Compounds and methods for reducing PLN expression

Abstract

To reduce the amount or activity of PLN RNA in cells or animals, in certain cases, oligomeric compounds, methods, and pharmaceutical compositions are provided for reducing the amount of phospholamban protein in cells or animals. Such oligomeric compounds, methods, and pharmaceutical compositions are useful for treating cardiomyopathy, heart failure, or arrhythmias.

Description

[Technical Field]

[0001] (Cross-referencing of related patent applications) This Specified Claims Priority to U.S. Provisional Patent Application No. 63 / 494,415 (filed April 5, 2023), U.S. Provisional Patent Application No. 63 / 508,453 (filed June 15, 2023), and U.S. Provisional Patent Application No. 63 / 561,700 (filed March 5, 2024). The full texts of the patent applications referenced above are incorporated herein by reference.

[0002] (Sequence Listing) This application is filed simultaneously with the electronic sequence listing. The sequence listing is provided as a file named 201366-WO-PCT.xml, created on March 8, 2024, with a size of 1,520 KB. The entire contents of the electronic version of this sequence listing are incorporated herein by reference.

[0003] (Field of Invention) The present invention relates to compounds, compositions, and uses thereof, and includes methods for reducing levels of PLN expression, PLN RNA, and / or phospholamban protein (and / or activity), as well as methods for preventing, treating, and / or alleviating at least one symptom of a cardiac disease, disorder, or condition, such as cardiomyopathy, heart failure, or arrhythmia. [Background technology]

[0004] The heart's pumping action, which circulates blood throughout the body, is produced by the repetitive contraction of the cardiac muscle (i.e., myocardium). The rhythmic contraction process of the cardiac muscle is regulated by changes in cytoplasmic calcium ion concentration in cardiac muscle cells (called cardiac muscle cells). An increase in cytoplasmic calcium ion concentration is associated with cardiac contraction (systole), while a decrease in cytoplasmic calcium ion concentration is associated with cardiac relaxation (diastole). The sarcoplasmic reticulum, a membranous intracellular tubular structure within cardiac and skeletal muscle cells, is involved in contractile calcium processing (i.e., the uptake and storage of calcium ions from the cytosol during relaxation, and the release of sequestered calcium ions into the cytosol for muscle contraction) and is associated with several proteins that promote and regulate calcium ion uptake and release. One such protein is sarco(endo)plasmic reticulum calcium ATPase (SERCA), which functions to pump cytoplasmic calcium into the sarcoplasmic reticulum during cardiac relaxation. SERCA is regulated by phospholamban (encoded by PLN). Phospholamban is a phosphorylated protein that inhibits SERCA activity in its dephosphorylated state by reducing SERCA's affinity for calcium ions. This, in turn, weakens the filling of sarcoplasmic reticulum calcium stores and reduces the generation of contractile force. Phospholamban phosphorylation reverses the inhibition of SERCA.

[0005] Heart failure is a condition in which the heart is unable to provide the body with sufficient blood flow and is a leading cause of death worldwide. Heart failure can be chronic, developing gradually over time, or acute, with a more sudden and rapid decline in cardiac function. Heart failure can be caused by conditions that damage, weaken, and / or overwork the heart, including cardiomyopathy. Cardiomyopathy refers to diseases, disorders, and conditions of the heart muscle that weaken the heart and eventually make it unable to pump effectively. When the heart weakens, normal heart muscle can thicken, harden, or thin, impairing its ability to pump blood, which can lead to heart failure.

[0006] Arrhythmias are irregular or abnormal heartbeats and are a leading cause of sudden cardiac death. Arrhythmias that occur in the ventricles (the ventricles of the heart) are particularly dangerous, causing the heart to beat excessively fast. This can impair blood circulation and lead to cardiac arrest. Ventricular fibrillation (vFIB) is a rapid, uncoordinated heart rhythm in which the electrical signals of the heart often lack a normal repetitive pattern. Ventricular tachycardia (vTAC) is a fast heart rhythm, and if it is too fast, it can prevent the heart from beating effectively or from pumping blood throughout the body, which can lead to loss of consciousness.

[0007] Effective management of intracellular calcium is a crucial factor in regulating myocardial contractility. Symptoms of heart failure include decreased contractility, which may manifest as cardiac blunting, slowness, desynchronous contractions, and impaired relaxation. Abnormal calcium cycling within cardiomyocytes and defective intracellular calcium ion homeostasis are associated with contractile dysfunction and arrhythmias in failing myocardium. Therapies targeting cardiac dysfunction and conditions associated with heart failure remain necessary. Therapeutics targeting cardiac calcium regulation may offer a new class of compounds for effective management of contractility and for the therapy of patients at risk of cardiomyopathy and heart failure. [Overview of the project]

[0008] This specification provides compounds, pharmaceutical compositions, and methods of use for reducing the amount or activity of PLN RNA, and, in certain embodiments, for reducing the expression of phospholamban in cells or subjects. In certain embodiments, the subject has a disease or disorder related to cardiac calcium regulation, regulation of myocardial contractility, or mutations in PLN. In certain embodiments, the subject has cardiomyopathy. In certain embodiments, the subject has cardiac arrhythmia. In certain embodiments, the subject has heart failure. In certain embodiments, compounds useful for reducing the amount or activity of PLN RNA are oligomeric compounds, oligomeric double helixes, antisense compounds, and RNAi agents. In certain embodiments, compounds useful for reducing phospholamban expression are oligomeric compounds, oligomeric double helixes, antisense compounds, and RNAi agents.

