NO: listed in the pair. In certain embodiments, the first oligomeric compound is an antisense compound. In certain embodiments, the first modified oligonucleotide is an antisense oligonucleotide. In certain embodiments, the second oligomeric compound is a sense compound. In certain embodiments, the second modified oligonucleotide is a sense oligonucleotide.

[0303] In any of the oligomeric duplexes described herein, at least one nucleoside of the first modified oligonucleotide and / or the second modified oligonucleotide can comprise a modified sugar moiety. Examples of suitable modified sugar moieties include, but are not limited to, bicyclic sugar moieties, e.g., a 2'-4' bridge selected from -O-CH2- and -O-CH(CH3)-, and non-bicyclic sugar moieties, e.g., a 2'-MOE sugar moiety, a 2'-F sugar moiety, a 2'-OMe sugar moiety, or a 2'-NMA sugar moiety. In certain embodiments, at least 80%, at least 90%, or 100% of the nucleosides of the first modified oligonucleotide and / or the second modified oligonucleotide comprise a modified sugar moiety selected from 2'-F and 2'-OMe.

[0304] In any of the oligomeric duplexes described herein, at least one nucleoside of the first modified oligonucleotide and / or the second modified oligonucleotide may comprise a sugar surrogate. Examples of suitable sugar surrogates include, but are not limited to, morpholino, peptide nucleic acid (PNA), glycol nucleic acid (GNA), and unlocked nucleic acid (UNA). In certain embodiments, at least one nucleoside of the first modified oligonucleotide comprises a sugar surrogate, which may be a GNA.

[0305] In any of the oligomeric duplexes described herein, at least one internucleoside linkage of the first modified oligonucleotide and / or the second modified oligonucleotide can comprise a modified internucleoside linkage. In certain embodiments, the modified internucleoside linkage is a phosphorothioate internucleoside linkage. In certain embodiments, at least one of the first, second, or third internucleoside linkages from the 5'-end and / or 3'-end of the first modified oligonucleotide comprises a phosphorothioate linkage. In certain embodiments, at least one of the first, second, or third internucleoside linkages from the 5'-end and / or 3'-end of the second modified oligonucleotide comprises a phosphorothioate linkage.

[0306] In any of the oligomeric duplexes described herein, at least one internucleoside linkage of the first modified oligonucleotide and / or the second modified oligonucleotide can comprise a phosphodiester internucleoside linkage. In any of the oligomeric duplexes described herein, at least one internucleoside linkage of the first modified oligonucleotide and / or the second modified oligonucleotide can comprise a mesyl phosphoramidate internucleoside linkage.

[0307] In any of the oligomeric duplexes described herein, each internucleoside linkage of the first modified oligonucleotide and / or the second modified oligonucleotide can be independently selected from a phosphodiester internucleoside linkage or a phosphorothioate internucleoside linkage. In any of the oligomeric duplexes described herein, each internucleoside linkage of the first modified oligonucleotide and / or the second modified oligonucleotide can be independently selected from a phosphodiester internucleoside linkage, a phosphorothioate internucleoside linkage, or a mesyl phosphoramidate internucleoside linkage.

[0308] In any of the oligomeric duplexes described herein, the internucleoside linkage motif of the second modified oligonucleotide can be ssooooooooooooooooooss, where each "o" represents a phosphodiester internucleoside linkage and each "s" represents a phosphorothioate internucleoside linkage.

[0309] In any of the oligomeric duplexes described herein, at least one nucleobase of the first modified oligonucleotide and / or the second modified oligonucleotide can be a modified nucleobase. In certain embodiments, the modified nucleobase is 5-methylcytosine.

[0310] In any of the oligomeric duplexes described herein, the first modified oligonucleotide can comprise a stabilizing phosphate group attached to the 5'-position of the 5'-most nucleoside. In certain embodiments, the stabilizing phosphate group comprises a cyclopropylphosphonate or an (E)-vinylphosphonate.

[0311] In any of the oligomeric duplexes described herein, the first modified oligonucleotide may comprise a conjugate group. In certain embodiments, the conjugate group comprises a conjugate linker and a conjugate moiety. In certain embodiments, the conjugate group is attached to the first modified oligonucleotide at the 5' end of the first modified oligonucleotide. In certain embodiments, the conjugate group is attached to the first modified oligonucleotide at the 3' end of the first modified oligonucleotide. In certain embodiments, the conjugate group comprises N-acetylgalactosamine. In certain embodiments, the conjugate group comprises a cell targeting moiety having affinity for transferrin receptor (TfR), also known as TfR1 and CD71. In certain embodiments, the conjugate group comprises an anti-TfR1 antibody or fragment thereof. In certain embodiments, the conjugate group comprises a protein or peptide capable of binding TfR1. In certain embodiments, the conjugate group comprises an aptamer capable of binding TfR1. In certain embodiments, the conjugate group can be selected from any of C22 alkyl, C20 alkyl, C16 alkyl, C10 alkyl, C21 alkyl, C19 alkyl, C18 alkyl, C15 alkyl, C14 alkyl, C13 alkyl, C12 alkyl, C11 alkyl, C9 alkyl, C8 alkyl, C7 alkyl, C6 alkyl, C5 alkyl, C22 alkenyl, C20 alkenyl, C16 alkenyl, C10 alkenyl, C21 alkenyl, C19 alkenyl, C18 alkenyl, C15 alkenyl, C14 alkenyl, C13 alkenyl, C12 alkenyl, C11 alkenyl, C9 alkenyl, C8 alkenyl, C7 alkenyl, C6 alkenyl, or C5 alkenyl. In certain embodiments, the conjugate group may be selected from any of C22 alkyl, C20 alkyl, C16 alkyl, C10 alkyl, C21 alkyl, C19 alkyl, C18 alkyl, C15 alkyl, C14 alkyl, C13 alkyl, C12 alkyl, C11 alkyl, C9 alkyl, C8 alkyl, C7 alkyl, C6 alkyl, and C5 alkyl, whose alkyl chain has one or more unsaturated bonds.

[0312] In any of the oligomeric duplexes described herein, the second modified oligonucleotide may comprise a conjugate group. In certain embodiments, the conjugate group comprises a conjugate linker and a conjugate moiety. In certain embodiments, the conjugate group is attached to the second modified oligonucleotide at the 5' end of the second modified oligonucleotide. In certain embodiments, the conjugate group is attached to the second modified oligonucleotide at the 3' end of the second modified oligonucleotide. In certain embodiments, the conjugate group comprises N-acetylgalactosamine. In certain embodiments, the conjugate group comprises a cell targeting moiety having affinity for transferrin receptor (TfR), also known as TfR1 and CD71. In certain embodiments, the conjugate group comprises an anti-TfR1 antibody or fragment thereof. In certain embodiments, the conjugate group comprises a protein or peptide capable of binding TfR1. In certain embodiments, the conjugate group comprises an aptamer capable of binding TfR1. In certain embodiments, the conjugate group can be selected from any of C22 alkyl, C20 alkyl, C16 alkyl, C10 alkyl, C21 alkyl, C19 alkyl, C18 alkyl, C15 alkyl, C14 alkyl, C13 alkyl, C12 alkyl, C11 alkyl, C9 alkyl, C8 alkyl, C7 alkyl, C6 alkyl, C5 alkyl, C22 alkenyl, C20 alkenyl, C16 alkenyl, C10 alkenyl, C21 alkenyl, C19 alkenyl, C18 alkenyl, C15 alkenyl, C14 alkenyl, C13 alkenyl, C12 alkenyl, C11 alkenyl, C9 alkenyl, C8 alkenyl, C7 alkenyl, C6 alkenyl, or C5 alkenyl. In certain embodiments, the conjugate group may be selected from any of C22 alkyl, C20 alkyl, C16 alkyl, C10 alkyl, C21 alkyl, C19 alkyl, C18 alkyl, C15 alkyl, C14 alkyl, C13 alkyl, C12 alkyl, C11 alkyl, C9 alkyl, C8 alkyl, C7 alkyl, C6 alkyl, and C5 alkyl, whose alkyl chain has one or more unsaturated bonds.

[0313] In certain embodiments, the antisense agent comprises an antisense compound, which comprises an oligomeric compound or oligomeric duplex described herein. In certain embodiments, the antisense agent, which may comprise an oligomeric compound or oligomeric duplex described herein, is an RNAi agent capable of reducing the amount of PLN nucleic acid by activating RISC / Ago2.

[0314] Certain embodiments provide oligomeric agents comprising two or more oligomeric duplexes. In certain embodiments, the oligomeric agent comprises two or more of any of the oligomeric duplexes described herein. In certain embodiments, the oligomeric agent comprises two or more of the same oligomeric duplexes, which may be any of the oligomeric duplexes described herein. In certain embodiments, the two or more oligomeric duplexes are linked together. In certain embodiments, the two or more oligomeric duplexes are covalently linked together. In certain embodiments, the second modified oligonucleotides of the two or more oligomeric duplexes are covalently linked together. In certain embodiments, the second modified oligonucleotides of the two or more oligomeric duplexes are covalently linked together at their 3' ends. In certain embodiments, the two or more oligomeric duplexes are covalently linked together by a glycol linker, for example, a tetraethylene glycol linker.

[0315] I. Specific Oligonucleotides In certain embodiments, provided herein are oligomeric compounds comprising oligonucleotides composed of linked nucleosides. The oligonucleotides may be unmodified oligonucleotides (RNA or DNA) or modified oligonucleotides. The modified oligonucleotides contain at least one modification relative to unmodified RNA or DNA. That is, the modified oligonucleotides contain at least one modified nucleoside (containing a modified sugar moiety and / or a modified nucleobase) and / or at least one modified internucleoside linkage. Certain modified nucleosides and modified internucleoside linkages suitable for use in modified oligonucleotides are described below.

[0316] A. Certain modified nucleosides Modified nucleosides comprise a modified sugar moiety or a modified nucleobase, or both a modified sugar moiety and a modified nucleobase. In certain embodiments, modified nucleosides comprising the following modified sugar moieties and / or the following modified nucleobases can be incorporated into modified oligonucleotides:

[0317] 1. Specific sugar moieties In certain embodiments, the modified sugar moiety is a non-bicyclic modified sugar moiety. In certain embodiments, the modified sugar moiety is a bicyclic or tricyclic sugar moiety. In certain embodiments, the modified sugar moiety is a sugar surrogate. Such sugar surrogates may contain one or more substitutions that correspond to those of other types of modified sugar moieties.

[0318] In certain embodiments, the modified sugar moiety is a non-bicyclic modified sugar moiety comprising a furanosyl ring bearing one or more substituents, none of which bridges two atoms of the furanosyl ring to form a bicyclic structure. Such non-bridging substituents may be at any position of the furanosyl, including, but not limited to, substituents at the 2', 3', 4', and / or 5' positions. In certain embodiments, one or more non-bridging substituents of a non-bicyclic modified sugar moiety are branched. Examples of suitable 2'-substituents for non-bicyclic modified sugar moieties include, but are not limited to, 2'-F, 2'-OCH3 ("OMe" or "O-methyl"), and 2'-O(CH2)2OCH3 ("MOE" or "O-methoxyethyl"). In certain embodiments, the 2'-substituent is halo, allyl, amino, azido, SH, CN, OCN, CF3, OCF3, O-C1-C 10 Alkoxy, O-C1-C 10 Substituted alkoxy, O-C-C 10 Alkyl, O-C1-C 10 Substituted alkyl, S-alkyl, N(R m )-alkyl, O-alkenyl, S-alkenyl, N(R m )-alkenyl, O-alkynyl, S-alkynyl, N(R m )-alkynyl, O-alkylenyl-O-alkyl, alkynyl, alkaryl, aralkyl, O-alkaryl, O-aralkyl, O(CH2)2SCH3, O(CH2)2ON(R m )(R n ) or OCH2C(=O)-N(R m )(R n ) wherein each R m and R n are independently H, an amino protecting group, or a substituted or unsubstituted C-C 10Examples of suitable 2'-substituted groups include alkyl, -O(CH2)2ON(CH3)2 ("DMAOE"), 2'-OCHOCH2N(CH2)2 ("DMAEOE"), and the 2'-substituted groups described in Cook et al., US Pat. No. 6,531,584, Cook et al., US Pat. No. 5,859,221, and Cook et al., US Pat. No. 6,005,087. Certain embodiments of these 2'-substituted groups may be further substituted with one or more substituents independently selected from hydroxyl, amino, alkoxy, carboxy, benzyl, phenyl, nitro(NO2), thiol, thioalkoxy, thioalkyl, halogen, alkyl, aryl, alkenyl, and alkynyl. In certain embodiments, the non-bicyclic modified sugar moiety comprises a substituent at the 3'-position. Examples of suitable substituents at the 3'-position of the modified sugar moiety include, but are not limited to, alkoxy (e.g., methoxy), alkyl (e.g., methyl, ethyl). In certain embodiments, the non-bicyclic modified sugar moiety comprises a substituent at the 4'-position. Examples of suitable 4' substituents for non-bicyclic modified sugar moieties include, but are not limited to, alkoxy (e.g., methoxy), alkyl, and those described in Manoharan et al., WO 2015 / 106128. Examples of suitable 5' substituents for non-bicyclic modified sugar moieties include, but are not limited to, 5'-methyl (R or S), 5'-vinyl, ethyl, and 5'-methoxy. In certain embodiments, non-bicyclic modified sugar moieties comprise two or more non-bridging sugar substituents, such as, for example, 2'-F-5'-methyl sugar moieties, and the modified sugar moieties and modified nucleosides described in Migawa et al., WO 2008 / 101157 and Rajeev et al., US 2013 / 0203836.

[0319] In certain embodiments, the 2'-substituted non-bicyclic modified nucleoside is selected from the group consisting of F, NH, N, OCF, OCH, O(CH)NH, CHCH=CH, OCHCH=CH, OCHCHOCH, O(CH)SCH, O(CH)ON(R m )(R n), O(CH2)2O(CH2)2N(CH3)2, and N-substituted acetamides (OCH2C(=O)-N(R m )(R n )) wherein R m and R n are independently H, an amino protecting group, or a substituted or unsubstituted C-C 10 It is alkyl.

[0320] In certain embodiments, the 2'-substituted nucleoside non-bicyclic modified nucleoside comprises a sugar moiety comprising a non-bridging 2'-substituent selected from F, OCF3, OCH3, OCH2CHOCH3, O(CH2)2SCH3, O(CH2)2ON(CH3)2, O(CH2)2O(CH2)2N(CH3)2, O(CH2)2ON(CH3)2 ("DMAOE"), OCHOCH2N(CH2)2 ("DMAEOE"), and OCH2C(=O)-N(H)CH3 ("NMA").

[0321] In certain embodiments, 2'-substituted non-bicyclic modified nucleosides comprise a sugar moiety comprising a non-bridging 2'-substituent selected from F, OCH3, and OCH2CH2OCH3.

[0322] In certain embodiments, modified furanosyl sugar moieties and nucleosides incorporating such modified furanosyl sugar moieties are further defined by their isomeric configuration. For example, 2'-deoxyfuranosyl sugar moieties can have seven isomeric configurations other than the naturally occurring β-D-deoxyribosyl configuration. Such modified sugar moieties are described, for example, in WO 2019 / 157531, which is incorporated herein by reference. 2'-modified sugar moieties have an additional stereocenter at the 2'-position relative to the 2'-deoxyfuranosyl sugar moiety. Thus, such sugar moieties can have a total of 16 isomeric configurations. 2'-modified sugar moieties described herein are in the β-D-ribosyl isomeric configuration unless otherwise specified.

[0323] In naturally occurring nucleic acids, sugars are linked to each other at 3' and 5'.In certain embodiments, oligonucleotides comprise one or more nucleosides or sugar moieties linked at alternative positions, for example, at 2', or linked in reverse from 5' to 3'.For example, if linkage is at 2' position, 2'-substituent may be at 3' position instead.

[0324] Certain modified sugar moieties include a substituent bridging two atoms of the furanosyl ring to form a second ring, resulting in a bicyclic sugar moiety. Nucleosides containing such bicyclic sugar moieties are called bicyclic nucleosides (BNAs), locked nucleosides, or conformationally restricted nucleotides (CRNs). Certain such compounds are described in U.S. Patent Publication No. 2013 / 0190383 and PCT Publication No. WO2013 / 036868. In certain such embodiments, the bicyclic sugar moiety includes a bridge between the 4'-furanose ring atom and the 2'-furanose ring atom. In certain such embodiments, the furanose ring is a ribose ring. Examples of such 4' to 2' bridging sugar substituents include 4'-CH2-2', 4'-(CH2)2-2', 4'-(CH2)3-2', 4'-CH2-O-2' ("LNA"), 4'-CH2-S-2', 4'-(CH2)2-O-2' ("ENA"), 4'-CH(CH3)-O-2' (when in the S configuration, referred to as "constrained ethyl" or "cEt"), 4'-CH2-O-CH2-2', 4'-CH2-N(R)-2', 4'-CH(CHOCH3)-O-2' ("constrained MOE" or "cMOE") and analogs thereof (see, e.g., Seth et al., US 7,399,845; Bhat et al., US 7,569,686; Swayze et al., US 7,569,686). al., US 7,741,457, and Swayze et al., US 8,022,193), 4'-C(CH3)(CH3)-O-2' and analogs thereof (see, e.g., Seth et al., US 8,278,283), 4'-CH2-N(OCH3)-2' and analogs thereof (see, e.g., Prakash et al., US 8,278,425), 4'-CH2-ON(CH3)-2' (see, e.g., Allerson et al., US 7,696,345, and Allerson et al., US 8,124,745), 4'-CH2-C(H)(CH3)-2' (see, e.g., Zhou, et al., US 7,696,345, and Allerson et al., US 8,124,745), al., J. Org. Chem., 2009, 74, 118-134), 4'-CH2-C(=CH2)-2' and analogs thereof (see, for example, Seth et al., US Pat. No. 8,278,426), 4'-C(R a R b)-N(R)-O-2',4'-C(R a R b )-ON(R)-2', 4'-CH2-ON(R)-2', and 4'-CH2-N(R)-O-2', wherein each R, R a , and R b are independently H, a protecting group, or C1-C 12 and alkyl (see, for example, Imanishi et al., US Pat. No. 7,427,672).

[0325] In certain embodiments, such 4' and 2' bridges comprise from 1 to 4 linking groups independently selected from -[C(Ra)(Rb)]n-, -[C(Ra)(Rb)]nO-, -C(Ra)=C(Rb)-, C(Ra)=N-, C(=NRa)-, -C(=O)-, -C(=S)-, -O-, -Si(Ra)a-, -S(=O)x-, and N(Ra)-; During the ceremony, x is 0, 1, or 2; n is 1, 2, 3, or 4; Each Ra and Rb is independently H, a protecting group, hydroxyl, C1-C 12 Alkyl, substituted C1-C 12 Alkyl, C2-C 12 Alkenyl, substituted C2-C 12 Alkenyl, C2-C 12 Alkynyl, substituted C2-C 12 Alkynyl, C5-C 20 Aryl, substituted C5-C 20 aryl, heterocyclic radical, substituted heterocyclic radical, heteroaryl, substituted heteroaryl, C5-C7 cycloaliphatic radical, substituted C5-C7 cycloaliphatic radical, halogen, OJ1, NJ1J2, SJ1, N3, COOJ1, acyl (C(=O)-H), substituted acyl, CN, sulfonyl (S(=O)2-J1), or sulfoxyl (S(=O)-J1); Each J1 and J2 is independently H, C1-C 12 Alkyl, substituted C1-C 12 Alkyl, C2-C 12 Alkenyl, substituted C2-C 12Alkenyl, C2-C 12 Alkynyl, substituted C2-C 12 Alkynyl, C5-C 20 Aryl, substituted C5-C 20 Aryl, acyl (C(=O)-H), substituted acyl, heterocyclic radical, substituted heterocyclic radical, C1-C 12 Aminoalkyl, substituted C1-C 12 aminoalkyl, or a protecting group.

[0326] The particle size of the solution was determined by Freier et al.,Nucleic Acids Research,1997,25(22),4429-4443,Albaek et al.,J.Org.Chem.,2006,71,7731-7740,Singh et al.,Chem.Commun.,1998,4,455-456、Koshkin et al al.,Tetrahedron,1998,54,3607-3630;Wahlestedt et al.,Proc.Natl.Acad.Sci.USA,2000,97,5633-5638;Kumar et al.,Bioorg.Med.Chem.Lett.,1998,8,2219-2222;Singh et al al.,J.Org.Chem.,1998,63,10035-10039;Srivastava et al.,J.Am.Chem.Soc.,2007,129,8362-8379;Elayadi et al.,Curr.Opinion Invens.Drugs,2001,2,558-561;Braasch et al al.,Chem.Biol.,2001,8,1-7、Orum et al.,Curr.Opinion Mol.Ther.,2001,3,239-243、Wengel et al.,US7,053,207,Imanishi et al.,US6,268,490,Imanishi et al.US6,770,748,Imanishi et al al.,USRE44,779; Wengel et al.,US6,794,499,Wengel et al.,US6,670,461;Wengel et al.,US7,034,133,Wengel et al.,US8,080,644; al.,US8,153,365、Wengel et al.,US7,572,582、Ramasamy et al.,US6,525,191,Torsten et al.,WO2004 / 106356,Wengel et al.,WO1999 / 014226、Seth et al.,WO2007 / 134181, Seth et al.,US7,547,684, Seth et al.,US7,666,854, Seth et al.,US8,088,746, Seth et al.,US7,750,131, Seth et al.,US8,030,467, Seth et al. al., US8,268,980, Seth et al., US8,546,556, Seth et al., US8,530,640, Migawa et al., US9,012,421, Seth et al., US8,501,805, Allerson et al., US2008 / 0039618, and Migawa et al. al., US2015 / 0191727. In certain embodiments, bicyclic sugar moieties and nucleosides incorporating such bicyclic sugar moieties are further defined by their isomeric configuration. For example, LNA nucleosides (described herein) can be in either the α-L or β-D configuration. [ka]

[0327] Alpha-L-methyleneoxy (4'-CH2-O-2') or alpha-L-LNA bicyclic nucleosides have been incorporated into oligonucleotides that have demonstrated antisense activity (Frieden et al., Nucleic Acids Research, 2003, 21, 6365-6372). The addition of locked nucleic acids to siRNA has been shown to increase the stability of siRNA in serum and reduce off-target effects (Elmen, J. et al., (2005) Nucleic Acids Research 33(1):439-447; Mook, OR. et al., (2007) Mal Cane Ther 6(3):833-843; Grunweller, A. et al., (2003) Nucleic Acids Research 31(12):3185-3193). In this specification, the general term bicyclic nucleoside includes both isomeric configurations. Where positions of particular bicyclic nucleosides (eg, LNA or cEt) are specified in exemplary embodiments herein, they are in the β-D configuration unless otherwise specified.

[0328] In certain embodiments, the modified sugar moiety comprises one or more non-bridging sugar substituents and one or more bridging sugar substituents (eg, 5'-substituted and 4'-2'-bridging sugars).

[0329] In certain embodiments, the modified sugar moiety is a sugar surrogate. In certain such embodiments, the oxygen atom of the sugar moiety is replaced with, for example, a sulfur, carbon, or nitrogen atom. In certain such embodiments, the modified sugar moiety also includes bridging and / or non-bridging substituents as described herein. For example, certain sugar surrogates include a 4'-sulfur atom and substitutions at the 2'-position (see, e.g., Bhat et al., US 7,875,733 and Bhat et al., US 7,939,677) and / or 5'-position.

[0330] In certain embodiments, the sugar surrogate comprises a ring having more than five atoms. For example, in certain embodiments, the sugar surrogate comprises a six-membered tetrahydropyran ("THP"). Such tetrahydropyrans may be further modified or substituted. Nucleosides containing such modified tetrahydropyrans include hexitol nucleic acid ("HNA"), anitol nucleic acid ("ANA"), mannitol nucleic acid ("MNA") (see, e.g., Leumann, CJ. Bioorg. & Med. Chem. 2002, 10, 841-854), fluoroHNA: [ka] ("F-HNA", see, e.g., Swayze et al., US 8,088,904, Swayze et al., US 8,440,803, Swayze et al., US 8,796,437, and Swayze et al., US 9,005,906; F-HNA may also be referred to as F-THP or 3'-fluorotetrahydropyran), and nucleosides including further modified THP compounds having the formula: [ka] wherein, for each of the modified THP nucleosides above, independently: Bx is a nucleobase moiety; T3 and T4 are each independently an internucleoside linking group that connects a modified THP nucleoside to the remainder of the oligonucleotide, or one of T3 and T4 is an internucleoside linking group that connects a modified THP nucleoside to the remainder of the oligonucleotide and the other of T3 and T4 is H, a hydroxyl protecting group, a linked conjugate group, or a 5' or 3' terminal group; q1, q2, q3, q4, q5, q6, and q7 are each independently H, C1-C6 alkyl, substituted C1-C6 alkyl, C2-C6 alkenyl, substituted C2-C6 alkenyl, C2-C6 alkynyl, or substituted C2-C6 alkynyl; Each of R1 and R2 is independently selected from hydrogen, halogen, substituted or unsubstituted alkoxy, NJ1J2, SJ1, N3, OC(=X)J1, OC(=X)NJ1J2, NJ3C(=X)NJ1J2, and CN, where X is O, S, or NJ1, and each J1, J2, and J3 is independently H or C1-C6 alkyl.