[0009] Also provided are methods useful for alleviating a cardiac disorder or at least one symptom of a cardiac injury. In certain embodiments, the disorder is cardiomyopathy. In certain embodiments, the disorder is arrhythmia. In certain embodiments, the injury is heart failure. In certain embodiments, the symptoms are selected from pain, hypokalemia, palpitations (e.g., irregular tempo, fast heartbeat, strong heartbeat, or flutter), chest pain, fatigue, shortness of breath, weakness, lightheadedness, dizziness, syncope, nausea, confusion, intolerance to exertion, thrombosis, or a combination thereof.

[0010] Modified oligonucleotides and compounds, and compositions comprising them, are provided, including but not limited to antisense compounds, oligomeric compounds, oligomeric double helixes, and pharmaceutical compositions comprising modified oligonucleotides. In certain embodiments, the modified oligonucleotides provided herein contain a nucleic acid base sequence that is at least 80% complementary to the isolength portion of the PLN nucleic acid. In certain embodiments, the modified oligonucleotides consist of 12-35, 14-30, 15-28, 16-25, or 18-23 linked nucleosides targeting the PLN nucleic acid. In certain embodiments, the modified oligonucleotides provided herein contain a sequence of nucleic acid bases complementary to the isolength portion of the nucleic acid base sequence of SEQ ID NO: 1 and / or SEQ ID NO: 2.

[0011] In certain embodiments, the modified oligonucleotides provided herein include at least one modified sugar moiety and / or at least one modified internucleoside bond. The modified oligonucleotides described herein and compositions comprising them (including, but not limited to, oligomeric compounds, oligomeric double helixes, antisense compounds, and pharmaceutical compositions) are useful for reducing or inhibiting PLN expression in cells, organs, tissues, systems, organisms, or animals.

[0012] Furthermore, methods for reducing or inhibiting PLN expression, PLN RNA levels, and / or phospholamban protein levels, and / or activity in cells or organisms (including, for example, animals) are provided herein. In certain embodiments, the method comprises contacting cells or subjects with a composition provided herein comprising modified oligonucleotides, oligomeric compounds, and / or oligomeric double helixes. In certain embodiments, subjects are human beings who have or are at risk of having a disease, disorder, condition, or injury related to cardiac calcium regulation, myocardial contractility regulation, or mutations in PLN. In certain embodiments, subjects are human beings who have or are at risk of having heart failure. In certain embodiments, subjects are human beings who have or are at risk of having arrhythmias and / or cardiomyopathy (including, for example, dilated, hypertrophic, arrhythmogenic, or restrictive cardiomyopathy).

[0013] Furthermore, methods for preventing, treating, delaying the onset or progression of, or mitigating diseases, disorders, conditions, or injuries related to cardiac calcium regulation, myocardial contractility regulation, or mutations in the PLN are also provided herein. In certain embodiments, the methods provided herein include methods for preventing, treating, delaying the onset or progression of, or mitigating cardiomyopathy, heart failure, and / or arrhythmias. In some embodiments, the methods provided herein include administering a composition provided herein (e.g., a modified oligonucleotide, oligomeric compound, oligomeric double-chain, or pharmaceutical composition provided herein) to a subject (e.g., a human subject) who has or is at risk of having a disease, disorder, condition, or injury related to cardiac calcium regulation, myocardial contractility regulation, or mutations in the PLN (e.g., cardiomyopathy, heart failure, and / or arrhythmias) to prevent, treat, delay the onset or progression of, or mitigate such a disease, disorder, condition, or injury (e.g., cardiomyopathy, heart failure, and / or arrhythmias). Also provided herein are methods for preventing, treating, alleviating, delaying the onset or progression of, or reducing the frequency of at least one symptom of cardiomyopathy, arrhythmia, and / or heart failure. Symptoms of cardiomyopathy, arrhythmia, and / or heart failure include, but are not limited to, shortness of breath, difficulty breathing, fatigue, swelling of the ankles, legs, or feet, cough, arrhythmia, palpitations, lightheadedness, dizziness, syncope, weakness, reduced exercise capacity, and abdominal distension. In some embodiments, methods provided herein for preventing, treating, alleviating, delaying the onset of, or reducing the frequency of at least one symptom of cardiomyopathy, arrhythmia, and / or heart failure include administering a composition provided herein (e.g., a modified oligonucleotide, oligomeric compound, oligomeric double-chain, or pharmaceutical composition provided herein) to a subject (e.g., a human subject) that has or is at risk of having at least one symptom. [Brief explanation of the drawing]

[0014] [Figure 1A]The experimental results from the tests described in Example 6 demonstrate the efficacy of 5'-C16, 3'-C16, 5'-BCY17901, or 3'-BCY17901 conjugate-modified oligonucleotides and oligomeric double helixes targeting human PLN. [Figure 1B] The experimental results from the tests described in Example 6 demonstrate the efficacy of 5'-C16, 3'-C16, 5'-BCY17901, or 3'-BCY17901 conjugate-modified oligonucleotides and oligomeric double helixes targeting human PLN. [Figure 2A] The experimental results from the test described in Example 11 demonstrate the efficacy of the BCY17901 conjugate-modified oligomeric double helix targeting human PLN. [Figure 2B] The experimental results from the test described in Example 11 demonstrate the efficacy of the BCY17901 conjugate-modified oligomeric double helix targeting human PLN. [Figure 3] The experimental results from the duration test described in Example 14, which demonstrate the efficacy and duration of the BCY17901 conjugate-modified oligomer double helix targeting human PLN, are shown. [Figure 4] A model of improved activity of PLN-targeting compounds is shown based on the results described herein (see also Example 15). [Modes for carrying out the invention]