[0331] In certain embodiments, modified THP nucleosides are provided wherein q1, q2, q3, q4, q5, q6, and q7 are each H. In certain embodiments, at least one of q1, q2, q3, q4, q5, q6, and q7 is other than H. In certain embodiments, at least one of q1, q2, q3, q4, q5, q6, and q7 is methyl. In certain embodiments, modified THP nucleosides are provided wherein one of R1 and R2 is F. In certain embodiments, R1 is F and R2 is H, in certain embodiments, R1 is methoxy and R2 is H, and in certain embodiments, R1 is methoxyethoxy and R2 is H.

[0332] In certain embodiments, the sugar surrogate comprises a ring having more than five atoms and more than one heteroatom. For example, nucleosides containing morpholino sugar moieties and their use in oligonucleotides have been reported (see, e.g., Braasch et al., Biochemistry, 2002, 41, 4503-4510, and Summerton et al., US 5,698,685, Summerton et al., US 5,166,315, Summerton et al., US 5,185,444, and Summerton et al., US 5,034,506). As used herein, the term "morpholino" refers to a sugar surrogate having the following structure: [ka]

[0333] In certain embodiments, morpholinos may be modified, for example, by adding or altering various substituents from the morpholino structures described above. Such sugar surrogates are referred to herein as "modified morpholinos."

[0334] In certain embodiments, the sugar surrogate comprises an acyclic moiety. Examples of nucleosides and oligonucleotides comprising such acyclic sugar surrogates include, but are not limited to, peptide nucleic acids ("PNAs"), acyclic butyl nucleic acids (see, e.g., Kumar et al., Org. Biomol. Chem., 2013, 11, 5853-5865), and the nucleosides and oligonucleotides described in Manoharan et al., WO2011 / 133876. In certain embodiments, the sugar surrogate comprises an acyclic moiety. Examples of nucleosides and oligonucleotides containing such acyclic sugar surrogates include, but are not limited to, peptide nucleic acids ("PNAs"), acyclic butyl nucleic acids (see, e.g., Kumar et al., Org. Biomol. Chem., 2013, 11, 5853-5865), and the nucleosides and oligonucleotides described in Manoharan et al., US2013 / 130378. Representative U.S. patents that teach the preparation of PNA compounds include, but are not limited to, U.S. Patent Nos. 5,539,082, 5,714,331, and 5,719,262. Additional PNA compounds suitable for use in the oligonucleotides of the invention are described, for example, in Nielsen et al., Science, 1991, 254, 1497-1500.

[0335] In certain embodiments, the sugar surrogate is the "unlocked" sugar structure of a UNA (unlocked nucleic acid) nucleoside. A UNA is an unlocked acyclic nucleic acid in which one of the sugar linkages has been removed to form the unlocked sugar surrogate. Representative U.S. publications that teach the preparation of UNAs include, but are not limited to, U.S. Patent No. 8,314,227, and U.S. Patent Publication Nos. 2013 / 0096289, 2013 / 0011922, and 2011 / 0313020, the entire contents of each of which are incorporated herein by reference.

[0336] In certain embodiments, the sugar surrogate is glycerol, as found in GNA (glycol nucleic acid) nucleosides, shown below: [ka] In the formula, Bx represents any nucleic acid base.

[0337] Many other bicyclic and tricyclic sugars and sugar surrogates are known in the art and can be used in modified nucleosides.

[0338] 2. Certain modified nucleobases In certain embodiments, modified oligonucleotides comprise one or more nucleosides that contain unmodified nucleobases.In certain embodiments, modified oligonucleotides comprise one or more nucleosides that contain modified nucleobases.In certain embodiments, modified oligonucleotides comprise one or more nucleosides that do not contain nucleobases, which are referred to as abasic nucleosides.In certain embodiments, modified oligonucleotides comprise one or more inosine nucleosides (i.e., nucleosides that contain hypoxanthine nucleobases).

[0339] In certain embodiments, the modified nucleobase is selected from 5-substituted pyrimidines, 6-azapyrimidines, alkyl- or alkynyl-substituted pyrimidines, alkyl-substituted purines, and N-2, N-6, and O-6 substituted purines. In certain embodiments, the modified nucleobase is selected from 5-methylcytosine, 2-aminopropyladenine, 5-hydroxymethylcytosine, xanthine, hypoxanthine, 2-aminoadenine, 6-N-methylguanine, 6-N-methyladenine, 2-propyladenine, 2-thiouracil, 2-thiothymine, and 2-thiocytosine, 5-propynyl (—C≡C—CH3) uracil, 5-propynylcytosine, 6-azouracil, 6-azocytosine, 6-azothymine, 5-ribosyluracil (pseudouracil), 4-thiouracil, 8-halo, 8-amino, 8-thiol, 8-thioalkyl, 8-hydroxy and 5-halo-, 8-aza- and other 8-substituted purines, 5-halo, especially 5-bromo, 5-trifluoromethyl, 5-halouracil, and 5-halocytosine, 7-methylguanine, 7-methyladenine, 2-F-adenine, 2-aminoadenine, 7-deazaguanine, 7-deazaadenine, 3-deazaguanine, 3-deazaadenine, 6-N-benzoyladenine, 2-N-isobutyrylguanine, 4-N-benzoylcytosine, 4-N-benzoyluracil, 5-methyl 4-N-benzoylcytosine, 5-methyl 4-N-benzoyluracil, universal bases, hydrophobic bases, promiscuous bases, size-expanded bases, and fluorinated bases. Further modified nucleobases include tricyclic pyrimidines, such as 1,3-diazaphenoxazin-2-one, 1,3-diazaphenothiazin-2-one, and 9-(2-aminoethoxy)-1,3-diazaphenoxazin-2-one (G-clamp).Modified nucleobases can also include those in which the purine or pyrimidine base is replaced with other heterocycles, such as 7-deaza-adenine, 7-deazaguanosine, 2-aminopyridine, and 2-pyridone.Further nucleobases include those disclosed in Merigan et al., US 3,687,808, The Concise Encyclopedia Of Polymer Science And Engineering, Kroschwitz, JI, Ed., John Wiley & Sons, 1990, 858-859, Englisch et al., Angewandte Chemie, International Edition, 1991, 30, 613, Sanghvi, YS, Chapter 15, Antisense Research and Applications, Crooke, ST and Lebleu, B., Eds., CRC Press, 1993, 273-288, and Chapters 6 and 15, Antisense Drug Technology, Crooke ST, Ed., CRC Press, 2008, 163-166 and 442-443.

[0340] Publications that teach the preparation of some of the above-mentioned and other modified nucleobases include Manoharan et al., US2003 / 0158403, Manoharan et al., US2003 / 0175906, Dinh et al., US4,845,205, Spielvogel et al., US5,130,302, Rogers et al., US5,134,066, Bischofberger et al., US5,175,273, Urdea et al., US5,367,066, Benner et al., US5,432,272, Matteucci et al., US5,434,257, Gmeiner et al., US5,457,187, Cook et al., US5,459,255, Froehler et al. al.,US5,484,908, Matteucci et al.,US5,502,177, Hawkins et al.,US5,525,711, Haralambidis et al.,US5,552,540, Cook et al.,US5,587,469, Froehler et al.,US5,594,121, Switzer et al. al.,US5,596,091, Cook et al.,US5,614,617, Froehler et al.,US5,645,985, Cook et al.,US5,681,941, Cook et al.,US5,811,534, Cook et al.,US5,750,692, Cook et al. al., US5,948,903, Cook et al. al., US 5,587,470, Cook et al., US 5,457,191, Matteucci et al., US 5,763,588, Froehler et al., US 5,830,653, Cook et al., US 5,808,027, Cook et al., US 6,166,199, and Matteucci et al., US 6,005,096.

[0341] 3. Specific modified internucleoside linkages The naturally occurring internucleoside linkage in RNA and DNA is a 3' to 5' phosphodiester linkage. In certain embodiments, the nucleosides of modified oligonucleotides can be linked using one or more modified internucleoside linkages. Two major classes of internucleoside linkage groups are defined by the presence or absence of a phosphorus atom. Representative phosphorus-containing internucleoside linkages include, but are not limited to, phosphodiester linkages ("P=O") (also referred to as unmodified or naturally occurring linkages), phosphotriesters, methylphosphonates, phosphoramidates, and phosphorothioates ("P=S"), and phosphate containing phosphorodithioates ("HS-P=S"). Representative non-phosphorus internucleoside linkage groups include, but are not limited to, methylenemethylimino (-CH-N(CH)-O-CH-), thiodiester, thionocarbamate (-OC(=O)(NH)-S-), siloxane (-O-SiH-O-), and N,N'-dimethylhydrazine (-CH-N(CH)-N(CH)-). Modified internucleoside linkages can be used to alter, typically increase, the nuclease resistance of oligonucleotides compared to naturally occurring phosphate linkages. In certain embodiments, internucleoside linkages having a chiral atom can be prepared as racemic mixtures or as separate enantiomers. Methods for preparing phosphorus- and non-phosphorus-containing internucleoside linkages are well known to those skilled in the art.

[0342] In certain embodiments, the modified internucleoside linkage is any of those described in WO / 2021 / 030778, which is incorporated herein by reference. In certain embodiments, the modified internucleoside linkage comprises the following formula: [ka] wherein, independently for each internucleoside linkage group of the modified oligonucleotide: X is selected from O or S; R1 is selected from H, C1-C6 alkyl, and substituted C1-C6 alkyl; T is selected from SO2R2, C(=O)R3, and P(=O)R4R5, wherein: R2 is selected from aryl, substituted aryl, heterocycle, substituted heterocycle, aromatic heterocycle, substituted aromatic heterocycle, diazole, substituted diazole, C1-C6 alkoxy, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, substituted C1-C6 alkyl, substituted C1-C6 alkenyl substituted C1-C6 alkynyl, and a conjugate group; R3 is selected from aryl, substituted aryl, CH3, N(CH3)2, OCH3, and a conjugate group; R4 is selected from OCH3, OH, C1-C6 alkyl, substituted C1-C6 alkyl, and a conjugate group; R5 is selected from OCH3, OH, C1-C6 alkyl, and substituted C1-C6 alkyl.

[0343] In certain embodiments, the modified internucleoside linkage comprises a mesyl phosphoramidate linking group having the following formula: [ka]

[0344] In certain embodiments, the mesyl phosphoramidate internucleoside linkage may contain a chiral center. In certain embodiments, modified oligonucleotides containing (Rp) and / or (Sp) mesyl phosphoramidates each comprise one or more of the following formulae, where "B" represents a nucleobase: [ka]

[0345] Representative internucleoside linkages with chiral centers include, but are not limited to, phosphoramidate, alkylphosphonate, and phosphorothioate. Modified oligonucleotides containing internucleoside linkages with chiral centers can be prepared as a group of modified oligonucleotides containing stereorandom internucleoside linkages, or as a group of modified oligonucleotides containing phosphorothioate or phosphoramidate linkages in specific stereochemical configurations. In certain embodiments, a group of modified oligonucleotides contains phosphorothioate internucleoside linkages, where all of the phosphorothioate internucleoside linkages are stereorandom. In certain embodiments, a group of modified oligonucleotides contains mesyl phosphoramidate internucleoside linkages, where all of the mesyl phosphoramidate internucleoside linkages are stereorandom. In certain embodiments, a group of modified oligonucleotides comprises phosphorothioate and mesyl phosphoramidate internucleoside linkages, and all of the phosphorothioate and mesyl phosphoramidate internucleoside linkages are stereorandom.Such modified oligonucleotides can be produced using a synthesis method in which the stereochemical configuration of each phosphorothioate linkage is randomly selected.Nevertheless, each individual phosphorothioate and each phosphoramidate of each individual oligonucleotide molecule has a defined stereoconfiguration.

[0346] In certain embodiments, the modified oligonucleotide population is enriched for modified oligonucleotides that comprise one or more specific phosphorothioate or phosphoramidate internucleoside linkages in independently selected specific stereochemical configurations.In certain embodiments, the specific configuration of the specific phosphorothioate linkages is present in at least 65% of the molecules of the population.In certain embodiments, the specific configuration of the specific phosphorothioate linkages is present in at least 70% of the molecules of the population.In certain embodiments, the specific configuration of the specific phosphorothioate linkages is present in at least 80% of the molecules of the population.In certain embodiments, the specific configuration of the specific phosphorothioate linkages is present in at least 90% of the molecules of the population.In certain embodiments, the specific configuration of the specific phosphorothioate linkages is present in at least 99% of the molecules of the population.In certain embodiments, the specific configuration of the specific mesyl phosphoramidate linkages is present in at least 65% of the molecules of the population. In certain embodiments, the specific arrangement of the specific mesyl phosphoramidate bond is present in at least 70% of the molecules of the group.In certain embodiments, the specific arrangement of the specific mesyl phosphoramidate bond is present in at least 80% of the molecules of the group.In certain embodiments, the specific arrangement of the specific mesyl phosphoramidate bond is present in at least 90% of the molecules of the group.In certain embodiments, the specific arrangement of the specific mesyl phosphoramidate bond is present in at least 99% of the molecules of the group.

[0347] Such chirally enriched populations of modified oligonucleotides can be produced using synthetic methods known in the art, such as those described in Oka et al., JACS 125, 8307 (2003), Wan et al., Nuc. Acid. Res. 42, 13456 (2014), and WO2017 / 015555. In certain embodiments, the population of modified oligonucleotides is enriched for modified oligonucleotides having at least one of the indicated phosphorothioates in the (Sp) configuration. In certain embodiments, the population of modified oligonucleotides is enriched for modified oligonucleotides having at least one phosphorothioate in the (Rp) configuration. In certain embodiments, modified oligonucleotides comprising (Rp) and / or (Sp) phosphorothioates each comprise one or more of the following formulae, where "B" represents a nucleobase: [ka]

[0348] In certain embodiments, the population of modified oligonucleotides is enriched for modified oligonucleotides having at least one of the indicated phosphoramidates in the (Sp) configuration. In certain embodiments, the population of modified oligonucleotides is enriched for modified oligonucleotides having at least one of the indicated phosphoramidates in the (Rp) configuration. Unless otherwise indicated, the chiral internucleoside linkages of the modified oligonucleotides described herein can be stereorandom or in a specific stereochemical configuration.

[0349] Neutral internucleoside linkages include, but are not limited to, phosphotriester, methylphosphonate, MMI (3'-CH2-N(CH3)-O-5'), amide-3 (3'-CH2-C(=O)-N(H)-5'), amide-4 (3'-CH2-N(H)-C(=O)-5'), formacetal (3'-O-CH2-O-5'), methoxypropyl (MOP), and thioformacetal (3'-S-CH2-O-5'). Further neutral internucleoside linkages include nonionic linkages, including siloxanes (dialkylsiloxanes), carboxylate esters, carboxamides, sulfides, sulfonate esters, and amides (see, e.g., Carbohydrate Modifications in Antisense Research; YS Sanghvi and PD Cook, Eds., ACS Symposium Series 580; Chapters 3 and 4, 40-65). Further neutral internucleoside linkages include nonionic linkages containing a mixture of N, O, S, and CH2 moieties.

[0350] In certain embodiments, modified oligonucleotides comprise one or more inverted nucleosides as shown below: [ka] In the formula, each Bx independently represents any nucleobase.

[0351] In certain embodiments, the inverted nucleoside is terminal (i.e., the last nucleoside at one end of the oligonucleotide), and therefore, only one internucleoside linkage as shown above is present. In certain such embodiments, additional features (such as a conjugate group) may be attached to the inverted nucleoside. Such terminal inverted nucleosides may be attached to one or both ends of the oligonucleotide.

[0352] In certain embodiments, such groups lack a nucleobase and are referred to herein as inverted sugar moieties. In certain embodiments, the inverted sugar moiety is terminal (i.e., attached to the last nucleoside at one end of the oligonucleotide), and thus, only one internucleoside linkage is present. In certain such embodiments, additional features (such as a conjugate group) may be attached to the inverted sugar moiety. Such terminal inverted sugar moieties may be attached to one or both ends of the oligonucleotide.

[0353] In certain embodiments, the nucleic acids may be linked 2' to 5' rather than the standard 3' to 5' linkage. Such linkages are shown below. [ka] In the formula, each Bx represents any nucleic acid base.

[0354] B. Specific motifs In certain embodiments, modified oligonucleotides comprise one or more modified nucleosides comprising modified sugar moieties. In certain embodiments, modified oligonucleotides comprise one or more modified nucleosides comprising modified nucleobases. In certain embodiments, modified oligonucleotides comprise one or more modified internucleoside linkages. In such embodiments, the modified, unmodified, and differently modified sugar moieties, nucleobases, and / or internucleoside linkages of modified oligonucleotides define a pattern or motif. In certain embodiments, the sugar moiety, nucleobase, and internucleoside linkage patterns are each independent of one another. Thus, a modified oligonucleotide can be described by its sugar motif, nucleobase motif, and / or internucleoside linkage motif (as used herein, nucleobase motif refers to modifications to the nucleobases independently of the sequence of the nucleobases).

[0355] 1. Specific glycomotifs In certain embodiments, oligonucleotides comprise one or more types of modified sugar and / or unmodified sugar moieties arranged in defined patterns or sugar motifs along the oligonucleotide or regions thereof, optionally including, but not limited to, any of the sugar modifications discussed herein.

[0356] Gapmer oligonucleotides In certain embodiments, modified oligonucleotides comprise or consist of a region having a gapmer motif defined by two external regions, or "wings," and a central or internal region, or "gap." The three regions of the gapmer motif (the 5' wing, the gap, and the 3' wing) form a contiguous nucleoside sequence in which at least some of the sugar moieties of each nucleoside in both wings are different from at least some of the sugar moieties of the nucleosides in the gap. Specifically, the sugar moieties of at least the nucleosides in each wing closest to the gap (the 3'-most nucleoside of the 5'-wing and the 5'-most nucleoside of the 3'-wing) are different from the sugar moieties of the adjacent gap nucleosides, thus defining the boundary between the wing and the gap (i.e., the wing / gap junction). In certain embodiments, the sugar moieties within the gap are the same as each other. In certain embodiments, the gap comprises one or more nucleosides having a sugar moiety that is different from the sugar moieties of one or more other nucleosides in the gap. In certain embodiments, the sugar motifs of the two wings are the same as each other (symmetric gapmer). In certain embodiments, the sugar motif of the 5'-wing is different from the sugar motif of the 3'-wing (asymmetric gapmer).

[0357] In certain embodiments, a gapmer wing comprises 1 to 6 nucleosides. In certain embodiments, each nucleoside in each wing of a gapmer comprises a modified sugar moiety. In certain embodiments, at least one nucleoside in each wing of a gapmer comprises a modified sugar moiety. In certain embodiments, at least two nucleosides in each wing of a gapmer comprise a modified sugar moiety. In certain embodiments, at least three nucleosides in each wing of a gapmer comprise a modified sugar moiety. In certain embodiments, at least four nucleosides in each wing of a gapmer comprise a modified sugar moiety.

[0358] In certain embodiments, the gapmer gap comprises 7 to 12 nucleosides. In certain embodiments, each nucleoside of the gapmer gap comprises a 2'-β-D-deoxyribosyl sugar moiety. In certain embodiments, at least one nucleoside of the gapmer gap comprises a modified sugar moiety.

[0359] In certain embodiments, the gapmer is a deoxygapmer. In certain embodiments, a nucleoside on the gap side of each wing / gap junction comprises a 2'-deoxyribosyl sugar moiety, and a nucleoside on the wing side of each wing / gap junction comprises a modified sugar moiety. In certain embodiments, each nucleoside of the gap comprises a 2'-β-D-deoxyribosyl sugar moiety. In certain embodiments, each nucleoside of each wing of a gapmer comprises a modified sugar moiety. In certain embodiments, at least one nucleoside of the gap of a gapmer comprises a modified sugar moiety. In certain embodiments, one nucleoside of the gap comprises a modified sugar moiety, and each remaining nucleoside of the gap comprises a 2'-deoxyribosyl sugar moiety. In certain embodiments, at least one nucleoside of the gap of a gapmer comprises a 2'-OMe sugar moiety.

[0360] As used herein, the lengths (number of nucleosides) of the three regions of a gapmer can be provided using the notation [number of nucleosides in the 5'-wing] - [number of nucleosides in the gap] - [number of nucleosides in the 3'-wing]. Thus, a 3-10-3 gapmer consists of each wing containing three linked nucleosides and a gap containing 10 linked nucleosides. When such a designation is followed by a specific modification, the modification is of each sugar moiety of each wing, and the gap nucleoside contains a 2'-β-D-deoxyribosyl sugar moiety. A 3-10-3 cEt gapmer consists of a 5'-wing containing three linked cEt nucleosides, a gap containing 10 linked 2'-β-D-deoxynucleosides, and a 3'-wing containing three linked cEt nucleosides.

[0361] In certain embodiments, modified oligonucleotides have, from 5' to 3', the sugar motif: ekdddddddddkekek, where each "d" represents a 2'-β-D-deoxyribosyl sugar moiety, each "e" represents a 2'-MOE sugar moiety, and each "k" represents a cEt-modified sugar moiety.

[0362] In certain embodiments, modified oligonucleotides have, from 5' to 3', the sugar motif: ekkddddddddddkkk, where each "d" represents a 2'-β-D-deoxyribosyl sugar moiety, each "e" represents a 2'-MOE sugar moiety, and each "k" represents a cEt-modified sugar moiety.

[0363] In certain embodiments, modified oligonucleotides have, from 5' to 3', the sugar motif: ekkdddddddddkkke, where each "d" represents a 2'-β-D-deoxyribosyl sugar moiety, each "e" represents a 2'-MOE sugar moiety, and each "k" represents a cEt-modified sugar moiety.

[0364] In certain embodiments, modified oligonucleotides have, from 5' to 3', the sugar motif: kedddddddddkekek, where each "d" represents a 2'-β-D-deoxyribosyl sugar moiety, each "e" represents a 2'-MOE sugar moiety, and each "k" represents a cEt-modified sugar moiety.

[0365] In certain embodiments, modified oligonucleotides have, from 5' to 3', the sugar motif: kekddddddddddkkk, where each "d" represents a 2'-β-D-deoxyribosyl sugar moiety, each "e" represents a 2'-MOE sugar moiety, and each "k" represents a cEt-modified sugar moiety.

[0366] In certain embodiments, modified oligonucleotides have, from 5' to 3', the sugar motif: kkeddddddddddkkk, where each "d" represents a 2'-β-D-deoxyribosyl sugar moiety, each "e" represents a 2'-MOE sugar moiety, and each "k" represents a cEt-modified sugar moiety.

[0367] In certain embodiments, modified oligonucleotides have, from 5' to 3', the sugar motif: kkedddddddddkkke, where each "d" represents a 2'-β-D-deoxyribosyl sugar moiety, each "e" represents a 2'-MOE sugar moiety, and each "k" represents a cEt-modified sugar moiety.

[0368] In certain embodiments, modified oligonucleotides have, from 5' to 3, the sugar motif: kkkdddddddddkkke, where each "d" represents a 2'-β-D-deoxyribosyl sugar moiety, each "e" represents a 2'-MOE sugar moiety, and each "k" represents a cEt-modified sugar moiety.

[0369] In certain embodiments, modified oligonucleotides have, from 5' to 3', the sugar motif: kkkdyddddddddkkk, where each "d" represents a 2'-β-D-deoxyribosyl sugar moiety, each "y" represents a 2'-OMe sugar moiety, and each "k" represents a cEt-modified sugar moiety.

[0370] In certain embodiments, modified oligonucleotides have, from 5' to 3', the sugar motif: kkddddddddddkk, where each "d" represents a 2'-β-D-deoxyribosyl sugar moiety and each "k" represents a cEt-modified sugar moiety.

[0371] In certain embodiments, modified oligonucleotides have, from 5' to 3', the sugar motif: kkkddddddddddkeee, where each "d" represents a 2'-β-D-deoxyribosyl sugar moiety, each "e" represents a 2'-MOE sugar moiety, and each "k" represents a cEt-modified sugar moiety.