[0015] It should be understood that both the general description above and the detailed description below are merely illustrative and descriptive, and not restrictive. In this specification, the use of the singular includes the plural unless otherwise explicitly stated. Where used herein, the use of "or" means "and / or" unless otherwise explicitly stated. Furthermore, the term "including," as well as its other forms "includes" and "included," are not restrictive. Also, terms such as "element" or "component" include both elements and components containing one unit, and elements and components containing two or more subunits, unless otherwise explicitly stated.

[0016] Section headings used herein are for structural purposes only and should not be construed as limiting the subject matter described herein. All documents or parts of documents cited herein, including but not limited to patents, patent applications, articles, books, and papers, are incorporated herein by express reference, both in part and in whole, of the documents discussed herein.

[0017] definition For a complete understanding of the present invention, the following definitions, along with additional definitions, are provided throughout this specification. Unless otherwise specified herein, the nomenclature, procedures, and techniques used in relation to analytical chemistry, synthetic organic chemistry, and medicinal chemistry and pharmaceutical chemistry described herein are well known and commonly used in the art. Unless otherwise indicated, certain terms have the following meanings:

[0018] As used herein, “2'-deoxynucleoside” means a nucleoside containing a 2'-deoxy sugar moiety. Unless otherwise indicated, a 2'-deoxynucleoside is a 2'-β-D-deoxyribosyl nucleoside containing a 2'-β-D-deoxyribosyl sugar moiety, which has a β-D ribosyl configuration as found in naturally occurring deoxyribonucleic acid (DNA).

[0019] As used herein, “2'-deoxy sugar moiety” means a 2'-H(H)deoxyribosyl sugar moiety. Unless otherwise indicated, a 2'-deoxy sugar moiety includes a 2'-β-D-deoxyribosyl sugar moiety having a β-D-ribosyl configuration as found in naturally occurring deoxyribonucleic acid (DNA). In this specification, in the context of oligomeric compounds containing ribonucleic acid oligonucleotides (e.g., siRNA), a 2'-deoxy sugar moiety is considered, for example, a modified sugar moiety.

[0020] As used herein, "2'-MOE" means a 2'-OCH2CH2OCH3 group instead of the 2'-OH group in the ribosyl sugar moiety. "2'-MOE sugar moiety" means a sugar moiety having a 2'-OCH2CH2OCH3 group instead of the 2'-OH group in the ribosyl sugar moiety. Unless otherwise indicated, the 2'-MOE sugar moiety is in a β-D-ribosyl configuration. "MOE" means O-methoxyethyl.

[0021] As used herein, "2'-MOE nucleoside" or "2'-O(CH2)2OCH3 nucleoside" means a nucleoside containing a 2'-MOE sugar moiety (or a 2'-OCH2CH2OCH3 ribosyl sugar moiety).

[0022] As used herein, "2'-OMe" means a 2'-OCH3 group instead of a 2'-OH group in the ribosyl sugar moiety. "2'-OMe sugar moiety" or "2'-O-methyl sugar moiety" means a sugar moiety having a 2'-OCH3 group instead of a 2'-OH group in the ribosyl sugar moiety. Unless otherwise indicated, 2'-OMe has a β-D-ribosyl stereochemical configuration.

[0023] As used herein, "2'-OMe nucleoside" means a nucleoside containing a 2'-OMe sugar moiety.

[0024] As used herein, "2'-F" means a 2'-fluoro group in place of the 2'-OH group in the furanosyl sugar moiety. "2'-F sugar moiety" (i.e., "2'-fluoro sugar moiety") means a sugar moiety having a 2'-F (i.e., 2'-fluoro) group in place of the 2'-OH group in the furanosyl sugar moiety. Unless otherwise indicated, the 2'-F sugar moiety is in a β-D-ribosyl configuration.

[0025] As used herein, "2'-F nucleoside" means a nucleoside containing a 2'-F sugar moiety.

[0026] As used herein, “2'-substituted nucleoside” means a nucleoside containing a 2'-substituted furanosyl sugar moiety. As used herein, with respect to the sugar moiety, “2'-substituted” means a sugar moiety in which at least one 2'-substituent is not H. Examples of 2'-substituted modified sugar moieties include, independently, sugar moieties containing 2'-substituents selected from 2'-F, 2'-MOE, 2'-OMe, and cEt.

[0027] As used herein, "5-methylcytosine" refers to cytosine modified with a methyl group attached at the 5-position. 5-methylcytosine is a modified nucleic acid base.

[0028] As used herein, “debasic sugar moiety” means the sugar portion of a nucleoside that is not bound to a nucleic acid base. Such debasic sugar moieties may be referred to in the art as “debasic nucleoside.”