[0372] In certain embodiments, modified oligonucleotides have, from 5' to 3', the sugar motif: kkkddddddddddkkee, where each "d" represents a 2'-β-D-deoxyribosyl sugar moiety, each "e" represents a 2'-MOE sugar moiety, and each "k" represents a cEt-modified sugar moiety.

[0373] In certain embodiments, modified oligonucleotides have, from 5' to 3', the sugar motif: kkkddddddddddkkkk, where each "d" represents a 2'-β-D-deoxyribosyl sugar moiety and each "k" represents a cEt-modified sugar moiety.

[0374] In certain embodiments, modified oligonucleotides have, from 5' to 3', the sugar motif: kkkkddddddddddddkkk, where each "d" represents a 2'-β-D-deoxyribosyl sugar moiety and each "k" represents a cEt-modified sugar moiety.

[0375] In certain embodiments, modified oligonucleotides have, from 5' to 3', the sugar motif: kkkddddddddddkeeee, where each "d" represents a 2'-β-D-deoxyribosyl sugar moiety, each "e" represents a 2'-MOE sugar moiety, and each "k" represents a cEt-modified sugar moiety.

[0376] In certain embodiments, modified oligonucleotides have, from 5' to 3', the sugar motif: kkkddddddddddkkeee, where each "d" represents a 2'-β-D-deoxyribosyl sugar moiety, each "e" represents a 2'-MOE sugar moiety, and each "k" represents a cEt-modified sugar moiety.

[0377] In certain embodiments, modified oligonucleotides have, from 5' to 3', the sugar motif: kkkkddddddddddddkkkk, where each "d" represents a 2'-β-D-deoxyribosyl sugar moiety and each "k" represents a cEt-modified sugar moiety.

[0378] In certain embodiments, modified oligonucleotides have, from 5' to 3', the sugar motif: kkkkkddddddddddddkkkk, where each "d" represents a 2'-β-D-deoxyribosyl sugar moiety and each "k" represents a cEt-modified sugar moiety.

[0379] In certain embodiments, modified oligonucleotides have, from 5' to 3', the sugar motif: kkdddddddddkekek, where each "d" represents a 2'-β-D-deoxyribosyl sugar moiety, each "e" represents a 2'-MOE sugar moiety, and each "k" represents a cEt-modified sugar moiety.

[0380] Specific target-independent glycomotifs Certain sugar motifs provided herein are generally useful for modified oligonucleotides, regardless of nucleobase sequence. The nucleobase sequence of the modified oligonucleotide can be complementary to any target. In certain embodiments, the oligomeric compound comprises a modified oligonucleotide that is a gapmer.

[0381] In certain embodiments, an oligomeric compound comprises a modified oligonucleotide having, from 5' to 3', the sugar motif: ekdddddddddkekek, where each "d" represents a 2'-β-D-deoxyribosyl sugar moiety, each "e" represents a 2'-MOE sugar moiety, and each "k" represents a cEt-modified sugar moiety. In certain embodiments, the modified oligonucleotide has a nucleobase sequence complementary to a target RNA.

[0382] In certain embodiments, an oligomeric compound comprises a modified oligonucleotide having, from 5' to 3', the sugar motif: ekkddddddddddkkk, where each "d" represents a 2'-β-D-deoxyribosyl sugar moiety, each "e" represents a 2'-MOE sugar moiety, and each "k" represents a cEt-modified sugar moiety. In certain embodiments, the modified oligonucleotide has a nucleobase sequence complementary to a target RNA.

[0383] In certain embodiments, an oligomeric compound comprises a modified oligonucleotide having, from 5' to 3', the sugar motif: ekkdddddddddkkke, where each "d" represents a 2'-β-D-deoxyribosyl sugar moiety, each "e" represents a 2'-MOE sugar moiety, and each "k" represents a cEt-modified sugar moiety. In certain embodiments, the modified oligonucleotide has a nucleobase sequence complementary to a target RNA.

[0384] In certain embodiments, an oligomeric compound comprises a modified oligonucleotide having, from 5' to 3', the sugar motif: kedddddddddkekek, where each "d" represents a 2'-β-D-deoxyribosyl sugar moiety, each "e" represents a 2'-MOE sugar moiety, and each "k" represents a cEt-modified sugar moiety. In certain embodiments, the modified oligonucleotide has a nucleobase sequence complementary to a target RNA.

[0385] In certain embodiments, an oligomeric compound comprises a modified oligonucleotide having, from 5' to 3', the sugar motif: kekddddddddddkkk, where each "d" represents a 2'-β-D-deoxyribosyl sugar moiety, each "e" represents a 2'-MOE sugar moiety, and each "k" represents a cEt-modified sugar moiety. In certain embodiments, the modified oligonucleotide has a nucleobase sequence complementary to a target RNA.

[0386] In certain embodiments, an oligomeric compound comprises a modified oligonucleotide having, from 5' to 3', the sugar motif: kkeddddddddddkkk, where each "d" represents a 2'-β-D-deoxyribosyl sugar moiety, each "e" represents a 2'-MOE sugar moiety, and each "k" represents a cEt-modified sugar moiety. In certain embodiments, the modified oligonucleotide has a nucleobase sequence complementary to a target RNA.

[0387] In certain embodiments, an oligomeric compound comprises a modified oligonucleotide having, from 5' to 3', the sugar motif: kkedddddddddkkke, where each "d" represents a 2'-β-D-deoxyribosyl sugar moiety, each "e" represents a 2'-MOE sugar moiety, and each "k" represents a cEt-modified sugar moiety. In certain embodiments, the modified oligonucleotide has a nucleobase sequence complementary to a target RNA.

[0388] In certain embodiments, an oligomeric compound comprises a modified oligonucleotide having, from 5' to 3', the sugar motif: kkdddddddddkekek, where each "d" represents a 2'-β-D-deoxyribosyl sugar moiety, each "e" represents a 2'-MOE sugar moiety, and each "k" represents a cEt-modified sugar moiety. In certain embodiments, the modified oligonucleotide has a nucleobase sequence complementary to a target RNA.

[0389] 2. Specific nucleobase motifs In certain embodiments, an oligonucleotide comprises modified and / or unmodified nucleobases arranged in a defined pattern or motif along the oligonucleotide or its region. In certain embodiments, each nucleobase is modified. In certain embodiments, none of the nucleobases is modified. In certain embodiments, each purine or each pyrimidine is modified. In certain embodiments, each adenine is modified. In certain embodiments, each guanine is modified. In certain embodiments, each thymine is modified. In certain embodiments, each uracil is modified. In certain embodiments, each cytosine is modified. In certain embodiments, some or all of the cytosine nucleobases of the modified oligonucleotide are 5-methylcytosine. In certain embodiments, all of the cytosine nucleobases are 5-methylcytosine, and all other nucleobases of the modified oligonucleotide are unmodified nucleobases.

[0390] In certain embodiments, modified oligonucleotides comprise a block of modified nucleobases.In certain such embodiments, the block is at the 3'-end of the oligonucleotide.In certain embodiments, the block is within 3 nucleosides of the 3'-end of the oligonucleotide.In certain embodiments, the block is at the 5'-end of the oligonucleotide.In certain embodiments, the block is within 3 nucleosides of the 5'-end of the oligonucleotide.

[0391] In certain embodiments, an oligonucleotide having a gapmer motif comprises a nucleoside comprising a modified nucleobase. In certain such embodiments, one nucleoside comprising a modified nucleobase is located in the central gap of the oligonucleotide having a gapmer motif. In certain such embodiments, the sugar moiety of the nucleoside is a 2'-deoxyribosyl sugar moiety. In certain embodiments, the modified nucleobase is selected from 2-thiopyrimidine and 5-propynepyrimidine.

[0392] 3. Specific internucleoside linkage motifs In certain embodiments, an oligonucleotide comprises modified and / or unmodified internucleoside linkages arranged in a defined pattern or motif along the oligonucleotide or region thereof. In certain embodiments, each internucleoside linkage group is a phosphodiester internucleoside linkage (P=O). In certain embodiments, each internucleoside linkage group of a modified oligonucleotide is a phosphorothioate internucleoside linkage (P=S). In certain embodiments, each internucleoside linkage of a modified oligonucleotide is independently selected from a phosphorothioate internucleoside linkage and a phosphodiester internucleoside linkage. In certain embodiments, each phosphorothioate internucleoside linkage is independently selected from a stereorandom phosphorothioate, (Sp) phosphorothioate, and (Rp) phosphorothioate.

[0393] In certain embodiments, the sugar motif of the modified oligonucleotide is a gapmer, and all internucleoside linkages within the gap are modified. In certain such embodiments, some or all of the internucleoside linkages in both wings are unmodified phosphodiester internucleoside linkages. In certain embodiments, the terminal internucleoside linkage is modified. In certain embodiments, the sugar motif of the modified oligonucleotide is a gapmer, and the internucleoside linkage motif comprises at least one phosphodiester internucleoside linkage in at least one wing, where this at least one phosphodiester linkage is not a terminal internucleoside linkage, and the remaining internucleoside linkages are phosphorothioate internucleoside linkages. In certain embodiments, the sugar motif of the modified oligonucleotide is a gapmer, and the internucleoside linkage motif comprises one, two, or three phosphodiester internucleoside linkages, and the remaining internucleoside linkages are phosphorothioate internucleoside linkages. In certain embodiments, the sugar motif of the modified oligonucleotide is a gapmer, and the internucleoside linkage motif comprises three phosphodiester internucleoside linkages, with the remaining internucleoside linkages being phosphorothioate internucleoside linkages. In certain such embodiments, all of the phosphorothioate linkages are stereorandom. In certain embodiments, all of the phosphorothioate linkages in both wings are (Sp) phosphorothioate, and the gap comprises at least one Sp, Sp, Rp motif. In certain embodiments, a population of modified oligonucleotides is enriched for modified oligonucleotides comprising such internucleoside linkage motifs.

[0394] C. A specific length The length of the oligonucleotide can be increased or decreased without eliminating activity. For example, Woolf et al. (Proc. Natl. Acad. Sci. USA 89:7305-7309, 1992) tested a series of oligonucleotides ranging from 13 to 25 nucleobases in length for their ability to induce target RNA cleavage in an oocyte injection model. 25 nucleobase-long oligonucleotides containing 8 or 11 mismatched bases near the end of the oligonucleotide were able to induce specific cleavage of the target RNA, although to a lesser extent than oligonucleotides without mismatches. Similarly, target-specific cleavage was achieved using 13 nucleobase oligonucleotides, including those with one or three mismatches.

[0395] In certain embodiments, oligonucleotides (including modified oligonucleotides) can have any of a variety of length ranges. In certain embodiments, an oligonucleotide consists of X to Y linked nucleosides, where X represents the minimum number of nucleosides in the range and Y represents the maximum number of nucleosides in the range. In certain such embodiments, X and Y are each independently selected from 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, and 50, provided that X≦Y. For example, in certain embodiments, the oligonucleotides may be 12-13, 12-14, 12-15, 12-16, 12-17, 12-18, 12-19, 12-20, 12-21, 12-22, 12-23, 12-24, 12-25, 12-26, 12-27, 12-28, 12-29, 12-30, 13-14, 13-15, 13~16 pieces, 13~17 pieces, 13~18 pieces, 13~19 pieces, 13~20 pieces, 13~21 pieces, 13~22 pieces, 13~23 pieces, 13~24 pieces, 13~25 pieces, 13~26 pieces, 13~27 pieces, 13~28 pieces, 13~29 pieces, 13~30 pieces, 14~15 pieces, 14~16 pieces, 14~17 pieces, 14~18 pieces, 14~19 pieces, 14~20 pieces, 14~21 pieces, 14~22 pieces, 14~23 pieces, 14~24 pieces, 14~25 pieces, 14~26 pieces, 14~27 pieces, 14~28 pieces, 14~29 pieces, 14~30 pieces, 15~16 pieces, 15~17 pieces, 15~18 pieces, 15~19 pieces, 15~20 pieces, 15~21 pieces, 15~22 pieces, 15~23 pieces, 15~24 pieces, 15~25 pieces, 15~26 pieces, 15~27 pieces, 15~28 pieces, 15~29 pieces, 15~30 pieces, 16~17 pieces, 16~18 pieces, 16~19 pieces, 16~20 pieces, 16~21 pieces, 16~22 pieces, 16~23 pieces, 16~24 pieces, 16~25 pieces, 16~26 pieces, 16~27 pieces, 16~28 pieces, 16~29 pieces, 16~30 pieces, 17~18 pieces, 17~19 pieces, 17~20 pieces, 17~21 pieces, 17~22 pieces, 17~23 pieces, 17~24 pieces, 17~25 pieces, 17~26 pieces, 17~27 pieces, 17~28 pieces, 17~29 pieces,17~30 pieces, 18~19 pieces, 18~20 pieces, 18~21 pieces, 18~22 pieces, 18~23 pieces, 18~24 pieces, 18~25 pieces, 18~26 pieces, 18~27 pieces, 1 8~28 pieces, 18~29 pieces, 18~30 pieces, 19~20 pieces, 19~21 pieces, 19~22 pieces, 19~23 pieces, 19~24 pieces, 19~25 pieces, 19~26 pieces, 19 ~29 pieces, 19~28 pieces, 19~29 pieces, 19~30 pieces, 20~21 pieces, 20~22 pieces, 20~23 pieces, 20~24 pieces, 20~25 pieces, 20~26 pieces, 20~ 27 pieces, 20~28 pieces, 20~29 pieces, 20~30 pieces, 21~22 pieces, 21~23 pieces, 21~24 pieces, 21~25 pieces, 21~26 pieces, 21~27 pieces, 21~28 pieces pieces, 21~29 pieces, 21~30 pieces, 22~23 pieces, 22~24 pieces, 22~25 pieces, 22~26 pieces, 22~27 pieces, 22~28 pieces, 22~29 pieces, 22~30 pieces , 23~24 pieces, 23~25 pieces, 23~26 pieces, 23~27 pieces, 23~28 pieces, 23~29 pieces, 23~30 pieces, 24~25 pieces, 24~26 pieces, 24~27 pieces, 2 It consists of 4 to 28, 24 to 29, 24 to 30, 25 to 26, 25 to 27, 25 to 28, 25 to 29, 25 to 30, 26 to 27, 26 to 28, 26 to 29, 26 to 30, 27 to 28, 27 to 29, 27 to 30, 28 to 29, 28 to 30, or 29 to 30 linked nucleosides.

[0396] D. Certain Modified Oligonucleotides In certain embodiments, the above-described modifications (sugar, nucleobase, internucleoside linkage) are incorporated into modified oligonucleotides. In certain embodiments, modified oligonucleotides are characterized by their modification motif and overall length. In certain embodiments, such parameters are each independent of one another. Thus, unless otherwise indicated, each internucleoside linkage of an oligonucleotide having a gapmer sugar motif may be modified or unmodified, and may or may not follow the gapmer modification pattern of sugar modification. For example, the internucleoside linkages within the wing regions of a sugar gapmer may be the same or different from one another and may be the same or different from the internucleoside linkages in the gap region of the sugar motif. Similarly, such sugar gapmer oligonucleotides may contain one or more modified nucleobases regardless of the gapmer pattern of sugar modification. Unless otherwise indicated, any modification is independent of the nucleobase sequence.

[0397] E. Specific populations of modified oligonucleotides A population of modified oligonucleotides, in which all modified oligonucleotides in the population have the same molecular formula, can be a stereorandom population or a chiral enriched population. All of the chiral centers of all modified oligonucleotides are stereorandom in a stereorandom population. In a chiral enriched population, at least one specific chiral center is not stereorandom in the modified oligonucleotides of the population. In certain embodiments, the modified oligonucleotides in a chiral enriched population are enriched for β-D ribosyl sugar moieties and all of the phosphorothioate internucleoside linkages are stereorandom. In certain embodiments, the modified oligonucleotides in a chiral enriched population are enriched for both β-D ribosyl sugar moieties and at least one specific phosphorothioate internucleoside linkage in a specific stereochemical configuration.

[0398] F. Nucleic Acid Sequence In certain embodiments, oligonucleotides (unmodified or modified oligonucleotides) are further represented by their nucleobase sequence.In certain embodiments, oligonucleotides have the nucleobase sequence complementary to a second oligonucleotide or identified reference nucleic acid, for example, target nucleic acid.In certain such embodiments, a region of the oligonucleotide has the nucleobase sequence complementary to a second oligonucleotide or identified reference nucleic acid, for example, target nucleic acid.In certain embodiments, the nucleobase sequence of a region or the entire length of the oligonucleotide is at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% complementary to a second oligonucleotide or nucleic acid, for example, target nucleic acid.

[0399] II. Certain Oligomeric Compounds In certain embodiments, provided herein are oligomeric compounds comprising an oligonucleotide (modified or unmodified) and, optionally, one or more conjugate groups and / or terminal groups. A conjugate group comprises one or more conjugate moieties and a conjugate linker connecting the conjugate moieties to the oligonucleotide. A conjugate group can be attached to one or both termini of the oligonucleotide and / or at any internal position. In certain embodiments, a conjugate group is attached to the 2'-position of a nucleoside of a modified oligonucleotide. In certain embodiments, a conjugate group attached to one or both termini of an oligonucleotide is a terminal group. In certain such embodiments, a conjugate group or terminal group is attached to the 3'-end and / or 5'-end of the oligonucleotide. In certain such embodiments, a conjugate group (or terminal group) is attached to the 3'-end of the oligonucleotide. In certain embodiments, a conjugate group (or terminal group) is attached near the 3'-end of the oligonucleotide. In certain embodiments, a conjugate group (or terminal group) is attached near the 5'-end of the oligonucleotide. In certain embodiments, a conjugate group (or terminal group) is attached near the 5'-end of the oligonucleotide.

[0400] Examples of terminal groups include, but are not limited to, a conjugate group, a capping group, a phosphate moiety, a protecting group, a modified or unmodified nucleoside, and two or more nucleosides that are independently modified or unmodified.

[0401] A. Specific Conjugate Groups In certain embodiments, the oligonucleotide is covalently linked to one or more conjugate groups, which in certain embodiments modify one or more properties of the linked oligonucleotide, including, but not limited to, the pharmacodynamic properties, pharmacokinetic properties, stability, binding, absorption, tissue distribution, cellular distribution, cellular uptake, charge, and clearance.

[0402] In certain embodiments, the conjugation of one or more carbohydrate moieties to a modified oligonucleotide can optimize one or more properties of the modified oligonucleotide. In certain embodiments, the carbohydrate moiety is attached to a modified subunit of the modified oligonucleotide. For example, the ribose sugar of one or more ribonucleotide subunits of a modified oligonucleotide can be replaced with another moiety, such as a non-carbohydrate (preferably cyclic) carrier bound to a carbohydrate ligand. A ribonucleotide subunit in which the ribose sugar of the subunit has been replaced in this manner is referred to herein as a modified sugar moiety, a ribose-replacement modified subunit (RRMS). The cyclic carrier can be a carbocyclic ring system, i.e., one or more ring atoms can be a heteroatom, such as nitrogen, oxygen, or sulfur. The cyclic carrier can be a monocyclic ring system or can contain two or more rings, such as fused rings. The cyclic carrier can be a fully saturated ring system or can contain one or more double bonds. In certain embodiments, the modified oligonucleotide is a gapmer.

[0403] In certain embodiments, the conjugate group confers a new property on the attached oligonucleotide, for example, a fluorophore or reporter group that allows for detection of the oligonucleotide. Certain conjugate groups and moieties have been previously described, such as cholesterol moieties (Letsinger et al., Proc. Natl. Acad. Sci. USA, 1989, 86, 6553-6556), choline acid (Manoharan et al., Bioorg. Med. Chem. Lett., 1994, 4, 1053-1060), thioethers such as hexyl-S-tritylthiol (Manoharan et al., Ann. NY Acad. Sci., 1992, 660, 306-309; Manoharan et al., Bioorg. Med. Chem. Lett., 1993, 3, 2765-2770), thiocholesterol (Oberhauser et al., Nucl. Acids Res., 1992, 20, 533-538), aliphatic chains such as dodecane-diol or undecyl residues (Saison-Behmoaras et al., EMBO J., 1991, 10, 1111-1118; Kabanov et al., FEBS Lett., 1990, 259, 327-330; Svinarchuk et al., Biochimie, 1993, 75, 49-54), phospholipids such as di-hexadecyl-rac-glycerol or triethyl-ammonium 1,2-di-O-hexadecyl-rac-glycero-3-H-phosphonate (Manoharan et al., Tetrahedron Lett., 1995, 36, 3651-3654; Shea et al., Nucl. Acids Res., 1990, 18, 3777-3783), polyamine or polyethylene glycol chains (Manoharan et al., Nucleosides & Nucleotides, 1995, 14, 969-973), or adamantane acetic acid, palmityl moiety (Mishra et al., Biochim. Biophys.Acta, 1995, 1264, 229-237), octadecylamine or hexylamino-carbonyl-oxycholesterol moieties (Crooke et al., J. Pharmacol. Exp. Ther., 1996, 277, 923-937), tocopherol groups (Nishina et al., Molecular Therapy Nucleic Acids, 2015, 4, e220, and Nishina et al., Molecular Therapy, 2008, 16, 734-740), or GalNAc clusters (e.g., WO2014 / 179620).

[0404] In certain embodiments, the conjugate group can be selected from any of C22 alkyl, C20 alkyl, C16 alkyl, C10 alkyl, C21 alkyl, C19 alkyl, C18 alkyl, C15 alkyl, C14 alkyl, C13 alkyl, C12 alkyl, C11 alkyl, C9 alkyl, C8 alkyl, C7 alkyl, C6 alkyl, C5 alkyl, C22 alkenyl, C20 alkenyl, C16 alkenyl, C10 alkenyl, C21 alkenyl, C19 alkenyl, C18 alkenyl, C15 alkenyl, C14 alkenyl, C13 alkenyl, C12 alkenyl, C11 alkenyl, C9 alkenyl, C8 alkenyl, C7 alkenyl, C6 alkenyl, or C5 alkenyl.

[0405] In certain embodiments, the conjugate group may be selected from any of C22 alkyl, C20 alkyl, C16 alkyl, C10 alkyl, C21 alkyl, C19 alkyl, C18 alkyl, C15 alkyl, C14 alkyl, C13 alkyl, C12 alkyl, C11 alkyl, C9 alkyl, C8 alkyl, C7 alkyl, C6 alkyl, and C5 alkyl, whose alkyl chain has one or more unsaturated bonds.

[0406] In certain embodiments, the conjugate group has the following structure: [ka]

[0407] 1. Conjugate moiety Conjugate moieties include, but are not limited to, intercalators, reporter molecules, polyamines, polyamides, peptides, carbohydrates (e.g., GalNAc), vitamin moieties, polyethylene glycol, thioethers, polyethers, cholesterol, thiocholesterol, cholic acid moieties, folic acid, lipids, phospholipids, biotin, phenazine, phenanthridine, anthraquinone, adamantane, acridine, fluorescein, rhodamine, coumarin, fluorophores, and dyes.

[0408] In certain embodiments, the conjugate moiety comprises an active drug substance, such as aspirin, warfarin, phenylbutazone, ibuprofen, suprofen, fenbufen, ketoprofen, (S)-(+)-pranoprofen, carprofen, dansylsarcosine, 2,3,5-triiodobenzoic acid, fingolimod, flufenamic acid, folinic acid, benzothiadiazide, chlorothiazide, diazepine, indomethacin, barbiturates, cephalosporins, sulfa drugs, antidiabetic drugs, antibacterial drugs, or antibiotics.

[0409] 2. Conjugate Linker Conjugate moiety is linked to oligonucleotide via conjugate linker.In some oligomer compounds, conjugate linker is a single chemical bond (i.e., conjugate moiety is directly linked to oligonucleotide via single bond).In some embodiments, the conjugate linker comprises a chain structure such as hydrocarbyl chain, or an oligomer of repeating units such as ethylene glycol, nucleoside or amino acid unit.

[0410] In certain embodiments, the conjugate linker comprises pyrrolidine.

[0411] In certain embodiments, the conjugate linker comprises one or more groups selected from alkyl, amino, oxo, amide, disulfide, polyethylene glycol, ether, thioether, and hydroxylamino. In certain such embodiments, the conjugate linker comprises a group selected from alkyl, amino, oxo, amide, and ether groups. In certain embodiments, the conjugate linker comprises a group selected from alkyl and amide groups. In certain embodiments, the conjugate linker comprises a group selected from alkyl and ether groups. In certain embodiments, the conjugate linker comprises at least one phosphorus moiety. In certain embodiments, the conjugate linker comprises at least one phosphate group. In certain embodiments, the conjugate linker comprises at least one neutral linking group.

[0412] In certain embodiments, conjugate linkers, including those described above, are bifunctional linking moieties known in the art to be useful for attaching conjugate groups to compounds such as the oligonucleotides provided herein. Generally, bifunctional linking moieties contain at least two functional groups. One of the functional groups is selected to bind to a specific site on the compound, and the other is selected to bind to the conjugate group. Examples of functional groups used in bifunctional linking moieties include, but are not limited to, electrophiles for reacting with nucleophilic groups and nucleophiles for reacting with electrophilic groups. In certain embodiments, the bifunctional linking moiety contains one or more groups selected from amino, hydroxyl, carboxylic acid, thiol, alkyl, alkenyl, and alkynyl.

[0413] Examples of conjugate linkers include, but are not limited to, pyrrolidine, 8-amino-3,6-dioxaoctanoic acid (ADO), succinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC), and 6-aminohexanoic acid (AHEX or AHA). Other conjugate linkers include substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C2-C 10 Alkenyl, or substituted or unsubstituted C-C 10 alkynyl, where a non-limiting list of preferred substituents includes hydroxyl, amino, alkoxy, carboxy, benzyl, phenyl, nitro, thiol, thioalkoxy, halogen, alkyl, aryl, alkenyl, and alkynyl.

[0414] In certain embodiments, a conjugate linker comprises 1 to 10 linker nucleosides. In certain embodiments, a conjugate linker comprises 2 to 5 linker nucleosides. In certain embodiments, a conjugate linker comprises exactly 3 linker nucleosides. In certain embodiments, a conjugate linker comprises a TCA motif. In certain embodiments, such linker nucleosides are modified nucleosides. In certain embodiments, such linker nucleosides comprise modified sugar moieties. In certain embodiments, linker nucleosides are unmodified. In certain embodiments, a linker nucleoside comprises an optionally protected heterocyclic base selected from a purine, a substituted purine, a pyrimidine, or a substituted pyrimidine. In certain embodiments, the cleavable moiety is a nucleoside selected from uracil, thymine, cytosine, 4-N-benzoylcytosine, 5-methylcytosine, 4-N-benzoyl-5-methylcytosine, adenine, 6-N-benzoyladenine, guanine, and 2-N-isobutyrylguanine. It is usually desirable for the linker nucleosides to be cleaved from the oligomeric compound after reaching the target tissue. Thus, the linker nucleosides are usually attached to each other and to the remainder of the oligomeric compound via a cleavable bond. In certain embodiments, such a cleavable bond is a phosphodiester bond.

[0415] As used herein, linker nucleosides are not considered part of the oligonucleotide. Thus, in embodiments where an oligomeric compound comprises an oligonucleotide consisting of a specific number or range of linked nucleosides and / or a specific percentage of complementarity to a reference nucleic acid, and the oligomeric compound also comprises a conjugate group containing a conjugate linker comprising linker nucleosides, these linker nucleosides are not counted in the length of the oligonucleotide and are not used in determining the percentage of complementarity of the oligonucleotide to the reference nucleic acid. For example, an oligomeric compound may comprise (1) a modified oligonucleotide consisting of 8 to 30 nucleosides and (2) a conjugate group comprising 1 to 10 linker nucleosides contiguous with a nucleoside of the modified oligonucleotide. The total number of contiguous linked nucleosides in such an oligomeric compound may be greater than 30. Alternatively, an oligomeric compound may comprise a modified oligonucleotide consisting of 8 to 30 nucleosides but without a conjugate group. The total number of consecutively linked nucleosides in such an oligomeric compound is 30 or less. Unless otherwise specified, a conjugate linker comprises 10 or fewer linker nucleosides. In certain embodiments, a conjugate linker comprises 5 or fewer linker nucleosides. In certain embodiments, a conjugate linker comprises 3 or fewer linker nucleosides. In certain embodiments, a conjugate linker comprises 2 or fewer linker nucleosides. In certain embodiments, a conjugate linker comprises only 1 linker nucleoside.

[0416] In certain embodiments, it is desirable for the conjugate group to be cleaved from the oligonucleotide. For example, in certain situations, oligomeric compounds containing certain conjugate moieties are more likely to be taken up by certain cell types, and after the oligomeric compound is taken up, it is desirable for the conjugate group to be cleaved to release the unconjugated or parent oligonucleotide. Thus, certain conjugate linkers may contain one or more cleavable moieties. In certain embodiments, the cleavable moiety is a cleavable bond. In certain embodiments, the cleavable moiety is an atomic group containing at least one cleavable bond. In certain embodiments, the cleavable moiety comprises an atomic group having one, two, three, four, or more than four cleavable bonds. In certain embodiments, the cleavable moiety is selectively cleaved inside a cell or in an intracellular compartment, such as a lysosome. In certain embodiments, the cleavable moiety is selectively cleaved by an endogenous enzyme, such as a nuclease.

[0417] In certain embodiments, the cleavable bond is selected from among amide, ester, ether, one or both esters of phosphodiester, phosphate ester, carbamate, or disulfide. In certain embodiments, the cleavable bond is one or both esters of phosphodiester. In certain embodiments, the cleavable moiety comprises a phosphate or phosphodiester. In certain embodiments, the cleavable moiety is a phosphate bond between the oligonucleotide and the conjugate moiety or conjugate group.

[0418] In certain embodiments, the cleavable moiety comprises or consists of one or more linker nucleosides. In certain such embodiments, the one or more linker nucleosides are linked to each other and / or to the remainder of the oligomeric compound by a cleavable bond. In certain embodiments, the cleavable bond is an unmodified phosphodiester bond. In certain embodiments, the cleavable moiety is a 2'-deoxynucleoside linked to either the 3'- or 5'-terminal nucleoside of the oligonucleotide by a phosphate internucleoside bond and covalently linked to the remainder of the conjugate linker or conjugate moiety by a phosphate or phosphorothioate bond. In certain such embodiments, the cleavable moiety is 2'-deoxyadenosine.

[0419] 3.Cell targeting part In certain embodiments, the conjugate group comprises a cell targeting moiety. In certain embodiments, the conjugate group has the general formula: [ka] In the formula, n is 1 to about 3, when n is 1, m is 0, when n is 2 or more, m is 1, j is 1 or 0, and k is 1 or 0.

[0420] In certain embodiments, n is 1, j is 1, and k is 0. In certain embodiments, n is 1, j is 0, and k is 1. In certain embodiments, n is 1, j is 1, and k is 1. In certain embodiments, n is 1, j is 1, and k is 1. In certain embodiments, n is 2, j is 1, and k is 0. In certain embodiments, n is 2, j is 0, and k is 1. In certain embodiments, n is 2, j is 1, and k is 1. In certain embodiments, n is 3, j is 1, and k is 0. In certain embodiments, n is 3, j is 0, and k is 1. In certain embodiments, n is 3, j is 1, and k is 1.

[0421] In certain embodiments, the conjugate group comprises a cell-targeting moiety having at least one tethered ligand, hi certain embodiments, the cell-targeting moiety comprises two tethered ligands covalently attached to a branching group.

[0422] In certain embodiments, each ligand of the cell targeting moiety has affinity for at least one receptor type on target cells.In certain embodiments, each ligand has affinity for at least one receptor type on the surface of mammalian liver cells.In certain embodiments, each ligand has affinity for the liver asialoglycoprotein receptor (ASGP-R).In certain embodiments, each ligand is a carbohydrate.

[0423] In certain embodiments, the oligomeric compound comprises a conjugate group comprising a cell targeting moiety having affinity for the transferrin receptor (TfR), also known as TfR1, and CD71. In certain embodiments, the conjugate group comprises an anti-TfR1 antibody or fragment thereof. In certain embodiments, the anti-TfR1 antibody or fragment thereof can be any known in the art, including, but not limited to, those described in WO / 1991 / 004753, WO / 2013 / 103800, WO / 2014 / 144060, WO / 2016 / 081643, WO2016 / 179257, WO / 2016 / 207240, WO / 2017 / 221883, WO / 2018 / 129384, WO / 2018 / 124121, WO / 2019 / 151539, WO / 2020 / 132584, WO / 2020 / 028864, US 7,208,174, US 9,034,329, and US 10,550,188. In certain embodiments, the fragment of the anti-TfR1 antibody is F(ab')2, Fab, Fab', Fv, or scFv.

[0424] In certain embodiments, the conjugate group comprises a protein or peptide capable of binding TfR1. In certain embodiments, the protein or peptide capable of binding TfR1 can be any known in the art, including, but not limited to, those described in WO / 2019 / 140050, WO / 2020 / 037150, WO / 2020 / 124032, and US 10,138,483.

[0425] In certain embodiments, the conjugate group comprises an aptamer capable of binding TfR1. In certain embodiments, the aptamer capable of binding TfR1 can be any known in the art, including, but not limited to, those described in WO / 2013 / 163303, WO / 2019 / 033051, and WO / 2020 / 245198.

[0426] B. Specific end groups In certain embodiments, the oligomeric compound comprises one or more terminal groups. In certain such embodiments, the oligomeric compound comprises a stabilized 5'-phosphate. Stabilized 5'-phosphates include 5'-phosphonates, including but not limited to 5'-vinylphosphonates. In certain embodiments, the terminal group comprises one or more abasic sugar moieties and / or inverted nucleosides. In certain embodiments, the terminal group comprises one or more 2'-linked nucleosides or sugar moieties. In certain such embodiments, the 2'-linked group is an abasic sugar moiety.

[0427] III. Antisense Activity In certain embodiments, oligomeric compounds and oligomeric duplexes can hybridize to a target nucleic acid to provide at least one antisense activity. Such oligomeric compounds and oligomeric duplexes are antisense compounds. In certain embodiments, an antisense compound has antisense activity if it reduces or inhibits the amount or activity of the target nucleic acid by 25% or more in a standard cell assay. In certain embodiments, an antisense compound selectively acts on one or more target nucleic acids. Such antisense compounds comprise a nucleobase sequence that hybridizes to one or more target nucleic acids to provide one or more desired antisense activities and does not hybridize to one or more non-target nucleic acids or does not hybridize to one or more non-target nucleic acids in a manner that results in significant undesired antisense activity.

[0428] In certain antisense activities, hybridization of an antisense compound to a target nucleic acid results in the recruitment of a protein that cleaves the target nucleic acid. For example, certain antisense compounds result in RNase H-mediated cleavage of the target nucleic acid. RNase H is a cellular endonuclease that cleaves the RNA strand of an RNA:DNA duplex. The DNA in such an RNA:DNA duplex need not be unmodified DNA. In certain embodiments, antisense compounds are described herein that are sufficiently "DNA-like" to induce RNase H activity. In certain embodiments, one or more non-DNA-like nucleosides are tolerated within the gap of a gapmer.

[0429] In certain antisense activity, antisense compound or antisense compound part is incorporated into RNA-induced silencing complex (RISC), and finally causes target nucleic acid to be cut.For example, certain antisense compound causes target nucleic acid to be cut by Argonaute.The antisense compound that is incorporated into RISC is RNAi compound.RNAi compound can be double-stranded (siRNA or dsRNAi) or single-stranded (ssRNA).

[0430] In certain embodiments, the hybridization of antisense compounds to target nucleic acid does not result in the recruitment of proteins that cleave the target nucleic acid.In certain embodiments, the hybridization of antisense compounds to target nucleic acid results in changes in the splicing of the target nucleic acid.In certain embodiments, the hybridization of antisense compounds to target nucleic acid results in the inhibition of the binding interaction between the target nucleic acid and proteins or other nucleic acids.In certain embodiments, the hybridization of antisense compounds to target nucleic acid results in changes in the translation of the target nucleic acid.

[0431] Antisense activity can be observed directly or indirectly. In certain embodiments, observing or detecting antisense activity involves observing or detecting a change in the amount of a target nucleic acid or the amount of a protein encoded by such a target nucleic acid, a change in the ratio of splice variants of a nucleic acid or protein, and / or a change in phenotype in a cell or animal.

[0432] IV. Specific Target Nucleic Acids In certain embodiments, the oligomeric compound comprises or consists of an oligonucleotide comprising a region complementary to a target nucleic acid. In certain embodiments, the target nucleic acid is an endogenous RNA molecule. In certain embodiments, the target nucleic acid encodes a protein. In certain such embodiments, the target nucleic acid is selected from mature mRNA and pre-mRNA (including introns, exons, and untranslated regions). In certain embodiments, the target RNA is mature mRNA. In certain embodiments, the target nucleic acid is pre-mRNA. In certain embodiments, the target region is entirely within an intron. In certain embodiments, the target region spans an intron / exon junction. In certain embodiments, the target region is located at least 50% within an intron.

[0433] A. Complementarity / Mismatch and Double-Stranded Complementarity to Target Nucleic Acid In certain embodiments, the oligonucleotide is complementary to the target nucleic acid over the entire length of the oligonucleotide. In certain embodiments, the oligonucleotide is 99%, 95%, 90%, 85%, or 80% complementary to the target nucleic acid. In certain embodiments, the oligonucleotide is at least 80% complementary to the target nucleic acid over the entire length of the oligonucleotide, and includes a region that is 100% or fully complementary to the target nucleic acid. In certain embodiments, the region of full complementarity is 6 to 20, 10 to 18, or 18 to 20 nucleobases in length.

[0434] It is possible to introduce mismatched bases without losing activity. For example, Gautschi et al. (J. Natl. Cancer Inst. 93:463-471, March 2001) demonstrated that an oligonucleotide with 100% complementarity to bcl-2 mRNA and three mismatches to bcl-xL mRNA can reduce the expression of both bcl-2 and bcl-xL in vitro and in vivo. Furthermore, this oligonucleotide also exhibited potent antitumor activity in vivo. Maher and Dolnick (Nuc. Acid. Res. 16:3341-3358, 1988) tested a tandem oligonucleotide consisting of a series of 14 nucleobases, as well as 28- and 42-nucleobase oligonucleotides containing two or three of the tandem oligonucleotide sequences, respectively, for their ability to terminate the translation of human DHFR in a rabbit reticulocyte assay. Each of these three 14 nucleobase oligonucleotides alone was able to inhibit translation, although to a lesser extent than the 28 or 42 nucleobase oligonucleotides.

[0435] In certain embodiments, the oligonucleotide contains one or more mismatched nucleobases relative to the target nucleic acid. In certain embodiments, such mismatches reduce the antisense activity against the target, while the activity against non-targets is more significantly reduced. Thus, in certain embodiments, the selectivity of the oligonucleotide is improved. In certain embodiments, the mismatches are specifically positioned within an oligonucleotide having a gapmer motif. In certain embodiments, the mismatches are located at positions 1, 2, 3, 4, 5, 6, 7, or 8 from the 5' end of the gap region. In certain embodiments, the mismatches are located at positions 9, 8, 7, 6, 5, 4, 3, 2, or 1 from the 3' end of the gap region. In certain embodiments, the mismatches are located at positions 1, 2, 3, or 4 from the 5' end of the wing region. In certain embodiments, the mismatches are located at positions 4, 3, 2, or 1 from the 3' end of the wing region.

[0436] B.PLN In certain embodiments, the oligomeric agent or oligomeric compound comprises or consists of an oligonucleotide comprising a region complementary to a target nucleic acid, the target nucleic acid being PLN. In certain embodiments, the PLN nucleic acid has the sequence set forth in SEQ ID NO: 1 (GENBANK Accession No. NM_002667.4) or SEQ ID NO: 2 (GENBANK Accession No. NC_000006.12, truncated from nucleoside 118545001 to 118565000). In certain embodiments, contacting cells with an oligomeric compound complementary to SEQ ID NO: 1 or 2 reduces the amount of PLN RNA, and in certain embodiments, reduces the amount of PLN protein. In certain embodiments, the oligomeric compound consists of a modified oligonucleotide. In certain embodiments, the oligomeric compound consists of a modified oligonucleotide and a conjugate group.

[0437] C. Specific target nucleic acids in specific tissues In certain embodiments, the oligomeric compound comprises or consists of an oligonucleotide comprising a region complementary to a target nucleic acid, said target nucleic acid being expressed in a pharmacologically relevant tissue, hi certain embodiments, said pharmacologically relevant tissue is a cardiac cell or tissue.

[0438] V. Specific Methods and Uses Certain embodiments provided herein relate to methods of inhibiting the expression of PLN, which may be useful in treating diseases associated with PLN in a subject, by administering an oligomeric agent, oligomeric compound, modified oligonucleotide, or oligomeric duplex, any of which comprises a modified oligonucleotide having a nucleobase sequence complementary to a PLN nucleic acid.

[0439] Examples of PLN-related diseases that can be treated with the oligomeric agents, oligomeric compounds, modified oligonucleotides, oligomeric duplexes, and methods provided herein include cardiomyopathy, heart failure, or arrhythmia. In certain embodiments, the cardiomyopathy is hereditary and includes mutations in p.Arg14del, Arg9Cys(R9C), and Arg25Cys(R25C). In certain embodiments, the cardiomyopathy is dilated cardiomyopathy (DCM). In certain embodiments, the DCM is hereditary and includes mutations in TTN, LMNA, RBM20, SCN5A, MYH7, TNNT2, and TPM1. In certain embodiments, the DCM is arrhythmogenic DCM. In certain embodiments, the heart failure is heart failure with preserved ejection fraction (HFpEF), heart failure with reduced ejection fraction (HFrEF), acute heart failure, or worsening chronic heart failure. In certain embodiments, the arrhythmia is ventricular tachycardia (Vtac) or ventricular fibrillation (Vfib).

[0440] In certain embodiments, a method comprises administering to a subject an oligomeric agent, oligomeric compound, modified oligonucleotide, or oligomeric duplex, all of which have a nucleobase sequence complementary to a PLN nucleic acid. In certain embodiments, the subject has cardiomyopathy, heart failure, or arrhythmia. In certain embodiments, the cardiomyopathy is hereditary and comprises p.Arg14del, Arg9Cys(R9C), and Arg25Cys(R25C) mutations. In certain embodiments, the cardiomyopathy is dilated cardiomyopathy (DCM). In certain embodiments, the DCM is hereditary and comprises TTN, LMNA, RBM20, SCN5A, MYH7, TNNT2, and TPM1 mutations. In certain embodiments, the DCM is arrhythmogenic DCM. In certain embodiments, the heart failure is heart failure with preserved ejection fraction (HFpEF), heart failure with reduced ejection fraction (HFrEF), acute heart failure, or worsening chronic heart failure. In certain embodiments, the arrhythmia is ventricular tachycardia (Vtac) or ventricular fibrillation (Vfib).

[0441] In certain embodiments, a method for treating cardiomyopathy, heart failure, or arrhythmia in a subject comprises administering to the subject a therapeutically effective amount of an oligomeric agent, oligomeric compound, modified oligonucleotide, or oligomeric duplex, all of which have a nucleobase sequence complementary to a PLN nucleic acid, thereby treating the subject. In certain embodiments, the cardiomyopathy is hereditary and includes p.Arg14del, Arg9Cys(R9C), and Arg25Cys(R25C) mutations. In certain embodiments, the cardiomyopathy is dilated cardiomyopathy (DCM). In certain embodiments, the DCM is hereditary and includes mutations in TTN, LMNA, RBM20, SCN5A, MYH7, TNNT2, and TPM1. In certain embodiments, the DCM is arrhythmogenic DCM. In certain embodiments, heart failure is heart failure with preserved ejection fraction (HFpEF), heart failure with reduced ejection fraction (HFrEF), acute heart failure, or worsening chronic heart failure.In certain embodiments, arrhythmia is ventricular tachycardia (Vtac) or ventricular fibrillation (Vfib).In certain embodiments, administering a therapeutically effective amount of oligomeric agent, oligomeric compound, modified oligonucleotide, or oligomeric duplex improves cardiac function, cardiovascular death, cardiac dilation, myocardial fibrosis, low-voltage ECG, diastolic calcium uptake, ejection fraction (EF), left ventricular ejection fraction (LVEF), left ventricular end-systolic volume (LVESV), left ventricular end-diastolic volume (LVEDV), mitral valve blood flow profile, left ventricular (LV) strain, left ventricular (LV) strain rate, infarct size, heart failure hospitalization, 6-minute walk test (6MWT), Kansas City Cardiomyopathy Questionnaire score (KCCQS), heart rate, or heart rhythm in the subject.

[0442] In certain embodiments, a method for inhibiting the expression of a PLN nucleic acid, e.g., RNA, in a subject with a PLN-related disease comprises administering to the subject an oligomeric agent, oligomeric compound, modified oligonucleotide, or oligomeric duplex, all of which have a nucleobase sequence complementary to a PLN nucleic acid, thereby inhibiting the expression of a PLN nucleic acid in the subject. In certain embodiments, administering the oligomeric agent, oligomeric compound, modified oligonucleotide, or oligomeric duplex inhibits the expression of PLN in the heart. In certain embodiments, the subject has cardiomyopathy, heart failure, or arrhythmia. In certain embodiments, the cardiomyopathy is hereditary and includes mutations p.Arg14del, Arg9Cys(R9C), and Arg25Cys(R25C). In certain embodiments, the cardiomyopathy is dilated cardiomyopathy (DCM). In certain embodiments, the DCM is hereditary and includes mutations in TTN, LMNA, RBM20, SCN5A, MYH7, TNNT2, and TPM1. In certain embodiments, the DCM is arrhythmogenic DCM. In certain embodiments, the heart failure is heart failure with preserved ejection fraction (HFpEF), heart failure with reduced ejection fraction (HFrEF), acute heart failure, or worsening chronic heart failure. In certain embodiments, the arrhythmia is ventricular tachycardia (Vtac) or ventricular fibrillation (Vfib).

[0443] In certain embodiments, a method for inhibiting expression of a PLN nucleic acid in a cell comprises contacting the cell with an oligomeric agent, oligomeric compound, modified oligonucleotide, or oligomeric duplex, all of which have a nucleobase sequence complementary to a PLN nucleic acid, thereby inhibiting expression of a PLN nucleic acid in the cell. In certain embodiments, the cell is a cardiac cell. In certain embodiments, the cell is included in a subject with cardiomyopathy, heart failure, or arrhythmia. In certain embodiments, the cardiomyopathy is hereditary and includes mutations in p.Arg14del, Arg9Cys (R9C), and Arg25Cys (R25C). In certain embodiments, the cardiomyopathy is dilated cardiomyopathy (DCM). In certain embodiments, the DCM is hereditary and includes mutations in TTN, LMNA, RBM20, SCN5A, MYH7, TNNT2, and TPM1. In certain embodiments, the DCM is arrhythmogenic DCM. In certain embodiments, the heart failure is heart failure with preserved ejection fraction (HFpEF), heart failure with reduced ejection fraction (HFrEF), acute heart failure, or worsening chronic heart failure. In certain embodiments, the arrhythmia is ventricular tachycardia (Vtac) or ventricular fibrillation (Vfib).

[0444] In certain embodiments, the present invention provides an oligomeric agent, oligomeric compound, modified oligonucleotide, or oligomeric duplex, each of which has a nucleobase sequence complementary to a PLN nucleic acid, for use in treating a disease associated with PLN. In certain embodiments, the disease is cardiomyopathy, heart failure, or arrhythmia. In certain embodiments, the cardiomyopathy is hereditary and includes mutations in p.Arg14del, Arg9Cys(R9C), and Arg25Cys(R25C). In certain embodiments, the cardiomyopathy is dilated cardiomyopathy (DCM). In certain embodiments, the DCM is hereditary and includes mutations in TTN, LMNA, RBM20, SCN5A, MYH7, TNNT2, and TPM1. In certain embodiments, the DCM is arrhythmogenic DCM. In certain embodiments, the heart failure is heart failure with preserved ejection fraction (HFpEF), heart failure with reduced ejection fraction (HFrEF), acute heart failure, or worsening chronic heart failure. In certain embodiments, the arrhythmia is ventricular tachycardia (Vtac) or ventricular fibrillation (Vfib). In certain embodiments, the oligomeric agent, oligomeric compound, modified oligonucleotide, or oligomeric duplex is for use in improving cardiac function, cardiovascular death, cardiac dilation, myocardial fibrosis, low-voltage ECG, diastolic calcium uptake, ejection fraction (EF), left ventricular ejection fraction (LVEF), left ventricular end-systolic volume (LVESV), left ventricular end-diastolic volume (LVEDV), mitral valve perfusion profile, left ventricular (LV) strain, left ventricular (LV) strain rate, infarct size, heart failure hospitalization, 6-minute walk test (6MWT), Kansas City Cardiomyopathy Questionnaire score (KCCQS), heart rate, or heart rhythm associated with cardiomyopathy, heart failure, or arrhythmia.