[0029] As used herein, “alleviate” means to improve or reduce at least one symptom of the disease, disorder, or condition in question. In certain embodiments, alleviation means a reduction in the severity or frequency of a symptom, or a delay in the onset or progression of the severity or frequency of a symptom. Measures of progression, frequency, or severity may be determined by subjective or objective measures known in the art and / or described herein.

[0030] As used herein, “antisense activity” means any detectable and / or measurable change resulting from the hybridization of an antisense compound to its target nucleic acid. In certain embodiments, antisense activity is a reduction in the amount or expression of the target nucleic acid or protein encoded by such target nucleic acid compared to the level of the target nucleic acid or target protein in the absence of the antisense compound. In certain embodiments, a compound has antisense activity if it reduces or inhibits the amount or activity of the target nucleic acid by 25% or more in an in vitro assay. In certain embodiments, a compound has antisense activity if it reduces or inhibits the amount or activity of the target nucleic acid by 25% or more in an in vivo assay. In certain embodiments, antisense activity is evaluated by a standard assay.

[0031] As used herein, “antisense compound” means an antisense oligonucleotide and, optionally, one or more additional features (e.g., a paired oligonucleotide, a conjugate group, and / or terminal group). As used herein, “antisense oligonucleotide” means an oligonucleotide that is capable of hybridizing to a target nucleic acid and is capable of at least one antisense activity. In certain embodiments, the antisense compound selectively affects one or more target nucleic acids. In certain embodiments, the antisense compound is a modified oligonucleotide provided herein that is capable of hybridizing to a target nucleic acid and is capable of at least one antisense activity. The antisense oligonucleotide may pair with a second oligonucleotide (hereinafter referred to as “sense oligonucleotide”) that is complementary to the antisense oligonucleotide (i.e., can hybridize to the antisense oligonucleotide to form a double-stranded antisense oligonucleotide), may be an unpaired antisense oligonucleotide (single-stranded antisense oligonucleotide), or may be a “hairpin” oligonucleotide having at least one self-complementary region. As used herein, “sense compound” means a sense oligonucleotide and, optionally, one or more additional features such as a conjugate group.

[0032] As used herein, "bicyclic nucleoside" means a nucleoside containing a bicyclic sugar moiety.

[0033] As used herein, “bicyclic sugar” or “bicyclic sugar moiety” means a modified sugar moiety containing two rings, the second ring being formed via a bridge connecting two of the atoms in the first ring, thereby forming a bicyclic structure, and the first ring of the bicyclic sugar moiety being a furanosyl ring. Examples of bicyclic sugar moieties include the LNA (locked nucleic acid) sugar moiety and the cEt sugar moiety as defined herein.

[0034] As used herein, "blunt" or "blunt-ended" with respect to an oligomeric double helix means that there are no unpaired nucleotides at the terminal (i.e., no overhanging nucleotides). One or both ends of an oligomeric double helix may be blunt.

[0035] As used herein, “cell-targeting moiety” means a conjugate group, or a portion of a conjugate group that can bind to a particular cell type or a group of cell types. In certain embodiments, the cell-targeting moiety binds to a surface portion, such as a surface receptor, on a particular cell type.

[0036] As used herein, “cleavable portion” means a bond or group of atoms that is cleaved under physiological conditions, for example, in a cell and / or upon administration to a subject.

[0037] As used herein, “complementary” with respect to an oligonucleotide or part thereof means that, when the nucleic acid base sequences of the oligonucleotide and another nucleic acid are aligned in opposite directions, at least 70% of the nucleic acid bases of such oligonucleotide or part thereof and the nucleic acid bases of another nucleic acid or part thereof can form hydrogen bonds with each other. As used herein, “complementary nucleic acid bases” means nucleic acid bases that can form hydrogen bonds with each other. Complementary nucleic acid base pairs include adenine (A) and thymine (T), adenine (A) and uracil (U), cytosine (C) and guanine (G), and 5-methylcytosine ( mThis includes C) and guanine (G). Certain modified nucleic acid bases that pair with unmodified nucleic acid bases or other modified nucleic acid bases are known in the art. For example, hypoxanthine (I), a nucleic acid base of the nucleoside inosine, can pair with adenine, cytosine, thymine, or uracil. In this specification, hypoxanthine (I) is considered a nucleic acid base complementary to thymine (T), adenine (A), uracil (U), and cytosine (C). Complementary oligonucleotides and / or nucleic acids do not need to have nucleic acid base complementarity at each nucleoside. Rather, some mismatches are acceptable. As used herein, “perfectly complementary” or “100% complementary” with respect to an oligonucleotide or part thereof means that the oligonucleotide or part thereof is complementary to another oligonucleotide or target nucleic acid at each nucleic acid base of the shorter of two oligonucleotides, or at each nucleoside if the oligonucleotides are of the same length.

[0038] As used herein, “complementary region” with respect to an oligonucleotide or a portion thereof means a range of nucleic acid bases of an oligonucleotide that is complementary to the nucleic acid base sequence of an isolength region of a second oligonucleotide or its region (e.g., an oligonucleotide and a target nucleic acid, or an antisense oligonucleotide and a sense oligonucleotide), or to the nucleic acid base sequence of an isolength region within the second region of the oligonucleotide (e.g., in a “hairpin oligonucleotide”). The complementary region of an oligonucleotide may be a portion of the oligonucleotide, may include the entire oligonucleotide, or may include substantially the entire oligonucleotide.