[0445] In certain embodiments, oligomeric agents, oligomeric compounds, modified oligonucleotides, or oligomeric duplexes are provided for the manufacture or preparation of a medicament for treating a disease associated with PLN, each of which comprises a modified oligonucleotide having a nucleobase sequence complementary to a PLN nucleic acid. In certain embodiments, the disease is cardiomyopathy, heart failure, or arrhythmia. In certain embodiments, the oligomeric agents, oligomeric compounds, modified oligonucleotides, or oligomeric duplexes are provided for the manufacture or preparation of a medicament for improving cardiac function, cardiovascular death, cardiac dilation, myocardial fibrosis, low-voltage ECG, diastolic calcium uptake, ejection fraction (EF), left ventricular ejection fraction (LVEF), left ventricular end-systolic volume (LVESV), left ventricular end-diastolic volume (LVEDV), mitral valve blood flow profile, left ventricular (LV) strain, left ventricular (LV) strain rate, infarct size, heart failure hospitalization, 6-minute walk test (6MWT), Kansas City Cardiomyopathy Questionnaire score (KCCQS), heart rate, or heart rhythm associated with cardiomyopathy, heart failure, or arrhythmia. In certain embodiments, the cardiomyopathy is hereditary and includes mutations in p.Arg14del, Arg9Cys (R9C), and Arg25Cys (R25C). In certain embodiments, the cardiomyopathy is dilated cardiomyopathy (DCM). In certain embodiments, the DCM is hereditary and includes mutations in TTN, LMNA, RBM20, SCN5A, MYH7, TNNT2, and TPM1. In certain embodiments, the DCM is arrhythmogenic DCM. In certain embodiments, the heart failure is heart failure with preserved ejection fraction (HFpEF), heart failure with reduced ejection fraction (HFrEF), acute heart failure, or worsening chronic heart failure. In certain embodiments, the arrhythmia is ventricular tachycardia (Vtac) or ventricular fibrillation (Vfib).

[0446] In any of the methods or uses described herein, the oligomeric agent, the oligomeric compound, the modified oligonucleotide, or the oligomeric duplex may be any described herein.

[0447] VI. Certain Pharmaceutical Compositions In certain embodiments, provided herein are pharmaceutical compositions comprising one or more oligomeric compounds. In certain embodiments, the one or more oligomeric compounds each comprise a modified oligonucleotide. In certain embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable diluent or carrier. In certain embodiments, the pharmaceutical composition comprises or consists of sterile saline and one or more oligomeric compounds. In certain embodiments, the sterile saline is pharmaceutical-grade saline. In certain embodiments, the pharmaceutical composition comprises or consists of one or more oligomeric compounds and sterile water. In certain embodiments, the sterile water is pharmaceutical-grade water. In certain embodiments, the pharmaceutical composition comprises or consists of one or more oligomeric compounds and phosphate-buffered saline (PBS). In certain embodiments, the sterile PBS is pharmaceutical-grade PBS.

[0448] In certain embodiments, pharmaceutical compositions comprise one or more oligomeric compounds and one or more excipients, hi certain embodiments, the excipients are selected from water, saline, alcohol, polyethylene glycol, gelatin, lactose, amylase, magnesium stearate, talc, silicic acid, viscous paraffin, hydroxymethylcellulose, and polyvinylpyrrolidone.

[0449] In certain embodiments, the oligomeric compounds may be mixed with pharmaceutically acceptable active and / or inactive substances for the preparation of pharmaceutical compositions or formulations. The composition and method for formulating a pharmaceutical composition depends on several criteria, including, but not limited to, the route of administration, the extent of the disease, or the dose to be administered.

[0450] In certain embodiments, pharmaceutical compositions comprising oligomeric compounds include any pharmaceutically acceptable salts of the oligomeric compounds, esters of the oligomeric compounds, or salts of such esters. In certain embodiments, pharmaceutical compositions comprising oligomeric compounds comprising one or more oligonucleotides can provide (directly or indirectly) biologically active metabolites or residues thereof upon administration to animals, including humans. Thus, for example, the present disclosure also relates to pharmaceutically acceptable salts of oligomeric compounds, prodrugs, pharmaceutically acceptable salts of such prodrugs, and other biological equivalents. Suitable pharmaceutically acceptable salts include, but are not limited to, sodium and potassium salts. In certain embodiments, prodrugs contain one or more conjugate groups attached to the oligonucleotide, which are cleaved by endogenous nucleases in the body.

[0451] Lipid moieties have been used in various ways in nucleic acid therapy. In certain such methods, nucleic acids, such as oligomeric compounds, are introduced into preformed liposomes or lipoplexes made of a mixture of cationic lipids and neutral lipids. In certain methods, DNA complexes with mono- or polycationic lipids are formed in the absence of neutral lipids. In certain embodiments, the lipid moiety is selected to increase the distribution of the drug to specific cells or tissues. In certain embodiments, the lipid moiety is selected to increase the distribution of the drug to adipose tissue. In certain embodiments, the lipid moiety is selected to increase the distribution of the drug to muscle tissue.

[0452] In certain embodiments, the pharmaceutical composition comprises a delivery system. Examples of delivery systems include, but are not limited to, liposomes and emulsions. Certain delivery systems are useful for preparing certain pharmaceutical compositions, including those containing hydrophobic compounds. In certain embodiments, certain organic solvents, such as dimethyl sulfoxide, are used.

[0453] In certain embodiments, the pharmaceutical composition comprises one or more tissue-specific delivery molecules designed to deliver one or more agents of the present invention to a particular tissue or cell type. For example, in certain embodiments, the pharmaceutical composition comprises a liposome coated with a tissue-specific antibody.

[0454] In certain embodiments, the pharmaceutical composition includes a cosolvent system. Certain such cosolvent systems include, for example, benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase. In certain embodiments, such cosolvent systems are used for hydrophobic compounds. A non-limiting example of such a cosolvent system is the VPD cosolvent system, which is a solution of 3% w / v benzyl alcohol, 8% w / v of the nonpolar surfactant Polysorbate 80™, and 65% w / v polyethylene glycol 300 in absolute ethanol. The proportions of such cosolvent systems may be varied significantly without significantly altering their solubility and toxicity. Furthermore, the identity of the cosolvent components may be varied; for example, other surfactants may be substituted for Polysorbate 80™, the fraction size of polyethylene glycol may be changed, other biocompatible polymers, such as polyvinylpyrrolidone, may replace polyethylene glycol, or other sugars or polysaccharides may replace dextrose.

[0455] In certain embodiments, the pharmaceutical composition is prepared for oral administration. In certain embodiments, the pharmaceutical composition is prepared for buccal administration. In certain embodiments, the pharmaceutical composition is prepared for administration by injection (e.g., intravenous, subcutaneous, intramuscular, intrathecal (IT), intracerebroventricular (ICV), etc.). In certain such embodiments, the pharmaceutical composition includes a carrier and is formulated in an aqueous solution, e.g., water or a physiologically compatible buffer, e.g., Hank's solution, Ringer's solution, or physiological saline buffer. In certain embodiments, other ingredients are included (e.g., ingredients that aid solubility or serve as preservatives). In certain embodiments, injectable suspensions are prepared using appropriate liquid carriers, suspending agents, and the like. Certain pharmaceutical compositions for injection are contained in unit dosage form, e.g., in ampoules or multi-dose containers. Certain pharmaceutical compositions for injection are suspensions, solutions, or emulsions in oily or aqueous vehicles and may include formulatory agents such as suspending agents, stabilizing agents, and / or dispersing agents. Certain solvents suitable for use in injectable pharmaceutical compositions include, but are not limited to, lipophilic solvents and fatty oils such as sesame oil, synthetic fatty acid esters, such as ethyl oleate or triglycerides, and liposomes.

[0456] Under certain conditions, certain compounds disclosed herein function as acids. Such compounds may be depicted or described in a protonated (free acid) form or an ionized (salt) form associated with a cation, and aqueous solutions of such compounds exist in equilibrium between these forms. For example, the phosphate linkage of an oligonucleotide in aqueous solution exists in equilibrium between the free acid, anionic, and salt forms. Unless otherwise indicated, the compounds disclosed herein are intended to include all such forms. Furthermore, certain oligonucleotides have several such linkages, each of which is in equilibrium. Thus, an oligonucleotide in solution exists as a collection of forms that are all in equilibrium at multiple positions. The term "oligonucleotide" is intended to include all such forms. Illustrated structures necessarily represent a single form. Nevertheless, unless otherwise indicated, such drawings are intended to include corresponding forms as well. As used herein, structures depicting the free acid of a compound followed by the term "or a salt thereof" explicitly include all such forms, which may be fully or partially protonated / deprotonated / associated with a cation. In some cases, one or more specific cations are identified.

[0457] In certain embodiments, the modified oligonucleotide or oligomeric compound is contained in an aqueous solution with sodium. In certain embodiments, the modified oligonucleotide or oligomeric compound is contained in an aqueous solution with potassium. In certain embodiments, the modified oligonucleotide or oligomeric compound is contained in PBS. In certain embodiments, the modified oligonucleotide or oligomeric compound is contained in water. In certain such embodiments, the pH of the solution is adjusted with NaOH and / or HCl until the desired pH is reached.

[0458] VII. Specific Hotspot Areas 1. Nucleic acid bases 3341 to 3368 of SEQ ID NO: 2 In certain embodiments, nucleobases 3341-3368 of SEQ ID NO:2 comprise a hotspot region. In certain embodiments, the modified oligonucleotide is complementary within nucleobases 3341-3368 of SEQ ID NO:2. In certain embodiments, the modified oligonucleotide is 16 nucleobases in length. In certain embodiments, the modified oligonucleotide is a gapmer. In certain embodiments, the gapmer is a cEt gapmer. In certain embodiments, the gapmer is a mixed MOE / cEt gapmer. In certain embodiments, the gapmer is a mixed 2'-OMe / cEt gapmer. In certain embodiments, the sugar motif of the gapmer is selected from (5' to 3'): kkkddddddddddkkk, kkdddddddddkekek, kkkdyddddddddkkk, kkkdddddddddkkke, where each "d" represents a 2'-β-D-deoxyribosyl sugar moiety, each "e" represents a 2'-MOE sugar moiety, each "y" represents a 2'-OMe sugar moiety, and each "k" represents a cEt-modified sugar moiety. Each cytosine residue is 5-methylcytosine. In certain embodiments, the nucleosides of the modified oligonucleotide are linked by a combination of phosphodiester and phosphorothioate internucleoside linkages. In certain embodiments, the nucleosides of the modified oligonucleotide are linked by phosphorothioate internucleoside linkages.

[0459] The nucleobase sequences of SEQ ID NOs: 636, 756, 818, 864, 1416, 1419, 1512, 1513, 1530, 1563, 1622, 1623, and 1625 are complementary to the interior of nucleobases 3341 to 3368 of SEQ ID NO: 2.

[0460] Compounds 1342326, 1342342, 1342785, 1342952, 1343238, 1343301, 1343367, 1393388, 1393391, 1393544, 1393555, 1393557, 1393559, 1393562, 1393563, 1393745, 1393747, 1393748, 139 3749, 1393750, 1393753, 1393934, 1393935, 1393936, 1393939, 1393940, 1393942, 1393997, 1394043, 1394091, 1446717, 1446691, and 1446737 are complementary to nucleobases 3341 to 3368 within SEQ ID NO:2.

[0461] In certain embodiments, modified oligonucleotides complementary to within nucleobases 3341-3368 of SEQ ID NO:2 achieve at least 58% reduction in PLN RNA in vitro in a standard cell assay. In certain embodiments, modified oligonucleotides complementary to within nucleobases 3341-3368 of SEQ ID NO:2 achieve an average of 77% reduction in PLN RNA in vitro in a standard cell assay.

[0462] 2. Nucleic acid bases 4516 to 4533 of SEQ ID NO: 2 In certain embodiments, nucleobases 4516-4533 of SEQ ID NO:2 comprise a hotspot region. In certain embodiments, the modified oligonucleotide is complementary within nucleobases 4516-4533 of SEQ ID NO:2. In certain embodiments, the modified oligonucleotide is 16 nucleobases in length. In certain embodiments, the modified oligonucleotide is a gapmer. In certain embodiments, the gapmer is a cEt gapmer. In certain embodiments, the gapmer is a mixed MOE / cEt gapmer. In certain embodiments, the gapmer is a mixed 2'-OMe / cEt gapmer. In certain embodiments, the sugar motif of the gapmer is selected from (5' to 3'): kkkddddddddddkkk, kkdddddddddkekek, kkkdddddddddkkke, kkkdyddddddddkkk, where each "d" represents a 2'-β-D-deoxyribosyl sugar moiety, each "e" represents a 2'-MOE sugar moiety, each "y" represents a 2'-OMe sugar moiety, and each "k" represents a cEt-modified sugar moiety. Each cytosine residue is 5-methylcytosine. In certain embodiments, the nucleosides of the modified oligonucleotide are linked by a combination of phosphodiester and phosphorothioate internucleoside linkages. In certain embodiments, the nucleosides of the modified oligonucleotide are linked by phosphorothioate internucleoside linkages.

[0463] The nucleic acid base sequences of SEQ ID NOs: 828, 1415, 1420, 1617, and 1621 are complementary to the interior of nucleic acid bases 4516 to 4533 of SEQ ID NO:2.

[0464] Compounds 1342919, 1393387, 1393392, 1393547, 1393551, 1393553, 1393736, 1393737, 1393742, 1393927, 1393929, 1393933, and 1446694 are complementary to within nucleobases 4516 to 4533 of SEQ ID NO:2.

[0465] In certain embodiments, modified oligonucleotides complementary to within nucleobases 4516-4533 of SEQ ID NO:2 achieve at least 60% reduction in PLN RNA in vitro in a standard cell assay. In certain embodiments, modified oligonucleotides complementary to within nucleobases 4516-4533 of SEQ ID NO:2 achieve an average of 80% reduction in PLN RNA in vitro in a standard cell assay.

[0466] 3. Nucleic acid bases 5498 to 5517 of SEQ ID NO: 2 In certain embodiments, nucleobases 5498-5517 of SEQ ID NO:2 comprise a hotspot region. In certain embodiments, the modified oligonucleotide is complementary within nucleobases 5498-5517 of SEQ ID NO:2. In certain embodiments, the modified oligonucleotide is 14, 16, 17, 18, or 20 nucleobases in length. In certain embodiments, the modified oligonucleotide is a gapmer. In certain embodiments, the gapmer is a cEt gapmer. In certain embodiments, the gapmer is a mixed MOE / cEt gapmer. In certain embodiments, the gapmer is a mixed 2'-OMe / cEt gapmer. In certain embodiments, the sugar motifs of the gapmer are (5' to 3'): kkkddddddddddkkk, kkdddddddddkekek, kkkdddddddddkkke, kkkdyddddddddkkk, kkkkddddddddddkkkk, kkddddddddddddkkkk, kkddddddddddddkkk, kkkddddddddddddkkk, kkkddddddddddddkkk, kkkkddddddddddddkkk, kkkkddddddddddkkk, kkkkddddddddddkkee, kkkddddddddddkeee, k The modified oligonucleotide is selected from kkddddddddddkkeee, kkkddddddddddkeeee, ekkddddddddddkkk, kekddddddddddkkk, kkeddddddddddkkk, ekkdddddddddddkkke, kekdddddddddkkke, kkedddddddddddkkke, where each "d" represents a 2'-β-D-deoxyribosyl sugar moiety, each "e" represents a 2'-MOE sugar moiety, each "y" represents a 2'-OMe sugar moiety, and each "k" represents a cEt-modified sugar moiety. Each cytosine residue is 5-methylcytosine. In certain embodiments, the nucleosides of the modified oligonucleotide are linked by a combination of phosphodiester and phosphorothioate internucleoside linkages. In certain embodiments, the nucleosides of the modified oligonucleotide are linked by phosphorothioate internucleoside linkages.

[0467] The nucleobase sequences of SEQ ID NOs: 538, 609, 675, 737, 1396, 1595, 1671, 1678, 1685, 1689, 1696, 1700, and 1703 are complementary to the interior of nucleobases 5498 to 5517 of SEQ ID NO: 2.

[0468] Compounds 1342668, 1342944, 1343077, 1343091, 1393355, 1393486, 1393487, 1393489, 1393490, 1393493, 1393674, 1393675, 139367 6, 1393677, 1393682, 1393863, 1393866, 1393868, 1393869, 1393871, 1446729, 1446701, 1436544, 1446730, 1436542, 1528609 , 1528610, 1528619, 1528620, 1528629, 1528630, 1528638, 1528639, 1528640, 1528649, 1528650, 1528662, 1528663, 1528671, 1528672, 1528682, 1528683, 1528842, 1528846, 1528850, 1528855, 1528858, and 1528864 are complementary to within nucleobases 5498 to 5517 of SEQ ID NO:2.

[0469] In certain embodiments, modified oligonucleotides complementary to within nucleobases 5498-5517 of SEQ ID NO:2 achieve at least 40% reduction in PLN RNA in vitro in a standard cell assay. In certain embodiments, modified oligonucleotides complementary to within nucleobases 5498-5517 of SEQ ID NO:2 achieve an average of 76% reduction in PLN RNA in vitro in a standard cell assay.

[0470] 4. Nucleic acid bases 14337 to 14357 of SEQ ID NO: 2 In certain embodiments, nucleobases 14337-14357 of SEQ ID NO:2 comprise a hotspot region. In certain embodiments, the modified oligonucleotide is complementary within nucleobases 14337-14357 of SEQ ID NO:2. In certain embodiments, the modified oligonucleotide is 16 nucleobases in length. In certain embodiments, the modified oligonucleotide is a gapmer. In certain embodiments, the gapmer is a cEt gapmer. In certain embodiments, the gapmer is a mixed MOE / cEt gapmer. In certain embodiments, the gapmer is a mixed 2'-OMe / cEt gapmer. In certain embodiments, the sugar motif of the gapmer is selected from (5' to 3'): kkkddddddddddkkk, kkdddddddddkekek, kkkdddddddddkkke, kkkdyddddddddkkk, where each "d" represents a 2'-β-D-deoxyribosyl sugar moiety, each "e" represents a 2'-MOE sugar moiety, each "y" represents a 2'-OMe sugar moiety, and each "k" represents a cEt-modified sugar moiety. Each cytosine residue is 5-methylcytosine. In certain embodiments, the nucleosides of the modified oligonucleotide are linked by a combination of phosphodiester and phosphorothioate internucleoside linkages. In certain embodiments, the nucleosides of the modified oligonucleotide are linked by phosphorothioate internucleoside linkages.

[0471] The nucleobase sequences of SEQ ID NOs: 336, 1360, 1469, 1485, 1486, 1488, 1600, and 1603 are complementary to the interior of nucleobases 14337 to 14357 of SEQ ID NO:2.

[0472] Compounds 1342523, 1342787, 1393367, 1393369, 1393371, 1393505, 1393508, 1393509, 1393512, 1393694, 1393696, 1393697, 1393698, 1393885, 1393887, 1393892, 1393893, 1393983, 1394029, 1394079, 1394104, 1446735, 1446697, 1446723, 1443260, and 1446741 are complementary to within nucleobases 14337 to 14357 of SEQ ID NO:2.

[0473] In certain embodiments, modified oligonucleotides complementary to within nucleobases 14337-14357 of SEQ ID NO:2 achieve at least 64% reduction in PLN RNA in vitro in a standard cell assay. In certain embodiments, modified oligonucleotides complementary to within nucleobases 14337-14357 of SEQ ID NO:2 achieve an average of 81% reduction in PLN RNA in vitro in a standard cell assay.

[0474] 5. Nucleic acid bases 14569 to 14588 of SEQ ID NO: 2 In certain embodiments, nucleobases 14569-14588 of SEQ ID NO:2 comprise a hotspot region. In certain embodiments, the modified oligonucleotide is complementary within nucleobases 14569-14588 of SEQ ID NO:2. In certain embodiments, the modified oligonucleotide is 16 nucleobases in length. In certain embodiments, the modified oligonucleotide is a gapmer. In certain embodiments, the gapmer is a cEt gapmer. In certain embodiments, the gapmer is a mixed MOE / cEt gapmer. In certain embodiments, the gapmer is a mixed 2'-OMe / cEt gapmer. In certain embodiments, the sugar motif of the gapmer is selected from (5' to 3'): kkkddddddddddkkk, kkdddddddddkekek, kkkdddddddddkkke, kkkdyddddddddkkk, where each "d" represents a 2'-β-D-deoxyribosyl sugar moiety, each "e" represents a 2'-MOE sugar moiety, each "y" represents a 2'-OMe sugar moiety, and each "k" represents a cEt-modified sugar moiety. Each cytosine residue is 5-methylcytosine. In certain embodiments, the nucleosides of the modified oligonucleotide are linked by a combination of phosphodiester and phosphorothioate internucleoside linkages. In certain embodiments, the nucleosides of the modified oligonucleotide are linked by phosphorothioate internucleoside linkages.

[0475] The nucleic acid base sequences of SEQ ID NOs: 1072, 1136, 1407, 1411, and 1615 are complementary to the interior of nucleic acid bases 14569 to 14588 of SEQ ID NO:2.

[0476] Compounds 1342898, 1343100, 1393379, 1393383, 1393535, 1393536, 1393537, 1393540, 1393726, 1393727, 1393728, 1393732, 1393916, 1393917, 1393919, 1393920, and 1446733 are complementary to within nucleobases 14569 to 14588 of SEQ ID NO:2.

[0477] In certain embodiments, modified oligonucleotides complementary to within nucleobases 14569-14588 of SEQ ID NO:2 achieve at least 44% reduction in PLN RNA in vitro in a standard cell assay. In certain embodiments, modified oligonucleotides complementary to within nucleobases 14569-14588 of SEQ ID NO:2 achieve an average of 77% reduction in PLN RNA in vitro in a standard cell assay.

[0478] 6. Nucleic acid bases 14607 to 14631 of SEQ ID NO: 2 In certain embodiments, nucleobases 14607-14631 of SEQ ID NO:2 comprise a hotspot region. In certain embodiments, the modified oligonucleotide is complementary within nucleobases 14607-14631 of SEQ ID NO:2. In certain embodiments, the modified oligonucleotide is 16 nucleobases in length. In certain embodiments, the modified oligonucleotide is a gapmer. In certain embodiments, the gapmer is a cEt gapmer. In certain embodiments, the gapmer is a mixed MOE / cEt gapmer. In certain embodiments, the gapmer is a mixed 2'-OMe / cEt gapmer. In certain embodiments, the sugar motif of the gapmer is selected from (5' to 3'): kkkddddddddddkkk, kkdddddddddkekek, kkkdyddddddddkkk, kkkdddddddddkkke, where each "d" represents a 2'-β-D-deoxyribosyl sugar moiety, each "e" represents a 2'-MOE sugar moiety, each "y" represents a 2'-OMe sugar moiety, and each "k" represents a cEt-modified sugar moiety. Each cytosine residue is 5-methylcytosine. In certain embodiments, the nucleosides of the modified oligonucleotide are linked by a combination of phosphodiester and phosphorothioate internucleoside linkages. In certain embodiments, the nucleosides of the modified oligonucleotide are linked by phosphorothioate internucleoside linkages.

[0479] The nucleic acid base sequences of SEQ ID NOs: 35, 110, 355, 457, 505, 611, 1234, 1269, 1319, 1500, 1548, 1568, and 1578 are complementary to the interior of nucleic acid bases 14607 to 14631 of SEQ ID NO: 2.

[0480] Compounds 1121401, 1121402, 1342190, 1342569, 1342673, 1342749, 1343124, 1343142, 134317 2, 1343258, 1343263, 1343320, 1343322, 1343357, 1343360, 1343438, 1343439, 1343440 , 1343442, 1343444, 1343548, 1343549, 1343551, 1343552, 1343553, 1343626, 1343629, 1343631, 1343633, 134363, 1443234, and 1443241 are complementary to nucleobases 14607 to 14631 within SEQ ID NO:2.

[0481] In certain embodiments, modified oligonucleotides complementary to within nucleobases 14607-14631 of SEQ ID NO:2 achieve at least 38% reduction in PLN RNA in vitro in a standard cell assay. In certain embodiments, modified oligonucleotides complementary to within nucleobases 14607-14631 of SEQ ID NO:2 achieve an average of 74% reduction in PLN RNA in vitro in a standard cell assay.

[0482] 7. Nucleic acid bases 14683 to 14703 of SEQ ID NO: 2 In certain embodiments, nucleobases 14683-14703 of SEQ ID NO:2 comprise a hotspot region. In certain embodiments, the modified oligonucleotide is complementary within nucleobases 14683-14703 of SEQ ID NO:2. In certain embodiments, the modified oligonucleotide is 14, 16, 17, 18, or 20 nucleobases in length. In certain embodiments, the modified oligonucleotide is a gapmer. In certain embodiments, the gapmer is a cEt gapmer. In certain embodiments, the gapmer is a mixed MOE / cEt gapmer. In certain embodiments, the gapmer is a mixed 2'-OMe / cEt gapmer. In certain embodiments, the sugar motifs of the gapmer are (5' to 3'): kkkddddddddddkkk, kkdddddddddkekek, kkkdyddddddddkkk, kkkdddddddddkkke, kkkkddddddddddddkkkk, kkkkkddddddddddkkkk, kkkkkddddddddddkkkkk, kkddddddddddddkkkk, kkkkkddddddddddkkk, kkkddddddddddkkk, kkkddddddddddkkk, kkkdddddddddd The modified oligonucleotide is selected from the group consisting of dkkee, kkkddddddddddkeee, kkkddddddddddkkeee, kkkddddddddddkeeee, ekkddddddddddkkk, kekddddddddddkkk, and kkeddddddddddkkk, where each "d" represents a 2'-β-D-deoxyribosyl sugar moiety, each "e" represents a 2'-MOE sugar moiety, each "y" represents a 2'-OMe sugar moiety, and each "k" represents a cEt-modified sugar moiety. Each cytosine residue is 5-methylcytosine. In certain embodiments, the nucleosides of the modified oligonucleotide are linked by a combination of phosphodiester and phosphorothioate internucleoside linkages. In certain embodiments, the nucleosides of the modified oligonucleotide are linked by phosphorothioate internucleoside linkages.

[0483] The nucleic acid base sequences of SEQ ID NOs: 185, 464, 474, 590, 647, 719, 1547, 1677, 1684, 1695, 1699, and 1708 are complementary to the interior of nucleic acid bases 14683 to 14703 of SEQ ID NO: 2.

[0484] Compounds 1121403, 1342270, 1342393, 1342536, 1342754, 1343191, 1343436, 134343 7, 1343454, 1343546, 1343562, 1343564, 1343627, 1343628, 1343630, 1443235 , 1528607, 1528615, 1528617, 1528627, 1528636, 1528647, 1528658, 1528669, 1528679, 1528844, 1528848, and 1528852 are complementary to nucleobases 14683 to 14703 within SEQ ID NO:2.

[0485] In certain embodiments, modified oligonucleotides complementary to within nucleobases 14683-14703 of SEQ ID NO:2 achieve at least 42% reduction in PLN RNA in vitro in a standard cell assay. In certain embodiments, modified oligonucleotides complementary to within nucleobases 14683-14703 of SEQ ID NO:2 achieve an average of 63% reduction in PLN RNA in vitro in a standard cell assay.

[0486] 8. Nucleic acid bases 14828 to 14848 of SEQ ID NO: 2 In certain embodiments, nucleobases 14828-14848 of SEQ ID NO:2 comprise a hotspot region. In certain embodiments, the modified oligonucleotide is complementary within nucleobases 14828-14848 of SEQ ID NO:2. In certain embodiments, the modified oligonucleotide is 16 nucleobases in length. In certain embodiments, the modified oligonucleotide is a gapmer. In certain embodiments, the gapmer is a cEt gapmer. In certain embodiments, the gapmer is a mixed MOE / cEt gapmer. In certain embodiments, the gapmer is a mixed 2'-OMe / cEt gapmer. In certain embodiments, the sugar motif of the gapmer is selected from (5' to 3'): kkkddddddddddkkk, kkdddddddddkekek, kkkdyddddddddkkk, kkkdddddddddkkke, where each "d" represents a 2'-β-D-deoxyribosyl sugar moiety, each "e" represents a 2'-MOE sugar moiety, each "y" represents a 2'-OMe sugar moiety, and each "k" represents a cEt-modified sugar moiety. Each cytosine residue is 5-methylcytosine. In certain embodiments, the nucleosides of the modified oligonucleotide are linked by a combination of phosphodiester and phosphorothioate internucleoside linkages. In certain embodiments, the nucleosides of the modified oligonucleotide are linked by phosphorothioate internucleoside linkages.

[0487] The nucleic acid base sequences of SEQ ID NOs: 39, 188, 264, 713, 802, 1502, and 1581 are complementary to the interior of nucleic acid bases 14828 to 14848 of SEQ ID NO:2.

[0488] Compounds 1121415, 1121416, 1121417, 1342279, 1342607, 1343264, 1343316, 134337 3, 1343457, 1343460, 1343461, 1343462, 1343465, 1343567, 1343569, 1343570, 1343571, 1343574, 1343649, 1343651, 1343652, 1343653, 1343655, 1443240, 1443266, 1443243, 1443270, and 1443245 are complementary to the interior of nucleobases 14828 to 14848 of SEQ ID NO:2.

[0489] In certain embodiments, modified oligonucleotides complementary to within nucleobases 14828-14848 of SEQ ID NO:2 achieve at least 43% reduction in PLN RNA in vitro in a standard cell assay. In certain embodiments, modified oligonucleotides complementary to within nucleobases 14828-14848 of SEQ ID NO:2 achieve an average of 68% reduction in PLN RNA in vitro in a standard cell assay.

[0490] 9. Nucleic acid bases 14939 to 14958 of SEQ ID NO: 2 In certain embodiments, nucleobases 14939-14958 of SEQ ID NO:2 comprise a hotspot region. In certain embodiments, the modified oligonucleotide is complementary within nucleobases 14939-14958 of SEQ ID NO:2. In certain embodiments, the modified oligonucleotide is 14, 16, 17, 18, or 20 nucleobases in length. In certain embodiments, the modified oligonucleotide is a gapmer. In certain embodiments, the gapmer is a cEt gapmer. In certain embodiments, the gapmer is a mixed MOE / cEt gapmer. In certain embodiments, the gapmer is a mixed 2'-OMe / cEt gapmer. In certain embodiments, the sugar motifs of the gapmer are (5' to 3'): kkkddddddddddkkk, kkdddddddddkekek, kkkdyddddddddkkk, kkkdddddddddkkke, kkkddddddddddkeeee, kkkkddddddddddkkkk, kkddddddddddddkkk, kkkddddddddddkkk, kkkddddddddddkkk, kkkddddddddddkkk, kkkddddddddddkkk, kkkddddddddddkkee, kkkkddddddddddddkkk, The modified oligonucleotide is selected from the group consisting of kkkddddddddddkeee, kkkddddddddddkkeee, kedddddddddkekek, ekdddddddddddkekek, ekkdddddddddkkke, kekdddddddddkkke, kkeddddddddddkkk, and kkedddddddddkkke, where each "d" represents a 2'-β-D-deoxyribosyl sugar moiety, each "e" represen...