[0039] As used herein, “restricted ethyl,” “cEt,” or “cEt sugar moiety” means a β-D-ribosyl bicyclic sugar moiety, wherein 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, the bridge having the formula 4'-CH(CH3)-O-2', and the methyl group of the bridge is in the S configuration.

[0040] As used herein, "cEt nucleoside" means a nucleoside containing a cEt sugar moiety.

[0041] As used herein, “hybridization” means the process by which two complementary nucleic acid sequences (e.g., oligonucleotides, nucleic acids) anneal or combine to form a double-stranded or double-stranded region or molecule. While not limited to specific mechanisms, the most common mechanism of hybridization involves hydrogen bonding, which may be Watson-Crick, Hoogsteen, or reverse Hoogsteen hydrogen bonding between complementary nucleic acid bases. In certain embodiments, complementary nucleic acid sequences in separate molecules include, but are not limited to, antisense compounds and nucleic acid targets. In certain embodiments, complementary nucleic acid sequences in separate molecules include, but are not limited to, the oligonucleotides and nucleic acid targets of the present invention. In certain embodiments, complementary nucleic acid sequences in separate molecules include, but are not limited to, antisense compounds and sense compounds. In certain embodiments, complementary nucleic acid sequences in the same molecule include, but are not limited to, oligomeric compounds (e.g., hairpin oligos) containing the oligonucleotides of the present invention.

[0042] As used herein, “nucleoside bond” refers to a covalent bond between adjacent nucleosides in an oligonucleotide. As used herein, “modified nucleoside bond” refers to any nucleoside bond other than a phosphodiester nucleoside bond. “Phosphothioate nucleoside bond” refers to a modified nucleoside bond in which one of the non-bridged oxygen atoms of a phosphodiester nucleoside bond is replaced by a sulfur atom.

[0043] As used herein, “inverted nucleoside” means a nucleoside having 3'-3' and / or 5'-5' internucleoside bonds, as shown herein. As used herein, “inverted sugar moiety” means the sugar moiety of an inverted nucleoside or a debasic sugar moiety having 3'-3' and / or 5'-5' internucleoside bonds.

[0044] As used herein, “concatenated nucleosides” are nucleosides connected in a continuous sequence (i.e., nucleosides that are directly adjacent to each other, with no additional nucleosides between them).

[0045] As used herein, “linker nucleoside” means a nucleoside that directly or indirectly links an oligonucleotide to a conjugate moiety. When present in a compound, the linker nucleoside is located within the conjugate linker of the compound of the present invention. The linker nucleoside is not considered part of the oligonucleotide moiety of the compound, even if it is contiguous with the oligonucleotide.

[0046] As used herein, “mismatch” or “non-complementary” means a nucleic acid base of the first nucleic acid sequence that is not complementary to the corresponding nucleic acid base of the second nucleic acid sequence when the first and second nucleic acid sequences are aligned in opposite directions.

[0047] As used herein, “modified nucleoside” means a nucleoside containing a modified nucleic acid base and / or a modified sugar moiety. Modified nucleosides include debased nucleosides.

[0048] As used herein, "modified sugar moiety" means the furanosyl sugar moiety of a nucleoside other than the β-D-ribosyl sugar moiety (the sugar moiety of unmodified RNA).

[0049] As used herein, “motif” means a pattern of unmodified and / or modified sugar moieties, nucleic acid bases, and / or nucleoside bonds in an oligonucleotide.

[0050] 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 the two sugar atoms necessary to form a second ring.

[0051] As used herein, “nucleic acid base” means an unmodified nucleic acid base or a modified nucleic acid base. As used herein, “unmodified nucleic acid base” means an unmodified adenine (A), an unmodified thymine (T), an unmodified cytosine (C), an unmodified uracil (U), or an unmodified guanine (G). As used herein, “modified nucleic acid base” means an atomic group other than unmodified A, T, C, U, or G that can pair with at least one unmodified nucleic acid base. 5-Methylcytosine and hypoxanthine are modified nucleic acid bases.

[0052] As used herein, the “nucleic acid sequence” in a reference sequence number refers only to the nucleic acid sequence provided by such a sequence number, and therefore, unless otherwise indicated, includes compounds in which each sugar moiety and each nucleoside bond are independently modified or unmodified, with or without the modifications indicated by the reference sequence number.

[0053] As used herein, “nucleic acid sequence” means the sequence of consecutive nucleic acid bases in a nucleic acid or oligonucleotide, independent of any sugar or internucleoside bond modifications.

[0054] As used herein, “nucleoside overhang” or “overhang” refers to an unpaired nucleoside at one or both ends of an oligomeric double helix formed by the hybridization of two oligonucleotide sequences.

[0055] As used herein, “nucleoside” means a compound or fragment of a compound comprising a nucleic acid base and a sugar moiety. The nucleic acid base and sugar moiety of each nucleoside are independently either unmodified or modified. Notwithstanding the foregoing, modified nucleosides, as described herein, include debasic nucleosides.