Claims

1. 1. An oligomeric compound comprising a modified oligonucleotide consisting of 8 to 80 linked nucleosides, said modified oligonucleotide having at least one modification selected from a modified sugar moiety and a modified internucleoside linkage; An oligomeric compound, wherein the modified oligonucleotide comprises a portion having a nucleobase sequence that is at least 80% complementary to an equal length portion within the following nucleobase sequences (a) or (b) or (c): a) nucleic acid bases 34-56, 44-66, 54-76, 64-86, 74-96, 84-106, 94-116, 104-126, 114-136, 124-146, 134-156, 144-166, 154-176, 164-186, 174-196, 184-206, 194-216, 204-226, 214-236, 224-246, 234-256, 244-266, 254-276, 264-286, 274-296, 284-306, 294-316, 304-326, 314-336, 324-346, 334-356, 3 44-366, 354-376, 364-386, 374-396, 384-406, 394-416, 404-426, 414-436, 424-446, 434-456, 444-466, 454-476, 464-486, 474-496, 484-506, 494-51 6, 504-526, 514-536, 524-546, 534-556, 544-566, 554-576, 564-586, 574-596, 584-606, 594-616, 604-626, 614-636, 624-646, 634-656, 644-666, 654 ~676, 664~686, 674~696, 684~706, 694~716, 704~726, 714~736, 724~746, 734~756, 744~766, 754~776, 764~786, 774~796, 784~806, 794~816, 804~826 , 814-836, 819-841, 834-856, 844-866, 854-876, 864-886, 874-896, 884-906, 894-916, 904-926, 914-936, 924-946, 934-956, 944-966, 954-976, 964- 986, 974-996, 984-1006, 994-1016, 1004-1026, 1014-1036, 1024-1046, 1034-1056, 1044-1066, 1054-1076, 1064-1086, 1074-1096, 1084-1106, 1094- 1116, 1104 to 1126, 1114 to 1136, 1124 to 1146, 1134 to 1156, 1144 to 1166, 1154 to 1176, 1164 to 1186, 1174 to 1196, 1184 to 1206, 1194 to 1216, 1204 to 1226, 1214 to 1236,１２２４～１２４６、１２３４～１２５６、１２３８～１２６０、１２４３～１２６５、１２４８～１２７０、１２５４～１２７６、１２６４～１２８６、１２７４～１２９６、１２７９～１３０１、１２８４～１３０６、１２９４～１３１６、１３０４～１３２６、１３１４～１３３６、１３２４～１３４６、１３３４～１３５６、１３４４～１３６６、１３５４～１３７６、１３６４～１３８６、１３７４～１３９６、１３８４～１４０６、１３９４～１４１６、１４０４～１４２６、１４１４～１４３６、１４２４～１４４６、１４３４～１４５６、１４４４～１４６６、１４５４～１４７６、１４６４～１４８６、１４７４～１４９６、１４８４～１５０６、１４９４～１５１６、１４９９～１５２１、１５０４～１５２６、１５１４～１５３６、１５２２～１５４４、１５３４～１５５６、１５４４～１５６６、１５５４～１５７６、１５６４～１５８６、１５７４～１５９６、１５８４～１６０６、１５９４～１６１６、１６０４～１６２６、１６１４～１６３６、１６２４～１６４６、１６３４～１６５６、１６４４～１６６６、１６５４～１６７６、１６６４～１６８６、１６７４～１６９６、１６８４～１７０６、１６９４～１７１６、１７０４～１７２６、１７１４～１７３６、１７２４～１７４６、１７３４～１７５６、１７４４～１７６６、１７５４～１７７６、１７６４～１７８６、１７７４～１７９６、１７８４～１８０６、１７９４～１８１６、１８０４～１８２６、１８１４～１８３６、１８２４～１８４６、１８３４～１８５６、１８４４～１８６６、１８５４～１８７６、１８６４～１８８６、１８７４～１８９６、１８８４～１９０６、１８９４～１９１６、１９０４～１９２６、１９１４～１９３６、１９２４～１９４６、１９３４～１９５６、１９４４～１９６６、１９５４～１９７６、１９６４～１９８６、１９７４～１９９６、１９８４～２００６、１９９４～２０１６、２００４～２０２６、２０１４～２０３６、２０１９～２０４１、２０２４～２０４６、２０３４～２０５６、２０４４～２０６６、２０５４～２０７６、２０６４～２０８６、２０７４～２０９６、２０８４～２１０６、２０９４～２１１６、２１０４～２１２６、２１１４～２１３６、２１２４～２１４６、２１３４～２１５６、２１４４～２１６６、２１５４～２１７６、２１６４～２１８６、2174-2196, 2184-2206, 2194-2216, 2204-2226, 2214-2236, 2219-2241, 2224-2246, 2234-2256, 2244-2266, 2254-2276, 2264-2286, 2274-2296, 2284-2306, 2294-2316, 2304-2326, 2314-2336, 2324-2346, 2334-2356, 2344-2366, 2354-2376, 2364-2386, 2374-2396, 2379-2401, 2 384-2406, 2394-2416, 2404-2426, 2414-2436, 2424-2446, 2434-2456, 2444-2466, 2454-2476, 2464-2486, 2474-2496, 2479-2501, 2484-2506, 2494-2516, 2504-2526, 2514-2536, 2524-2546, 2534-2556, 2544-2566, 2554-2576, 2564-2586, 2574-2596, 2584-2606, 2594-2616, 26 04-2626, 2614-2636, 2619-2641, 2624-2646, 2634-2656, 2644-2666, 2654-2676, 2664-2686, 2674-2696, 2684-2706, 2694-2716, 2699-2721, 2704-2726, 2714-2736, 2724-2746, 2734-2756, 2744-2766, 2754-2776, 2759-2781, 2764-2786, 2774-2796, 2784-2806, 2794-2816, 280 4-2826, 2814-2836, 2824-2846, 2834-2856, 2844-2866, 2854-2876, 2864-2886, 2874-2896, 2879-2901, 2884-2906, 2894-2916, 2904-2926, 2914-2936, 2919-2941, 2924-2946, 2934-2956, 2944-2966, 2954-2976, 2964-2986, 2974-2996, 2981-3003, 2987-3009, or 2994-3016; b) nucleic acid bases 3278-3293, 3281-3296, 3282-3297, 3284-3299, 3286-3301, 3287-3302, 3288-3303, 3327-3342, 3329-3344, 3332-3347, 3333-3348, 3336-3351, 3337-3352, 3338-3353, 3339-3354, 3340-3355, 3341-3356, 3343-3358, 3345-3360, 3348-3363, 3349-3364, 3350-3365, 3351-3366, 3352-3 367, 3353-3368, 3354-3369, 3355-3370, 3356-3371, 3357-3372, 3358-3373, 3395-3410, 3396-3411, 3405-3420, 3406-3421, 3408-3423, 3409-3424, 3410-3425, 3412-3427, 3496-3511, 3497-3512, 3498-3513, 3499-3514, 3598-3613, 3612-3627, 3614-3629, 3615-3630, 3616-3631, 3617-3632, 3618 ~3633, 3619~3634, 3620~3635, 3622~3637, 3703~3718, 3704~3719, 3715~3730, 3716~3731, 3723~3738, 3724~3739, 3799~3814, 3801~3816, 3802~381 7, 3803-3818, 3804-3819, 3805-3820, 3806-3821, 3807-3822, 3808-3823, 3809-3824, 3811-3826, 3814-3829, 3815-3830, 3816-3831, 3817-3832, 38 21-3836, 3823-3838, 3830-3845, 3831-3846, 3848-3863, 3849-3864, 3850-3865, 3851-3866, 3861-3876, 3863-3878, 3864-3879, 3869-3884, 3871-3 886, 3976-3991, 3977-3992, 3978-3993, 3980-3995, 3981-3996, 4116-4131, 4159-4174, 4204-4219, 4207-4222, 4208-4223, 4209-4224, 4210-4225,４２１１～４２２６、４２１２～４２２７、４２１４～４２２９、４２２１～４２３６、４２３１～４２４６、４２３２～４２４７、４２３３～４２４８、４２３４～４２４９、４２３５～４２５０、４２３６～４２５１、４２３８～４２５３、４２５２～４２６７、４２５３～４２６８、４２６６～４２８１、４３４８～４３６３、４３４９～４３６４、４３５０～４３６５、４３６７～４３８２、４３７３～４３８８、４３７４～４３８９、４３７５～４３９０、４５１０～４５２５、４５１１～４５２６、４５１３～４５２８、４５１５～４５３０、４５１６～４５３１、４５１７～４５３２、４５１８～４５３３、４５１９～４５３４、４５３０～４５４５、４５３７～４５５２、４５３９～４５５４、４５４０～４５５５、４５４１～４５５６、４５４２～４５５７、４５４３～４５５８、４５４４～４５５９、４５４５～４５６０、４５６２～４５７７、４６１４～４６２９、４６１７～４６３２、４６１９～４６３４、４６２０～４６３５、４６２１～４６３６、４６２２～４６３７、４６２３～４６３８、４６２４～４６３９、４６３８～４６５３、４６４０～４６５５、４６４１～４６５６、４６４２～４６５７、４６４３～４６５８、４６６５～４６８０、４６７２～４６８７、４６９３～４７０８、４６９４～４７０９、４６９５～４７１０、４６９６～４７１１、４６９７～４７１２、４７５０～４７６５、４７５１～４７６６、４７５２～４７６７、４７５３～４７６８、４７７４～４７８９、４８０２～４８１７、４８０４～４８１９、４８０５～４８２０、４８０６～４８２１、４８０７～４８２２、４８２３～４８３８、４８２５～４８４０、４８２６～４８４１、４８２８～４８４３、４８６０～４８７５、４８６２～４８７７、４８６９～４８８４、４８７２～４８８７、４８７４～４８８９、４８７８～４８９３、４８８１～４８９６、４８８３～４８９８、４８８４～４８９９、４９４２～４９５７、４９４３～４９５８、４９４５～４９６０、４９４６～４９６１、４９５７～４９７２、４９５８～４９７３、４９６０～４９７５、４９６１～４９７６、４９６４～４９７９、４９６５～４９８０、４９６６～４９８１、４９６８～４９８３、４９６９～４９８４、４９７１～４９８６、４９７２～４９８７、４９７４～４９８９、４９８４～４９９９、４９８５～５０００、４９８７～５００２、４９８８～５００３、５０２４～５０３９、５１２７～５１４２、５１３３～５１４８、５１３４～５１４９、５１５８～５１７３、５１５９～５１７４、５１６０～５１７５、５１６３～５１７８、５２９４～５３０９、５３４１～５３５６、５３５９～５３７４、５３９４～５４０９、５３９９～５４１４、５４００～５４１５、５４０１～５４１６、５４０２～５４１７、５４０４～５４１９、５４１１～５４２６、５４１３～５４２８、５４１４～５４２９、５４１５～５４３０、５４１６～５４３１、５４１７～５４３２、５４１８～５４３３、５４１９～５４３４、５４２１～５４３６、５４２７～５４４２、５４２８～５４４３、５４８９～５５０４、５４９４～５５０９、５４９５～５５１０、５４９７～５５１２、５４９８～５５１３、５４９８～５５１５、５４９８～５５１７、５４９９～５５１４、５４９９～５５１５、５４９９～５５１６、５４９９～５５１８、５５００～５５１５、５５００～５５１６、５５００～５５１７、５５０１～５５１６、５５０１～５５１４、５５０１～５５１７、５５０２～５５１７、５５０２～５５１５、５５０３～５５１８、５５０４～５５１９、５５０５～５５２０、５５０６～５５２１、５５１１～５５２６、５５３２～５５４７、５５３３～５５４８、５５３４～５５４９、５５４７～５５６２、５５５７～５５７２、５５５８～５５７３、５５５９～５５７４、５５６０～５５７５、５５６２～５５７７、５５６３～５５７８、５５６５～５５８０、５５９９～５６１４、５６７３～５６８８、５６７４～５６８９、５６７５～５６９０、５６７６～５６９１、５６７７～５６９２、５６７８～５６９３、５６７９～５６９４、５６９４～５７０９、５６９５～５７１０、５６９６～５７１１、５６９７～５７１２、５６９８～５７１３、５７７４～５７８９、５８２７～５８４２、５８４５～５８６０、５８４７～５８６２、５８４８～５８６３、５８５０～５８６５、５８５１～５８６６、５８５５～５８７０、５８５９～５８７４、５９２４～５９３９、５９２５～５９４０、５９２６～５９４１、５９２７～５９４２、５９２９～５９４４、５９３０～５９４５、５９３１～５９４６、５９３２～５９４７、６００８～６０２３、６００９～６０２４、６０３９～６０５４、６０５３～６０６８、６０５４～６０６９、６０５５～６０７０、６０５９～６０７４、６０６６～６０８１、６０６９～６０８４、６０７０～６０８５、６０７６～６０９１、６０９２～６１０７、６０９８～６１１３、６１１２～６１２７、６１１４～６１２９、６１１７～６１３２、６１１８～６１３３、６１１９～６１３４、６１２４～６１３９、６１２５～６１４０、６１２６～６１４１、６１４７～６１６２、６１５４～６１６９、６１５５～６１７０、６１５６～６１７１、６１５７～６１７２、６１７６～６１９１、６１７７～６１９２、６１８５～６２００、６１８６～６２０１、６１８７～６２０２、６１８８～６２０３、６２０２～６２１７、６２０９～６２２４、６２４３～６２５８、６２４９～６２６４、６２６７～６２８２、６２６８～６２８３、６２７４～６２８９、６２７５～６２９０、６２９１～６３０６、６３３８～６３５３、６３５２～６３６７、６３５３～６３６８、６３５４～６３６９、６３６５～６３８０、６３６６～６３８１、６３６８～６３８３、６３６９～６３８４、６４０３～６４１８、６４０５～６４２０、６４０６～６４２１、６４０７～６４２２、６４０８～６４２３、６４０９～６４２４、６４１０～６４２５、６４１１～６４２６、６４１３～６４２８、６４６８～６４８３、６４７１～６４８６、６５０２～６５１７、６５４６～６５６１、６５５４～６５６９、６５５５～６５７０、６５５６～６５７１、６５５７～６５７２、６５６９～６５８４、６５７４～６５８９、６５７５～６５９０、６５７６～６５９１、６５７７～６５９２、６５７８～６５９３、６５７９～６５９４、６６４４～６６５９、６６４６～６６６１、６６４７～６６６２、６６６４～６６７９、６６６５～６６８０、６６６６～６６８１、６６６７～６６８２、６６７６～６６９１、６６７７～６６９２、６７４６～６７６１、６８０４～６８１９、６８０６～６８２１、６８２５～６８４０、６８２６～６８４１、６８２７～６８４２、６８２８～６８４３、６８３１～６８４６、６８３３～６８４８、６８３４～６８４９、６８７５～６８９０、６８７７～６８９２、６８７９～６８９４、６８８０～６８９５、６８８１～６８９６、６８９３～６９０８、６８９６～６９１１、６８９８～６９１３、６８９９～６９１４、６９００～６９１５、６９０１～６９１６、６９０３～６９１８、６９０４～６９１９、６９０６～６９２１、６９０７～６９２２、６９０８～６９２３、６９２０～６９３５、６９２１～６９３６、６９２２～６９３７、６９２３～６９３８、６９２７～６９４２、６９２８～６９４３、６９３０～６９４５、６９３７～６９５２、６９３９～６９５４、６９４０～６９５５、６９４１～６９５６、６９４２～６９５７、６９４３～６９５８、６９４４～６９５９、６９４５～６９６０、６９４７～６９６２、６９６５～６９８０、６９６６～６９８１、６９６７～６９８２、６９６８～６９８３、６９７２～６９８７、６９７５～６９９０、７０２９～７０４４、７０４２～７０５７、７０４７～７０６２、７０５０～７０６５、７０７３～７０８８、７０８２～７０９７、７０８３～７０９８、７１０２～７１１７、７１０６～７１２１、７１０７～７１２２、７１０８～７１２３、７１２０～７１３５、７１２２～７１３７、７１２３～７１３８、７１２４～７１３９、７１２５～７１４０、７１２６～７１４１、７１２８～７１４３、７１２９～７１４４、７１３０～７１４５、７１３１～７１４６、７２７９～７２９４、７２８０～７２９５、７２８２～７２９７、７２８３～７２９８、７２８４～７２９９、７２８５～７３００、７２８６～７３０１、７２８７～７３０２、７３２０～７３３５、７３４１～７３５６、７３４２～７３５７、７３４４～７３５９、７３５３～７３６８、７３５４～７３６９、７３５６～７３７１、７３５７～７３７２、７３５８～７３７３、７３５９～７３７４、７３６０～７３７５、７３６１～７３７６、７３６２～７３７７、７３７７～７３９２、７３７８～７３９３、７３９２～７４０７、７３９３～７４０８、７４１１～７４２６、７４２５～７４４０、７４３６～７４５１、７４５７～７４７２、７４５８～７４７３、７４５９～７４７４、７４６０～７４７５、７４６１～７４７６、７４６３～７４７８、７４６４～７４７９、７４７０～７４８５、７５１６～７５３１、７５１８～７５３３、７５１９～７５３４、７５２０～７５３５、７５２１～７５３６、７５２２～７５３７、７５４６～７５６１、７５４８～７５６３、７５５３～７５６８、７５５４～７５６９、７５５５～７５７０、７５５６～７５７１、７５５８～７５７３、７５６０～７５７５、７５６１～７５７６、７５６２～７５７７、７５６３～７５７８、７５６４～７５７９、７５６５～７５８０、７５６６～７５８１、７５６８～７５８３、７５８７～７６０２、７５８８～７６０３、７５８９～７６０４、７５９５～７６１０、７６３８～７６５３、７６７９～７６９４、７７２６～７７４１、７７７９～７７９４、７７９７～７８１２、７７９９、 ～７８１４、７８０６～７８２１、７８５７～７８７２、７８５９～７８７４、７８６０～７８７５、７８６１～７８７６、７８６２～７８７７、７８６３～７８７８、７８６４～７８７９、７８６５～７８８０、７８６７～７８８２、７８７６～７８９１、７８７８～７８９３、７８８８～７９０３、７８８９～７９０４、７８９３～７９０８、７９０８～７９２３、７９２９～７９４４、７９６５～７９８０、７９６７～７９８２、７９６８～７９８３、８０４７～８０６２、８０５８～８０７３、８０６１～８０７６、８０８９～８１０４、８０９０～８１０５、８１６３～８１７８、８１８２～８１９７、８１９４～８２０９、８１９５～８２１０、８１９６～８２１１、８１９７～８２１２、８２８４～８２９９、８２８５～８３００、８２８６～８３０１、８２８７～８３０２、８２８８～８３０３、８３２６～８３４１、８３３６～８３５１、８３５２～８３６７、８３５３～８３６８、８３６８～８３８３、８３９３～８４０８、８４１２～８４２７、８４１３～８４２８、８４１５～８４３０、８４１８～８４３３、８４２７～８４４２、８４４７～８４６２、８４９３～８５０８、８４９４～８５０９、８４９５～８５１０、８４９６～８５１１、８４９８～８５１３、８５４２～８５５７、８５７３～８５８８、８６２１～８６３６、８６２７～８６４２、８６２８～８６４３、８６３８～８６５３、８６３９～８６５４、８６４１～８６５６、８６５３～８６６８、８６５５～８６７０、８７０３～８７１８、８７０８～８７２３、８７３２～８７４７、８７３３～８７４８、８７３９～８７５４、８７７４～８７８９、８７７６～８７９１、８７７７～８７９２、８８１８～８８３３、８８２３～８８３８、８８２４～８８３９、８８２６～８８４１、８８２７～８８４２、８８５０～８８６５、８８５５～８８７０、８９４２～８９５７、８９４３～８９５８、８９４４～８９５９、８９５５～８９７０、８９６１～８９７６、８９６２～８９７７、８９６３～８９７８、８９６４～８９７９、９３７７～９３９２、９４４３～９４５８、９４７４～９４８９、９５２３～９５３８、９５２４～９５３９、９５２５～９５４０、９５２６～９５４１、９５２８～９５４３、９５３６～９５５１、９５３７～９５５２、９５３８～９５５３、９５４０～９５５５、９５４１～９５５６、９５４５～９５６０、９５４９～９５６４、９５５０～９５６５、９５８７～９６０２、９６３０～９６４５、９６４１～９６５６、９６４２～９６５７、９６４６～９６６１、９６４７～９６６２、９６４８～９６６３、９６４９～９６６４、９６５１～９６６６、９６６０～９６７５、９６６８～９６８３、９６６９～９６８４、９６７２～９６８７、９６９７～９７１２、９７０２～９７１７、９７０３～９７１８、９７０６～９７２１、９７０７～９７２２、９７０８～９７２３、９７０９～９７２４、９７１０～９７２５、９７１１～９７２６、９７２０～９７３５、９７２７～９７４２、９７５２～９７６７、９７５６～９７７１、９７８８～９８０３、９９３４～９９４９、９９３６～９９５１、９９３７～９９５２、９９３８～９９５３、９９３９～９９５４、９９４０～９９５５、１００１９～１００３４、１００５４～１００６９、１００６２～１００７７、１００８１～１００９６、１０１０６～１０１２１、１０１１７～１０１３２、１０４４３～１０４５８、１０４４４～１０４５９、１０４４５～１０４６０、１０４８０～１０４９５、１０４８１～１０４９６、１０４８６～１０５０１、１０４８９～１０５０４、１０４９０～１０５０５、１０４９１～１０５０６、１０５３２～１０５４７、１０６２３～１０６３８、１０６３８～１０６５３、１０６４５～１０６６０、１０７１８～１０７３３、１０７１９～１０７３４、１０７２０～１０７３５、１０７２１～１０７３６、１０７２２～１０７３７、１０７２３～１０７３８、１０７２４～１０７３９、１０７４７～１０７６２、１０７７０～１０７８５、１１０６６～１１０８１、１１０６８～１１０８３、１１１０４～１１１１９、１１１１１～１１１２６、１１１１２～１１１２７、１１１１５～１１１３０、１１１１６～１１１３１、１１１１８～１１１３３、１１１３０～１１１４５、１１１４４～１１１５９、１１２２４～１１２３９、１１２２５～１１２４０、１１２３７～１１２５２、１１２５８～１１２７３、１１２５９～１１２７４、１１３０２～１１３１７、１１３５３～１１３６８、１１３５６～１１３７１、１１３６８～１１３８３、１１３６９～１１３８４、１１４０９～１１４２４、１１４１０～１１４２５、１１４１１～１１４２６、１１４１２～１１４２７、１１４１３～１１４２８、１１４１４～１１４２９、１１４１５～１１４３０、１１４１７～１１４３２、１１４５７～１１４７２、１１４５８～１１４７３、１１４６７～１１４８２、１１４７４～１１４８９、１１４７５～１１４９０、１１５０９～１１５２４、１１５１０～１１５２５、１１５１１～１１５２６、１１５２４～１１５３９、１１５２５～１１５４０、１１５２６～１１５４１、１１５２７～１１５４２、１１５２９～１１５４４、１１５３０～１１５４５、１１６２２～１１６３７、１１６３１～１１６４６、１１６３２～１１６４７、１１６３３～１１６４８、１１６３４～１１６４９、１１６３５～１１６５０、１１６３６～１１６５１、１１６３９～１１６５４、１１６７０～１１６８５、１１６７８～１１６９３、１１６７９～１１６９４、１１６８０～１１６９５、１１６８１～１１６９６、１１６８２～１１６９７、１１６８４～１１６９９、１１６８５～１１７００、１１７２６～１１７４１、１１７２７～１１７４２、１１７４０～１１７５５、１１７４１～１１７５６、１１７４２～１１７５７、１１７４３～１１７５８、１１７９９～１１８１４、１１８３２～１１８４７、１１８３３～１１８４８、１１８５４～１１８６９、１１８５５～１１８７０、１１８５６～１１８７１、１１８５７～１１８７２、１１８５８～１１８７３、１１８５９～１１８７４、１１９００～１１９１５、１１９３１～１１９４６、１１９５６～１１９７１、１１９８８～１２００３、１１９８９～１２００４、１１９９０～１２００５、１１９９１～１２００６、１１９９２～１２００７、１１９９３～１２００８、１１９９４～１２００９、１１９９５～１２０１０、１１９９７～１２０１２、１１９９８～１２０１３、１１９９９～１２０１４、１２０００～１２０１５、１２０１５～１２０３０、１２０１６～１２０３１、１２０１７～１２０３２、１２０２７～１２０４２、１２０３２～１２０４７、１２０４０～１２０５５、１２０４１～１２０５６、１２０４２～１２０５７、１２０７６～１２０９１、１２０８０～１２０９５、１２０８１～１２０９６、１２０８２～１２０９７、１２０８４～１２０９９、１２０８５～１２１００、１２０８６～１２１０１、１２０８７～１２１０２、１２０８８～１２１０３、１２０８９～１２１０４、１２０９０～１２１０５、１２０９２～１２１０７、１２１９４～１２２０９、１２１９５～１２２１０、１２２３８～１２２５３、１２２３９～１２２５４、１２２４１～１２２５６、１２２４２～１２２５７、１２２４３～１２２５８、１２２４６～１２２６１、１２２８２～１２２９７、１２２８３～１２２９８、１２２８５～１２３００、１２２８６～１２３０１、１２２８７～１２３０２、１２２８８～１２３０３、１２３０７～１２３２２、１２３０８～１２３２３、１２３１０～１２３２５、１２３１２～１２３２７、１２３１５～１２３３０、１２３４８～１２３６３、１２３５５～１２３７０、１２３５６～１２３７１、１２３５７～１２３７２、１２３６８～１２３８３、１２３８８～１２４０３、１２３８９～１２４０４、１２３９０～１２４０５、１２３９１～１２４０６、１２３９２～１２４０７、１２４７０～１２４８５、１２４７１～１２４８６、１２４７２～１２４８７、１２４７３～１２４８８、１２４７４～１２４８９、１２４９８～１２５１３、１２５２９～１２５４４、１２５３０～１２５４５、１２５４６～１２５６１、１２５４８～１２５６３、１２５５０～１２５６５、１２５５１～１２５６６、１２５８５～１２６００、１２７２１～１２７３６、１２７２２～１２７３７、１２７２３～１２７３８、１２７２４～１２７３９、１２７２７～１２７４２、１２７３２～１２７４７、１２７３３～１２７４８、１２７３４～１２７４９、１２７３５～１２７５０、１２７６０～１２７７５、１２８１２～１２８２７、１２８１３～１２８２８、１２８１７～１２８３２、１２８１８～１２８３３、１２９１２～１２９２７、１２９１５～１２９３０、１２９２９～１２９４４、１２９４３～１２９５８、１２９４６～１２９６１、１３２４３～１３２５８、１３３２７～１３３４２、１３４０９～１３４２４、１３４３１～１３４４６、１３４３８～１３４５３、１３４６０～１３４７５、１３４６１～１３４７６、１３４８４～１３４９９、１３４８５～１３５００、１３４８６～１３５０１、１３４８９～１３５０４、１３４９０～１３５０５、１３４９１～１３５０６、１３４９２～１３５０７、１３４９３～１３５０８、１３５２５～１３５４０、１３５２８～１３５４３、１３５２９～１３５４４、１３５３０～１３５４５、１３７１７～１３７３２、１３７３６～１３７５１、１３７７０～１３７８５、１３７７６～１３７９１、１３７７７～１３７９２、１３７８６～１３８０１、１３８１４～１３８２９、１３８１６～１３８３１、１３８１８～１３８３３、１３８１９～１３８３４、１３８２０～１３８３５、１３８２１～１３８３６、１３８２２～１３８３７、１３８２３～１３８３８、１３８３５～１３８５０、１３８３６～１３８５１、１３８３７～１３８５２、１３８３８～１３８５３、１３８３９～１３８５４、１３８４３～１３８５８、１３８７０～１３８８５、１３８７２～１３８８７、１３８７５～１３８９０、１３８７６～１３８９１、１３８７７～１３８９２、１３８７８～１３８９３、１３８７９～１３８９４、１３８８０～１３８９５、１３８８１～１３８９６、１３８８２～１３８９７、１３８８３～１３８９８、１３８８５～１３９００、１３９０４～１３９１９、１３９０５～１３９２０、１３９０６～１３９２１、１３９０７～１３９２２、１３９０８～１３９２３、１３９１０～１３９２５、１３９１２～１３９２７、１３９１８～１３９３３、１３９２４～１３９３９、１３９２６～１３９４１、１３９２７～１３９４２、１３９３０～１３９４５、１３９３４～１３９４９、１３９３５～１３９５０、１３９３６～１３９５１、１３９３７～１３９５２、１３９３８～１３９５３、１３９３９～１３９５４、１３９４０～１３９５５、１３９４１～１３９５６、１３９４２～１３９５７、１３９４３～１３９５８、１３９４４～１３９５９、１３９４５～１３９６０、１３９４６～１３９６１、１３９５２～１３９６７、１３９５３～１３９６８、１３９５４～１３９６９、１３９５５～１３９７０、１３９５６～１３９７１、１３９５７～１３９７２、１３９５８～１３９７３、１３９５９～１３９７４、１３９６０～１３９７５、１３９６１～１３９７６、１３９６２～１３９７７、１３９６３～１３９７８、１３９６４～１３９７９、１３９６５～１３９８０、１３９６６～１３９８１、１３９６７～１３９８２、１３９６８～１３９８３、１３９６９～１３９８４、１３９７０～１３９８５、１３９７３～１３９８８、１３９７６～１３９９１、１４０００～１４０１５、１４００３～１４０１８、１４０２８～１４０４３、１４０３０～１４０４５、１４０３２～１４０４７、１４０３５～１４０５０、１４０３６～１４０５１、１４０３８～１４０５３、１４０３９～１４０５４、１４０４０～１４０５５、１４０４１～１４０５６、１４０４５～１４０６０、１４０４７～１４０６２、１４０４８～１４０６３、１４０４９～１４０６４、１４０５０～１４０６５、１４０５１～１４０６６、１４０５３～１４０６８、１４０５４～１４０６９、１４０５５～１４０ ７０、１４０５６～１４０７１、１４０５９～１４０７４、１４０６０～１４０７５、１４０６１～１４０７６、１４０６２～１４０７７、１４０６３～１４０７８、１４０６４～１４０７９、１４０６５～１４０８０、１４０６６～１４０８１、１４０７８～１４０９３、１４０８１～１４０９６、１４０８２～１４０９７、１４０８４～１４０９９、１４０８５～１４１００、１４０８６～１４１０１、１４０８７～１４１０２、１４０８８～１４１０３、１４０８９～１４１０４、１４０９０～１４１０５、１４０９１～１４１０６、１４０９２～１４１０７、１４０９３～１４１０８、１４０９５～１４１１０、１４０９６～１４１１１、１４０９７～１４１１２、１４０９８～１４１１３、１４０９９～１４１１４、１４１００～１４１１５、１４１０２～１４１１７、１４１０５～１４１２０、１４１１０～１４１２５、１４１１１～１４１２６、１４１１２～１４１２７、１４１１３～１４１２８、１４１１５～１４１３０、１４１１７～１４１３２、１４１１９～１４１３４、１４１３０～１４１４５、１４１６３～１４１７８、１４１６５～１４１８０、１４１６６～１４１８１、１４１６７～１４１８２、１４１６９～１４１８４、１４１７０～１４１８５、１４１７４～１４１８９、１４１８０～１４１９５、１４１８１～１４１９６、１４２０３～１４２１８、１４２０７～１４２２２、１４２０９～１４２２４、１４２１２～１４２２７、１４２１７～１４２３２、１４２２０～１４２３５、１４２２２～１４２３７、１４２２３～１４２３８、１４２２４～１４２３９、１４２２５～１４２４０、１４２３２～１４２４７、１４２３３～１４２４８、１４２３５～１４２５０、１４２４２～１４２５７、１４２４４～１４２５９、１４２４７～１４２６２、１４２４８～１４２６３、１４２４９～１４２６４、１４２５０～１４２６５、１４２５１～１４２６６、１４２５２～１４２６７、１４２５３～１４２６８、１４２５４～１４２６９、１４２５５～１４２７０、１４２５６～１４２７１、１４２５７～１４２７２、１４３１６～１４３３１、１４３１７～１４３３２、１４３１８～１４３３３、１４３１９～１４３３４、１４３２１～１４３３６、１４３２４～１４３３９、１４３２７～１４３４２、１４３３７～１４３５２、１４３３８～１４３５３、１４３３９～１４３５４、１４３４０～１４３５５、１４３４１～１４３５６、１４３４２～１４３５７、１４３４３～１４３５８、１４３４４～１４３５９、１４３４５～１４３６０、１４３４６～１４３６１、１４３４７～１４３６２、１４３９８～１４４１３、１４４００～１４４１５、１４４０１～１４４１６、１４４０３～１４４１８、１４４０４～１４４１９、１４４０５～１４４２０、１４４０６～１４４２１、１４４０８～１４４２３、１４４０９～１４４２４、１４４１０～１４４２５、１４４１２～１４４２７、１４４４３～１４４５８、１４４７９～１４４９４、１４４８０～１４４９５、１４４８２～１４４９７、１４５０４～１４５１９、１４５０７～１４５２２、１４５０８～１４５２３、１４５０９～１４５２４、１４５１０～１４５２５、１４５１１～１４５２６、１４５１２～１４５２７、１４５１３～１４５２８、１４５１４～１４５２９、１４５１５～１４５３０、１４５１５～１４５３２、１４５１５～１４５３４、１４５１６～１４５３１、１４５１６～１４５３２、１４５１６～１４５３３、１４５１７～１４５３２、１４５１７～１４５３３、１４５１８～１４５３１、１４５１９～１４５３４、１４５２０～１４５３５、１４５２２～１４５３７、１４５３４～１４５４９、１４５３５～１４５５０、１４５５３～１４５６８、１４５６９～１４５８４、１４５７０～１４５８５、１４５７１～１４５８６、１４５７３～１４５８８、１４６０１～１４６１６、１４６０２～１４６１７、１４６０３～１４６１８、１４６０５～１４６２０、１４６０６～１４６２１、１４６０７～１４６２２、１４６０８～１４６２３、１４６０９～１４６２４、１４６１０～１４６２５、１４６１１～１４６２６、１４６１２～１４６２７、１４６１３～１４６２８、１４６１４～１４６２９、１４６１５～１４６３０、１４６１６～１４６３１、１４６５５～１４６７０、１４６５６～１４６７１、１４６５８～１４６７３、１４６５９～１４６７４、１４６８１～１４６９６、１４６８３～１４６９８、１４６８４～１４６９９、１４６８４～１４７０１、１４６８４～１４７０３、１４６８５～１４７００、１４６８５～１４７０１、１４６８５～１４７０２、１４６８６～１４７０１、１４６８６～１４７０２、１４６８７～１４７０２、１４６８７～１４７００、１４６８８～１４７０３、１４６８９～１４７０４、１４６９１～１４７０６、１４６９２～１４７０７、１４６９６～１４７１１、１４７０３～１４７１８、１４７０４～１４７１９、１４７０５～１４７２０、１４７０６～１４７２１、１４７０７～１４７２２、１４７０８～１４７２３、１４７０９～１４７２４、１４７１０～１４７２５、１４７１１～１４７２６、１４７１２～１４７２７、１４７１３～１４７２８、１４７１４～１４７２９、１４７５９～１４７７４、１４７６０～１４７７５、１４７６１～１４７７６、１４７６２～１４７７７、１４７６３～１４７７８、１４７６４～１４７７９、１４７６５～１４７８０、１４７６６～１４７８１、１４７６７～１４７８２、１４７６８～１４７８３、１４７６９～１４７８４、１４７７０～１４７８５、１４７７１～１４７８６、１４７７２～１４７８７、１４７７３～１４７８８、１４７７４～１４７８９、１４７７５～１４７９０、１４７７６～１４７９１、１４７７９～１４７９４、１４７８７～１４８０２、１４７９２～１４８０７、１４７９３～１４８０８、１４７９４～１４８０９、１４７９７～１４８１２、１４７９８～１４８１３、１４８００～１４８１５、１４８１８～１４８３３、１４８２２～１４８３７、１４８２３～１４８３８、１４８２４～１４８３９、１４８２５～１４８４０、１４８２６～１４８４１、１４８２７～１４８４２、１４８２８～１４８４３、１４８２９～１４８４４、１４８３０～１４８４５、１４８３１～１４８４６、１４８３２～１４８４７、１４８３３～１４８４８、１４８３４～１４８４９、１４８３５～１４８５０、１４８４１～１４８５６、１４８４２～１４８５７、１４８４３～１４８５８、１４８４４～１４８５９、１４８４５～１４８６０、１４８４６～１４８６１、１４８４７～１４８６２、１４８４８～１４８６３、１４８４９～１４８６４、１４８５０～１４８６５、１４８５１～１４８６６、１４８５２～１４８６７、１４８５３～１４８６８、１４８５５～１４８７０、１４８５６～１４８７１、１４８５７～１４８７２、１４８５８～１４８７３、１４８５９～１４８７４、１４８６１～１４８７６、１４８６２～１４８７７、１４８６３～１４８７８、１４８６４～１４８７９、１４８６６～１４８８１、１４８７７～１４８９２、１４８７８～１４８９３、１４８８０～１４８９５、１４８８１～１４８９６、１４８８９～１４９０４、１４８９８～１４９１３、１４８９９～１４９１４、１４９０１～１４９１６、１４９０３～１４９１８、１４９０４～１４９１９、１４９０５～１４９２０、１４９０６～１４９２１、１４９１３～１４９２８、１４９１５～１４９３０、１４９１６～１４９３１、１４９１７～１４９３２、１４９１８～１４９３３、１４９１９～１４９３４、１４９２１～１４９３６、１４９２２～１４９３７、１４９２３～１４９３８、１４９２４～１４９３９、１４９２５～１４９４０、１４９２６～１４９４１、１４９２７～１４９４２、１４９２８～１４９４３、１４９２９～１４９４４、１４９３０～１４９４５、１４９３１～１４９４６、１４９３２～１４９４７、１４９３３～１４９４８、１４９３４～１４９４９、１４９３５～１４９５０、１４９３６～１４９５１、１４９３７～１４９５２、１４９３８～１４９５３、１４９３８～１４９５５、１４９３８～１４９５７、１４９３９～１４９５４、１４９３９～１４９５５、１４９３９～１４９５６、１４９３９～１４９５８、１４９４０～１４９５５、１４９４０～１４９５６、１４９４０～１４９５７、１４９４０～１４９５９、１４９４１～１４９５６、１４９４１～１４９５４、１４９４１～１４９５７、１４９４１～１４９５８、１４９４１～１４９６０、１４９４２～１４９５７、１４９４２～１４９５５、１４９４２～１４９５８、１４９４２～１４９５９、１４９４２～１４９６１、１４９４３～１４９５８、１４９４３～１４９５６、１４９４３～１４９５９、１４９４３～１４９６０、１４９４３～１４９６２、１４９４４～１４９５９、１４９４４～１４９５７、１４９４４～１４９６０、１４９４４～１４９６１、１４９４５～１４９６０、１４９４５～１４９５８、１４９４５～１４９６１、１４９４６～１４９６１、１４９４６～１４９５９、１４９４８～１４９６３、１４９５６～１４９７１、１４９５７～１４９７２、１４９５８～１４９７３、１４９５９～１４９７４、１４９６０～１４９７５、１４９６１～１４９７６、１４９６２～１４９７７、１４９６３～１４９７８、１４９６４～１４９７９、１４９６５～１４９８０、１４９６６～１４９８１、１４９６８～１４９８３、１４９６９～１４９８４、１４９７０～１４９８５、１４９８７～１５００２、１４９９２～１５００７、１４９９３～１５００８、１４９９４～１５００９、１４９９５～１５０１０、１４９９６～１５０１１、１５００３～１５０１８、１５００５～１５０２０、１５００６～１５０２１、１５００７～１５０２２、１５００８～１５０２３、１５００９～１５０２４、１５０１０～１５０２５、１５０１１～１５０２６、１５０１２～１５０２７、１５０１３～１５０２８、１５０１４～１５０２９、１５０１５～１５０３０、１５０１６～１５０３１、１５０１７～１５０３２、１５０１９～１５０３４、１５１４２～１５１５７、１５１４３～１５１５８、１５１５０～１５１６５、１５１５１～１５１６６、１５１５２～１５１６７、１５１５３～１５１６８、１５１５４～１５１６９、１５１５５～１５１７０、１５１５６～１５１７１、１５１５７～１５１７２、１５１５８～１５１７３、１５１５９～１５１７４、１５１６０～１５１７５、１５１６１～１５１７６、１５１６２～１５１７７、１５１６３～１５１７８、１５１６４～１５１７９、１５１８２～１５１９７、１５１８４～１５１９９、１５１８５～１５２００、１５１８６～１５２０１、１５１９５～１５２１０、１５１９７～１５２１２、１５１９８～１５２１３、１５１９９～１５２１４、１５２００～１５２１５、１５２０１～１５２１６、１５２０２～１５２１７、１５２０３～１５２１８、１５２０４～１５２１９、１５２０５～１５２２０、１５２０６～１５２２１、１５２０７～１５２２２、１５２０８～１５２２３、１５２０９～１５２２４、１５２１０～１５２２５、１５２１１～１５２２６、１５２１４～１５２２９、１５２１５～１５２３０、１５２１６～１５２３１、１５２１７～１５２３２、１５２１８～１５２３３、１５２１９～１５２３４、１５２２０～１５２３５、１５２２１～１５２３６、１５２２２～１５２３７、１５２２２～１５２３９、１５２２２～１５２４１、１５２２３～１５２３８、１５２２３～１５２３９、１５２２３～１５２４０、１５２２４～１５２３９、１５２２４～１５２４０、１５２２５～１５２４０、１５２２５～１５２３８、１５２２７～１５２４２、１５２２８～１５２４３、１５２２９～１５２４４、１５２３０～１５２４５、１５２３１～１５２４６、１５２３２～１５２４７、１５２３３～１５２４８、１５２３４～１５２４９、１５２３５～１５２５０、１５２３６～１５２５１、１５２３７～１５２５２、１５２３８～１５２５３、１５２３９～１５２５４、１５２４７～１５２６２、１５２４８～１５２６３、１５２４９～１５２６４、１５２５０～１５２６５、１５２５１～１５２６６、１５２５２～１５２６７、１５２５３～ １５２６８、１５２５４～１５２６９、１５２５５～１５２７０、１５２５６～１５２７１、１５２５７～１５２７２、１５２５８～１５２７３、１５２５９～１５２７４、１５２６０～１５２７５、１５２６１～１５２７６、１５２９３～１５３０８、１５２９９～１５３１４、１５３０１～１５３１６、１５３０２～１５３１７、１５３０３～１５３１８、１５３０４～１５３１９、１５３０５～１５３２０、１５３２０～１５３３５、１５３２１～１５３３６、１５３２３～１５３３８、１５４１１～１５４２６、１５４１４～１５４２９、１５４１５～１５４３０、１５４１６～１５４３１、１５４１７～１５４３２、１５４９６～１５５１１、１５５０１～１５５１６、１５５０４～１５５１９、１５５０５～１５５２０、１５５０６～１５５２１、１５５０７～１５５２２、１５５０８～１５５２３、１５５０９～１５５２４、１５５１０～１５５２５、１５５１１～１５５２６、１５５１２～１５５２７、１５５１３～１５５２８、１５５１５～１５５３０、１５５５６～１５５７１、１５５５８～１５５７３、１５５５９～１５５７４、１５５６０～１５５７５、１５５６２～１５５７７、１５５６９～１５５８４、１５５７１～１５５８６、１５５７４～１５５８９、１５５９３～１５６０８、１５５９４～１５６０９、１５５９５～１５６１０、１５５９６～１５６１１、１５５９８～１５６１３、１５５９９～１５６１４、１５６００～１５６１５、１５６０１～１５６１６、１５６０２～１５６１７、１５６０３～１５６１８、１５６０４～１５６１９、１５６０５～１５６２０、１５６２７～１５６４２、１５６２９～１５６４４、１５６３０～１５６４５、１５６３１～１５６４６、１５６３２～１５６４７、１５６３３～１５６４８、１５６３５～１５６５０、１５６３６～１５６５１、１５６３９～１５６５４、１５６４０～１５６５５、１５６４１～１５６５６、１５６４２～１５６５７、１５６５８～１５６７３、１５６５９～１５６７４、１５６６０～１５６７５、１５６６１～１５６７６、１５６６５～１５６８０、１５６６６～１５６８１、１５６６７～１５６８２、１５６６８～１５６８３、１５６７１～１５６８６、１５６７３～１５６８８、１５６７４～１５６８９、１５６７５～１５６９０、１５６８１～１５６９６、１５６８２～１５６９７、１５６８３～１５６９８、１５６８４～１５６９９、１５６８５～１５７００、１５６８６～１５７０１、１５６８７～１５７０２、１５７４０～１５７５５、１５７４１～１５７５６、１５７５３～１５７６８、１５７５７～１５７７２、１５７５８～１５７７３、１５７６１～１５７７６、１５７６２～１５７７７、１５７６３～１５７７８、１５７６５～１５７８０、１５７８８～１５８０３、１５８１２～１５８２７、１５８１３～１５８２８、１５８１４～１５８２９、１５８１５～１５８３０、１５８１６～１５８３１、１５８２６～１５８４１、１５８２７～１５８４２、１５８３３～１５８４８、１５８５８～１５８７３、１５８６１～１５８７６、１５８６３～１５８７８、１５８６４～１５８７９、１５８６５～１５８８０、１５８６６～１５８８１、１５８６７～１５８８２、１５８６８～１５８８３、１５８６９～１５８８４、１５８７０～１５８８５、１５８７１～１５８８６、１５８７２～１５８８７、１５８７３～１５８８８、１５８７４～１５８８９、１５８７５～１５８９０、１５８７６～１５８９１、１５８７７～１５８９２、１５８７８～１５８９３、１５８８２～１５８９７、１５８８３～１５８９８、１５９１０～１５９２５、１５９１１～１５９２６、１５９１２～１５９２７、１５９１３～１５９２８、１５９１４～１５９２９、１５９４３～１５９５８、１５９４７～１５９６２、１５９４９～１５９６４、１５９５０～１５９６５、１５９５１～１５９６６、１５９５５～１５９７０、１５９７３～１５９８８、１５９７４～１５９８９、１５９７９～１５９９４、１５９８０～１５９９５、１６０００～１６０１５、１６００８～１６０２３、１６０１０～１６０２５、１６０２６～１６０４１、１６０２７～１６０４２、１６０３０～１６０４５、１６０３２～１６０４７、１６０３４～１６０４９、１６０３６～１６０５１、１６０３７～１６０５２、１６０３８～１６０５３、１６０３９～１６０５４、１６０５６～１６０７１、１６０５７～１６０７２、１６０８０～１６０９５、１６１１７～１６１３２、１６１１８～１６１３３、１６２１６～１６２３１、１６２４８～１６２６３、１６２６５～１６２８０、１６２６６～１６２８１、１６２６８～１６２８３、１６２６９～１６２８４、１６２７３～１６２８８、１６３００～１６３１５、16305-16320, 16306-16321, 16327-16342, 16329-16344, 16422-16437, 16427-16442, 16428-16443, 16550-16565, 16557-16572, 16564-16579, 16569-16584, 16582-16597, 16592-16607, 16617-16632, or 16676-16691; or c) nucleobases 3341 to 3368, 4516 to 4533, 5498 to 5517, 14337 to 14357, 14569 to 14588, 14607 to 14631, 14683 to 14703, 14828 to 14848, 14939 to 14958, 15222 to 15243, or 15251 to 15273 of SEQ ID NO:

2.

2. 2. The oligomeric compound of claim 1, wherein the nucleobase sequence of said modified oligonucleotide is at least 80% complementary to an isometric portion within nucleobases 3341-3368, 4516-4533, 5498-5517, 14337-14357, 14569-14588, 14607-14631, 14683-14703, 14828-14848, 14939-14958, 15222-15243, or 15251-15273 of SEQ ID NO:

2.

3. The oligomeric compound of claim 1 or 2, wherein the nucleobase sequence of the modified oligonucleotide is at least 80%, at least 85%, at least 90%, at least 95%, or 100% complementary to an equal length portion of the nucleobases of SEQ ID NO: 1 or 2 of claim 1 or 2.

4. 1. An oligomeric compound comprising a modified oligonucleotide consisting of 8 to 80 linked nucleosides, the nucleobase sequence of said modified oligonucleotide being: a) at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 contiguous nucleobases of any of the nucleobase sequences of any of SEQ ID NOs: 1713-2024; or b) a nucleic acid sequence of any of SEQ ID NOs: 1713-2024; or c) at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, or at least 20 contiguous nucleobases of any of the nucleobase sequences of any of SEQ ID NOs: 15-1712; or d) any of the nucleic acid sequences of SEQ ID NOs: 15 to 1712 The oligomeric compound comprising:

5. 5. The oligomeric compound according to any one of claims 1 to 4, wherein at least one nucleoside of the modified oligonucleotide comprises a modified sugar moiety and / or a sugar surrogate; and / or the modified oligonucleotide comprises at least one modified internucleoside linkage and / or at least one modified nucleobase, Optionally: a) the modified sugar moiety comprises a bicyclic sugar moiety or a non-bicyclic modified sugar moiety; optionally, the bicyclic sugar moiety may comprise a 2'-4' bridge selected from -O-CH2- and -O-CH(CH3)-; or the non-bicyclic modified sugar moiety may be a 2'-MOE sugar moiety or a 2'-OMe sugar moiety; and / or b) each internucleoside linkage is a modified internucleoside linkage; or each internucleoside linkage of said modified oligonucleotide is independently selected from a phosphodiester internucleoside linkage, a phosphorothioate internucleoside linkage, and a mesyl phosphoramidate internucleoside linkage; and / or c) the modified nucleobase is 5-methylcytosine; Oligomeric compounds.

6. The oligomeric compound according to claim 1, comprising the following conjugate group (a) and / or terminal group (b): a) a conjugate group, ai) comprising a conjugate linker and a conjugate moiety, optionally wherein the conjugate group is attached to the modified oligonucleotide at the 5'-end or the 3'-end of the modified oligonucleotide; and / or aii) comprises a C22 alkyl, a C20 alkyl, a C16 alkyl, a C10 alkyl, a C21 alkyl, a C19 alkyl, a C18 alkyl, a C15 alkyl, a C14 alkyl, a C13 alkyl, a C12 alkyl, a C11 alkyl, a C9 alkyl, a C8 alkyl, a C7 alkyl, a C6 alkyl, a C5 alkyl, a C22 alkenyl, a C20 alkenyl, a C16 alkenyl, a C10 alkenyl, a C21 alkenyl, a C19 alkenyl, a C18 alkenyl, a C15 alkenyl, a C14 alkenyl, a C13 alkenyl, a C12 alkenyl, a C11 alkenyl, a C9 alkenyl, a C8 alkenyl, a C7 alkenyl, a C6 alkenyl, or a C5 alkenyl; or is a 6-palmitamidohexyl conjugate moiety, 【Chemistry 1】 or a conjugate group comprising a cell targeting moiety; and / or b) Terminal group.

7. An oligomeric duplex comprising: a) a first oligomeric compound and a second oligomeric compound, wherein the first oligomeric compound is an oligomeric compound according to any one of claims 1 to 6, and the second oligomeric compound comprises a second modified oligonucleotide consisting of 8 to 80 linked nucleosides, the nucleobase sequence of the second modified oligonucleotide comprising a complementary region of at least 8 nucleobases that is at least 90% complementary to an equal length portion of the first modified oligonucleotide; or b) a first oligomeric compound comprising a first modified oligonucleotide consisting of 19 to 29 linked nucleosides, wherein the nucleobase sequence of the first modified oligonucleotide comprises at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 consecutive nucleobases of the nucleobase sequence of any of SEQ ID NOs: 1713-2024; and a second oligomeric compound comprising a second modified oligonucleotide consisting of 15 to 29 linked nucleosides, said second modified oligonucleotide comprising a complementary region of at least 8 nucleobases that is at least 90% complementary to an equal length portion of said first modified oligonucleotide; or c) a first oligomeric compound comprising a first modified oligonucleotide consisting of 19 to 29 linked nucleosides, wherein the nucleobase sequence of the first modified oligonucleotide comprises at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 consecutive nucleobases of the nucleobase sequence of any of SEQ ID NOs: 1713-2024; and A second oligomeric compound comprising a second modified oligonucleotide consisting of 15 to 29 linked nucleosides, wherein the nucleobase sequence of said second modified oligonucleotide comprises at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, or at least 21 contiguous nucleobases of the nucleobase sequence of any of SEQ ID NOs: 2025-2336, and wherein the nucleobase sequence of said second modified oligonucleotide is at least 90% complementary to an equal length portion of the first modified oligonucleotide.

8. The oligomeric duplex of claim 7, wherein said modified oligonucleotide of said first oligomeric compound comprises a 5'-stabilized phosphate group, such as cyclopropylphosphonate or vinylphosphonate.

9. 9. The oligomeric duplex of claim 7 or 8, wherein the first modified oligonucleotide and / or the second modified oligonucleotide comprise at least one modified sugar moiety and / or at least one sugar surrogate, and / or at least one modified internucleoside linkage and / or at least one modified nucleobase, optionally comprising: a) the modified sugar moiety comprises a bicyclic sugar moiety or a non-bicyclic modified sugar moiety; wherein optionally, the bicyclic sugar moiety of the second modified oligonucleotide comprises a 2'-4' bridge selected from -O-CH2- and -O-CH(CH3)-; or the non-bicyclic modified sugar moiety of the second modified oligonucleotide can be a 2'-MOE sugar moiety, a 2'-F sugar moiety, or a 2'-OMe sugar moiety; and / or b) each internucleoside linkage of the first and / or the second modified oligonucleotide is independently selected from a phosphodiester, phosphorothioate, or mesyl phosphoramidate internucleoside linkage; and / or c) the modified nucleobase is 5-methylcytosine; Oligomeric duplex.

10. 10. The oligomeric duplex of any of claims 7-9, wherein the internucleoside linkage motif of the first modified oligonucleotide is ssooooooooooooooooooooooooss and the internucleoside linkage motif of the second modified oligonucleotide is ssooooooooooooooooooooooss, where each "o" represents a phosphodiester internucleoside linkage and each "s" represents a phosphorothioate internucleoside linkage.

11. The oligomeric duplex of any one of claims 7 to 10, wherein the second oligomeric compound comprises a conjugate group (a) and / or a terminal group (b) as follows: a) a conjugate group, ai) a conjugate group comprising a conjugate linker and a conjugate moiety; optionally, said conjugate group is attached to said second modified oligonucleotide at the 5' end of said second modified oligonucleotide; and / or aii) C22 alkyl, C20 alkyl, C16 alkyl, C10 alkyl, C21 alkyl, C19 alkyl, C18 alkyl, C15 alkyl, C14 alkyl, C13 alkyl, C12 alkyl, C11 alkyl, C9 alkyl, C8 alkyl, C7 alkyl, C6 alkyl, C5 alkyl, C22 alkenyl, C20 alkenyl, C16 alkenyl, C10 alkenyl, C21 alkenyl, C19 alkenyl, C18 alkenyl, C15 alkenyl, C14 alkenyl, C13 alkenyl or a conjugate group comprising a cell targeting moiety, which may optionally have affinity for TfR1, or which may optionally be an anti-TfR1 antibody or fragment thereof, or a protein or peptide capable of binding TfR1, or an aptamer capable of binding TfR1; and / or b) Terminal group.

12. The conjugate group having the following structure: 【Chemistry 2】 The oligomeric duplex of claim 11 having the formula:

13. 12. The oligomeric duplex of claim 11, wherein the terminal group is an abasic sugar moiety.

14. The second modified oligonucleotide is 10-25, 10-30, 10-50, 12-20, 12-25, 12-30, 12-50, 13-20, 13-25, 13-30, 13-50, 14-20, 14-25, 14-30, 14-50, 15-20, 15-25, 15-30, 15-50, 16-18, 16-20, 16-25, 16-30, 16-50, 17-20, 17-25, 14. The oligomeric duplex of any of claims 7-13, consisting of 7-30, 17-50, 18-20, 18-25, 18-30, 18-50, 19-20, 19-25, 19-30, 19-50, 20-25, 20-30, 20-50, 21-25, 21-30, 21-50, 22-25, 22-30, 22-50, 23-25, 23-30, or 23-50 linked nucleosides.

15. The oligomeric duplex of any of claims 7 to 14, wherein the oligomeric duplex is as defined in (a) of claim 7, and the nucleobase sequence of the first modified oligonucleotide is at least 80%, at least 85%, at least 90%, or at least 95% complementary to an equal length portion within nucleobases 304 to 326, 324 to 346, or 514 to 536 of SEQ ID NO:

1.

16. A method for the preparation of a modified oligonucleotide comprising the steps of: a) administering to a patient a modified oligonucleotide comprising: a) administering to a patient a modified oligonucleotide comprising: a) administering to a patient a modified oligonucleotide comprising: a) administering to a patient a modified oligonucleotide comprising: 3, 1722 / 2034, 1723 / 2035, 1724 / 2036, 1725 / 2037, 1726 / 2038, 1727 / 2039, 1728 / 2040, 1729 / 2041, 1730 / 2042, 1731 / 2043, 1732 / 2044, 1733 / 2045, 1 734 / 2046, 1735 / 2047, 1736 / 2048, 1737 / 2049, 1738 / 2050, 1739 / 2051, 1740 / 2052, 1741 / 2053, 1742 / 2054, 1743 / 2055, 1744 / 2056, 1745 / 2057, 1746 / 2058, 1747 / 2059, 1748 / 2060, 1749 / 2061, 1750 / 2062, 1751 / 2063, 1752 / 2064, 1753 / 2065, 1754 / 2066, 1755 / 2067, 1756 / 2068, 1757 / 2069, 1758 / 207 0, 1759 / 2071, 1760 / 2072, 1761 / 2073, 1762 / 2074, 1763 / 2075, 1764 / 2076, 1765 / 2077, 1766 / 2078, 1767 / 2079, 1768 / 2080, 1769 / 2081, 1770 / 2082, 17 71 / 2083, 1772 / 2084, 1773 / 2085, 1774 / 2086, 1775 / 2087, 1776 / 2088, 1777 / 2089, 1778 / 2090, 1779 / 2091, 1780 / 2092, 1781 / 2093, 1782 / 2094, 1783 / 2 095, 1784 / 2096, 1785 / 2097, 1786 / 2098, 1787 / 2099, 1788 / 2100, 1789 / 2101, 1790 / 2102, 1791 / 2103, 1792 / 2104, 1793 / 2105, 1794 / 2106, 1795 / 2107,１７９６／２１０８、１７９７／２１０９、１７９８／２１１０、１７９９／２１１１、１８００／２１１２、１８０１／２１１３、１８０２／２１１４、１８０３／２１１５、１８０４／２１１６、１８０５／２１１７、１８０６／２１１８、１８０７／２１１９、１８０８／２１２０、１８０９／２１２１、１８１０／２１２２、１８１１／２１２３、１８１２／２１２４、１８１３／２１２５、１８１４／２１２６、１８１５／２１２７、１８１６／２１２８、１８１７／２１２９、１８１８／２１３０、１８１９／２１３１、１８２０／２１３２、１８２１／２１３３、１８２２／２１３４、１８２３／２１３５、１８２４／２１３６、１８２５／２１３７、１８２６／２１３８、１８２７／２１３９、１８２８／２１４０、１８２９／２１４１、１８３０／２１４２、１８３１／２１４３、１８３２／２１４４、１８３３／２１４５、１８３４／２１４６、１８３５／２１４７、１８３６／２１４８、１８３７／２１４９、１８３８／２１５０、１８３９／２１５１、１８４０／２１５２、１８４１／２１５３、１８４２／２１５４、１８４３／２１５５、１８４４／２１５６、１８４５／２１５７、１８４６／２１５８、１８４７／２１５９、１８４８／２１６０、１８４９／２１６１、１８５０／２１６２、１８５１／２１６３、１８５２／２１６４、１８５３／２１６５、１８５４／２１６６、１８５５／２１６７、１８５６／２１６８、１８５７／２１６９、１８５８／２１７０、１８５９／２１７１、１８６０／２１７２、１８６１／２１７３、１８６２／２１７４、１８６３／２１７５、１８６４／２１７６、１８６５／２１７７、１８６６／２１７８、１８６７／２１７９、１８６８／２１８０、１８６９／２１８１、１８７０／２１８２、１８７１／２１８３、１８７２／２１８４、１８７３／２１８５、１８７４／２１８６、１８７５／２１８７、１８７６／２１８８、１８７７／２１８９、１８７８／２１９０、１８７９／２１９１、１８８０／２１９２、１８８１／２１９３、１８８２／２１９４、１８８３／２１９５、１８８４／２１９６、１８８５／２１９７、１８８６／２１９８、１８８７／２１９９、１８８８／２２００、１８８９／２２０１、１８９０／２２０２、１８９１／２２０３、１８９２／２２０４、１８９３／２２０５、１８９４／２２０６、１８９５／２２０７、１８９６／２２０８、１８９７／２２０９、１８９８／２２１０、１８９９／２２１１、１９００／２２１２、１９０１／２２１３、１９０２／２２１４、１９０３／２２１５、１９０４／２２１６、１９０５／２２１７、１９０６／２２１８、１９０７／２２１９、１９０８／２２２０、１９０９／２２２１、１９１０／２２２２、１９１１／２２２３、１９１２／２２２４、１９１３／２２２５、１９１４／２２２６、１９１５／２２２７、１９１６／２２２８、１９１７／２２２９、１９１８／２２３０、１９１９／２２３１、１９２０／２２３２、１９２１／２２３３、１９２２／２２３４、１９２３／２２３５、１９２４／２２３６、１９２５／２２３７、１９２６／２２３８、１９２７／２２３９、１９２８／２２４０、１９２９／２２４１、１９３０／２２４２、１９３１／２２４３、１９３２／２２４４、１９３３／２２４５、１９３４／２２４６、１９３５／２２４７、１９３６／２２４８、１９３７／２２４９、１９３８／２２５０、１９３９／２２５１、１９４０／２２５２、１９４１／２２５３、１９４２／２２５４、１９４３／２２５５、１９４４／２２５６、１９４５／２２５７、１９４６／２２５８、１９４７／２２５９、１９４８／２２６０、１９４９／２２６１、１９５０／２２６２、１９５１／２２６３、１９５２／２２６４、１９５３／２２６５、１９５４／２２６６、１９５５／２２６７、１９５６／２２６８、１９５７／２２６９、１９５８／２２７０、１９５９／２２７１、１９６０／２２７２、１９６１／２２７３、１９６２／２２７４、１９６３／２２７５、１９６４／２２７６、１９６５／２２７７、１９６６／２２７８、１９６７／２２７９、１９６８／２２８０、１９６９／２２８１、１９７０／２２８２、１９７１／２２８３、１９７２／２２８４、１９７３／２２８５、１９７４／２２８６、１９７５／２２８７、１９７６／２２８８、１９７７／２２８９、１９７８／２２９０、１９７９／２２９１、１９８０／２２９２、１９８１／２２９３、１９８２／２２９４、１９８３／２２９５、１９８４／２２９６、１９８５／２２９７、１９８６／２２９８、１９８７／２２９９、１９８８／２３００、１９８９／２３０１、１９９０／２３０２、１９９１／２３０３、１９９２／２３０４、１９９３／２３０５、１９９４／２３０６、１９９５／２３０７、1996 / 2308, 1997 / 2309, 1998 / 2310, 1999 / 2311, 2000 / 2312, 2001 / 2313, 2002 / 2314, 2003 / 2315, 2004 / 2316, 2005 / 2317, 2006 / 2318, 2007 / 2319, 2008 / 2320, 2009 / 2321, 2010 / 2322 , 2011 / 2323, 2012 / 2324, 2013 / 2325, 2014 / 2326, 2015 / 2327, 2016 / 2328, 2017 / 2329, 2018 / 2330, 2019 / 2331, 2020 / 2332, 2021 / 2333, 2022 / 2334, 2023 / 2335, or 2024 / 2336 The oligomeric duplex of any of claims 7 to 13, wherein the nucleobase sequence of a first modified oligonucleotide comprises contiguous nucleobases in the nucleobase sequence of a first SEQ ID NO: recited in the pair, and the nucleobase sequence of a second modified oligonucleotide comprises contiguous nucleobases in the nucleobase sequence of a second SEQ ID NO: recited in the pair.

17. 17. The oligomeric duplex of any of claims 7-16, wherein said modified oligonucleotide of said first oligomeric compound consists of 23 linked nucleosides and said second modified oligonucleotide consists of 21 linked nucleosides.

18. 18. The oligomeric duplex of claim 17, wherein said modified oligonucleotide of said first oligomeric compound has the sugar motif (5' to 3'): yfyfyfyfyfyfyfyfyfyfyyy and said second modified oligonucleotide has the sugar motif (5' to 3'): fyfyfyfyfyfyfyfyfyfyf, wherein each "y" represents a 2'-OMe sugar moiety and each "f" represents a 2'-F sugar moiety.

19. The oligomeric duplex of any one of claims 7 to 18, wherein the first modified oligonucleotide is an antisense oligonucleotide and the second modified oligonucleotide is a sense oligonucleotide.

20. An antisense agent comprising an antisense compound, said antisense compound being an oligomeric compound according to any one of claims 1 to 6.

21. 21. An antisense agent which is an oligomeric duplex according to any one of claims 7 to 20.

22. 22. The antisense agent of claim 20 or 21, i. an RNase H agent capable of reducing the amount of PLN nucleic acid by activating RNase H, or ii. RNAi agents capable of reducing the amount of PLN nucleic acid by activating RISC / Ago2 The antisense agent,

23. 23. A pharmaceutical composition comprising an oligomeric compound according to any one of claims 1 to 6, or an oligomeric duplex according to any one of claims 7 to 19, or an antisense agent according to any one of claims 20 to 22, and a pharma- ceutically acceptable diluent or carrier.

24. A medicament for use in treating a disease associated with PLN, comprising an oligomeric compound according to any one of claims 1 to 6, an oligomeric duplex according to any one of claims 7 to 19, an antisense agent according to any one of claims 20 to 22, or a pharmaceutical composition according to claim 23.

25. The pharmaceutical according to claim 24, wherein the PLN-related disease is cardiomyopathy, heart failure, or arrhythmia.

26. The pharmaceutical composition according to claim 25, a) the cardiomyopathy is an inherited cardiomyopathy, and the inherited cardiomyopathy may be associated with a p.Arg14del, Arg9Cys (R9C), or Arg25Cys (R25C) genetic mutation; or b) the cardiomyopathy is dilated cardiomyopathy (DCM), for example an inherited DCM, the inherited DCM being associated with mutations in TTN, LMNA, RBM20, SCN5A, MYH7, TNNT2, and TPM1; or c) the heart failure is heart failure with preserved ejection fraction (HFpEF), heart failure with reduced ejection fraction (HFrEF), acute heart failure, or worsening chronic heart failure; or d) The medicament, wherein the arrhythmia is ventricular tachycardia (Vtac) or ventricular fibrillation (Vfib).

27. The pharmaceutical agent according to claim 25 or 26, which improves cardiac function, cardiovascular death, cardiac dilation, myocardial fibrosis, low voltage ECG, diastolic calcium uptake, ejection fraction (EF), left ventricular ejection fraction (LVEF), left ventricular end systolic volume (LVESV), left ventricular end diastolic volume (LVEDV), mitral valve blood flow profile, left ventricular (LV) strain, left ventricular (LV) strain rate, infarct size, hospitalization for heart failure, 6-minute walk test (6MWT), Kansas City Cardiomyopathy Questionnaire score (KCCQS), heart rate, or heart rhythm.

Images