[0056] As used herein, “oligomer compound” means an oligonucleotide and, optionally, one or more additional features (e.g., a conjugate group or a terminal group). “Single-stranded oligomer compound” is an unpaired oligomer compound. “Double-stranded oligomer compound” is a paired oligomer compound that may be formed by a single oligonucleotide of an oligomer compound forming a hairpin structure, resulting in at least one region of a double-stranded oligonucleotide sequence, or by two oligonucleotides, each of separate oligomer compounds, where one or both optionally include additional features, and the oligonucleotide sequence or a portion thereof pairs to form a double-stranded oligomer double helix. The term “oligomer double helix” means a double helix formed by two oligomer compounds, where at least a portion is complementary to one another and hybridizes with one another. Each oligomer compound in an oligomer double helix may be referred to as a “double-stranded oligomer compound.”

[0057] As used herein, “oligonucleotide” means a chain of linked nucleosides connected via nucleoside bonds, where each nucleoside and / or each nucleoside bond may independently be modified or unmodified. Unless otherwise indicated, an oligonucleotide consists of 12 to 50 linked nucleosides. As used herein, “modified oligonucleotide” means an oligonucleotide containing one or more modified nucleosides and / or having one or more modified nucleoside bonds. As used herein, “unmodified oligonucleotide” means an oligonucleotide that does not contain any nucleoside modifications or nucleoside bond modifications. An oligonucleotide may or may not be paired with a second oligonucleotide complementary to the oligonucleotide. As used herein, “single-stranded” means a nucleic acid (including, but not limited to, oligonucleotides) that is unpaired and not part of a double helix. Single-stranded nucleic acids (e.g., oligonucleotides) can hybridize with complementary nucleic acids to form double helixes, at which point they are no longer single-stranded. As used herein, “double helix” means a structure formed by two distinct nucleic acid molecules or parts thereof (e.g., two distinct oligonucleotides) that are at least part complementary and hybridize with each other but are not covalently bonded to each other. As used herein, “double-stranded” means a region of hybridized oligonucleotides. A double-stranded oligonucleotide means either two distinct oligonucleotides (double helix) hybridizing with each other, or a single molecule (e.g., oligonucleotide) folded on itself (e.g., a hairpin structure). In certain embodiments, such a double helix results from the hybridization of oligonucleotides (or parts thereof) to a target region of a transcript. In certain embodiments, a double helix results from the hybridization of two oligonucleotides (or parts thereof) with each other.In certain embodiments, the hybridized region is part (or all) of two separate molecules (e.g., without a covalent bond connecting the two complementary chains). In certain embodiments, the hybridized region is part of the same molecule that hybridized (e.g., a hairpin structure).

[0058] As used herein, “pharmaceutical composition” means a mixture of substances suitable for administration to a subject. For example, a pharmaceutical composition may include the compounds of the present invention (e.g., oligomeric compounds, modified oligonucleotides, oligomeric double-chain compounds, or antisense compounds) and a sterile aqueous solution. In certain embodiments, the pharmaceutical composition exhibits activity in certain cell lines. As used herein, “pharmaceutically acceptable carrier or diluent” means a component in a pharmaceutical composition suitable for use when administered to a subject. Typically, a “carrier” or “diluent” lacks pharmacological activity but is necessary or desirable when preparing a pharmaceutical composition. For example, a diluent in a composition to be injected may be a liquid, such as PBS or saline solution. Certain carriers or diluents enable the pharmaceutical composition to be formulated, for example, as tablets, pills, sugar-coated tablets, capsules, liquids, gels, syrups, slurries, suspensions, and lozenges for oral administration by a subject. In certain embodiments, a pharmaceutically acceptable carrier or diluent is sterile water, sterile saline, sterile buffer, or sterile artificial cerebrospinal fluid.

[0059] As used herein, “reduced fluorine content” with respect to a sequence of linked nucleosides, e.g., oligonucleotides (including antisense oligonucleotides and sense oligonucleotides), means a sequence of linked nucleosides in which less than 51% of the nucleosides contain a sugar moiety or sugar surrogate containing a fluorine atom, e.g., a 2'-fluorosugar moiety or a fluorohexitol (3'-FHNA) sugar moiety. In certain embodiments, 42% or less, 40% or less, 35% or less, 30% or less, 25% or less, 20% or less, 16% or less, 15% or less, 14% or less, 13% or less, 12% or less, 10% or less, 9% or less, or 5% or less of the nucleosides in the sequence of linked nucleosides contain a sugar moiety containing a fluorine atom. In certain embodiments, none of the nucleosides in the sequence of linked nucleosides contain a sugar moiety containing a fluorine atom. In some embodiments, less than 48%, less than 45%, less than 42%, less than 40%, less than 35%, less than 30%, less than 25%, less than 20%, less than 15%, less than 14%, less than 13%, less than 12%, less than 10%, or less than 5% of the nucleosides in a contiguously linked sequence of nucleosides contain a sugar moiety with a fluorine atom. When "reduced fluorine content" refers to the total fluorine content of a double-stranded or bifurcated nucleic acid, it refers to a double-stranded or bifurcated nucleic acid in which less than 50% of the total nucleosides of the nucleic acid (i.e., all nucleosides in both strands) contain a sugar moiety with a fluorine atom. In certain embodiments, less than 45%, less than 42%, less than 40%, less than 35%, less than 30%, less than 27%, less than 26%, less than 25%, less than 22%, less than 15%, less than 10%, or less than 5% of the total nucleosides in a double-stranded or bifurcated nucleic acid contain a sugar moiety with a fluorine atom. In certain embodiments, none of the nucleosides in the double-stranded or bilayer nucleic acid contain a sugar moiety with a fluorine atom. In some embodiments, less than 42%, less than 40%, less than 35%, less than 30%, less than 27%, less than 26%, less than 22%, less than 20%, less than 15%, less than 10%, or less than 5% of the total nucleosides in the double-stranded or bilayer nucleic acid contain a sugar moiety with a fluorine atom.

[0060] As used herein, “RNAi agent” means an antisense compound that acts, at least in part, via RISC or Ago2 to modulate a target nucleic acid and / or the protein encoded by the target nucleic acid. RNAi agents include, but are not limited to, double-stranded siRNA, single-stranded RNAi (ssRNAi), and microRNA (including microRNA mimes). RNAi agents may include conjugate groups and / or terminal groups. In certain embodiments, RNAi agents modulate the amount and / or activity of the target nucleic acid. The term RNAi agent excludes antisense compounds that act via RNase H.

[0061] As used herein, “stabilized phosphate group” means a 5' phosphate analog that is metabolically more stable than the 5' phosphate naturally present on DNA or RNA.

[0062] As used herein, “standard cell assay” means the assay described in the examples and any reasonable variations thereof.

[0063] As used herein, “stereorandom” or “stereorandom chiral center” in the context of a group of molecules of the same molecular formula means a chiral center that is not controlled during synthesis or enriched after synthesis with respect to a particular absolute stereochemical configuration. It is understood that a stereorandom chiral center may not be racemic because, for example, due to steric and electronic interactions between the reagent and the reactant molecule, one absolute configuration may prevail after synthesis. In certain embodiments, the stereorandom chiral center is located on the phosphorus atom of a stereorandom phosphorothioate or mesylphosphoamide nucleoside bond.

[0064] As used herein, “subject” means human or non-human animal. In certain embodiments, the subject is human.

[0065] As used herein, “sugar moiety” means either an unmodified sugar moiety or a modified sugar moiety. As used herein, “unmodified sugar moiety” means a 2'-OH(H)β-D-ribosyl sugar moiety (“unmodified RNA sugar moiety”), such as that found in RNA. An unmodified sugar moiety has one hydrogen at each of the 1', 3', and 4' positions, one oxygen at the 3' position, one hydrogen and OH at the 2' position, and two hydrogens at the 5' position. A modified sugar moiety differs from unmodified RNA by having a different substituent (e.g., 2'-F, 2'-MOE, cEt, etc.), having a 2'-deoxy sugar moiety, and / or having a different stereochemistry (e.g., a 2'-α-L-deoxyribosyl sugar moiety). In certain embodiments, the modified sugar moiety is a modified ribosyl sugar moiety. In certain embodiments, the modified sugar moiety differs from unmodified RNA by having both a different chemistry (e.g., a different substituent, a 2'-deoxy sugar moiety) and a different stereochemistry.

[0066] As used herein, “sugar surrogate” means a portion of an oligonucleotide that can link a nucleic acid base to another group, such as an internucleoside bond, a conjugate group, or a terminal group, but is not a furanosyl sugar moiety, a bicyclic sugar moiety, or a non-bicyclic sugar moiety. A sugar surrogate may include one or more substitutions corresponding to other types of modified sugar moieties. Modified nucleosides containing sugar surrogates can be incorporated into one or more positions in an oligonucleotide, and such oligonucleotides can hybridize to complementary oligonucleotide compounds or target nucleic acids. Examples of sugar surrogates include GNA (glycol nucleic acid), FHNA (fluorohexitol nucleic acid), morpholino, and other structures described herein and known in the art for use in oligonucleotides.

[0067] As used herein, “Symptom” means any manifestation, indication, sign, evidence, physical feature, or test result indicating the presence or degree of a disease or disorder. Symptoms include subjective and objective signs of a disease, which may be perceived, experienced, detected, observed, measured, and / or quantified. In certain embodiments, symptoms are evident to the subject or to the medical professional examining or testing the subject. In certain embodiments, symptoms are evident during an invasive diagnostic test, including but not limited to postmortem testing. Symptoms may be feature deficiencies, such as the inability to reach expected developmental milestones.

[0068] As used herein, “target nucleic acid” means the PLN nucleic acid designed to be affected by the antisense compound. As used herein, “target RNA” means the PLN RNA transcript, and unless otherwise specified or relevant, includes premRNA and / or mRNA (e.g., intron sequences in premRNA). As used herein, “target region” means the portion of the PLN target nucleic acid designed to be hybridized by the compound of the present invention (e.g., modified oligonucleotide, antisense compound).

[0069] As used herein, “therapeutic index” refers to the quantitative relationship (e.g., ratio) between the concentration (or dose) at which a compound becomes toxic or induces an unacceptable adverse effect (or the highest concentration or dose at which a compound is non-toxic or acceptable before becoming toxic or inducing an unacceptable adverse effect) and the concentration (or dose) at which the compound is pharmacologically effective or produces a desired effect. These concentrations or doses can be determined using a variety of parameters, in part depending on the indication for which the compound is used as a therapeutic agent. A higher therapeutic index indicates a more favorable safety profile of the compound. The therapeutic index provides a range of effective concentrations (or doses) of the compound for achieving effective results without unacceptable adverse events. The therapeutic index can be increased by increasing the concentration (or dose) at which the compound becomes toxic or induces an adverse effect, and / or by decreasing the concentration (or dose) at which the compound is effective.

[0070] As used herein, “to treat” means to improve, prevent or delay the onset or progression of a disease, disorder, condition, or injury in a subject by administering a compound or therapeutic agent (e.g., a modified oligonucleotide, oligomeric double-chain, or antisense compound as described herein) to a subject (e.g., a subject having a disease, disorder, or condition, or injury, or being at risk of developing such a disease, disorder, or condition, or injury). In certain embodiments, treating a subject results in an improvement of the symptoms compared to the same symptoms in the absence of treatment. In certain embodiments, treatment reduces the severity or frequency of symptoms, delays the onset of symptoms, slows the progression of symptoms, slows the increase in severity of symptoms, or slows the frequency (or increase in frequency) of symptoms. In some embodiments, treatment reduces, improves, and / or prevents one or more symptoms such that the symptoms of a disorder or disease are reduced or no longer apparent.

[0071] Embodiment Embodiment 1. An oligomeric double chain comprising a first oligomeric compound and a second oligomeric compound, (1) The first oligomer compound comprises a modified oligonucleotide consisting of 8 to 50 linked nucleosides, the nucleic acid base 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 nucleic acid bases of any one nucleic acid base sequence from SEQ ID NOs. 3 to 314, 627 to 782, 939 to 976, 1033 to 1038, 1254 to 1255, or 1258 to 1287, each of the nucleosides of the first modified oligonucleotide independently comprises a modified sugar moiety or sugar surrogate, and at least one modified nucleoside of the first modified oligonucleotide and less than 40% of the nucleoside contain fluorine. (2) The second oligomer compound comprises a second modified oligonucleotide consisting of 8 to 50 consecutively linked nucleosides, which includes a region having a nucleic acid base sequence complementary to the region of the first modified oligonucleotide, wherein the nucleic acid base sequence of the second modified oligonucleotide is at least 8, and at least 8 of any one of the nucleic acid base sequences of SEQ ID NOs. 315 to 626, 783 to 938, 977 to 1016, 1027 to 1032, 1256 to 1257, or 1288 to 1290 An oligomeric double helix comprising 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 nucleic acid bases, wherein each of the nucleosides of the second modified oligonucleotide independently comprises a modified sugar moiety or sugar surrogate, and less than 40% of the nucleosides of the second modified oligonucleotide contain fluorine.

[0072] Embodiment 2. The oligomeric double helix according to Embodiment 1, wherein the first modified oligonucleotide is at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%, or 100% complementary to the isolength portion of the PLN nucleic acid, and the PLN nucleic acid has the nucleic acid base sequence of SEQ ID NO: 1 or SEQ ID NO: 2.

[0073] Embodiment 3. The oligomer double chain according to Embodiment 1 or 2, wherein each of the nucleosides of the first modified oligonucleotide independently comprises (i) a modified sugar moiety or sugar surrogate, or (ii) independently a sugar moiety selected from a 2'-F sugar moiety, a 2'-MOE sugar moiety, a 2'-OMe sugar moiety, a 2'-deoxy sugar moiety, and a 3'-fluoro-hexitol sugar moiety, or (iii) a modified sugar moiety, and each of the nucleosides of the second modified oligonucleotide independently comprises (i) a modified sugar moiety or sugar surrogate, or (ii) independently a sugar moiety selected from a 2'-F sugar moiety, a 2'-MOE sugar moiety, a 2'-OMe sugar moiety, a 2'-deoxy sugar moiety, and a 3'-fluoro-hexitol sugar moiety, or (iii) a modified sugar moiety.

[0074] Embodiment 4. An oligomeric double chain according to any one of Embodiments 1 to 3, wherein less than 35%, less than 30%, less than 25%, less than 20%, less than 15%, less than 14%, less than 13%, less than 12%, less than 10%, less than 5%, or less than 1% of the nucleoside in the first modified oligonucleotide contains fluorine.

[0075] Embodiment 5. An oligomer double chain according to any one of Embodiments 1 to 4, wherein one or fewer nucleosides, two or fewer nucleosides, three or fewer nucleosides, or four or fewer nucleosides in the first modified oligonucleotide contain a fluorine-containing modified sugar moiety or a fluorine-containing sugar surrogate.

[0076] Embodiment 6. An oligomeric double chain according to any one of Embodiments 1 to 5, wherein the space between the 3rd and 21st nucleosides from the 5' end of the modified oligonucleotide, and one or fewer nucleosides, two or fewer nucleosides, or three or fewer nucleosides in the sequence of the first modified oligonucleotide containing them, comprises a fluorine-containing modified sugar moiety or a fluorine-containing sugar surrogate.

[0077] Embodiment 7.i) one or more nucleosides of the first modified oligonucleotide containing a fluorine-containing modified sugar moiety or ii) a fluorine-containing sugar surrogate, independently i. The second nucleoside from the 5' end, ii. The 14th and 16th nucleosides counting from the 5' end, or iii. Selected from the 2nd, 14th, and 16th nucleosides counting from the 5' end, The oligomeric double chain according to any one of Embodiments 1 to 6, wherein each i) fluorine-containing modified sugar moiety or ii) fluorine-containing sugar surrogate is independently a 2'-fluorosugar moiety or a 3'-fluoro-hexitol sugar moiety.

[0078] Embodiment 8. The oligomeric double chain according to any one of Embodiments 1 to 7, wherein one or less of the fluorine-containing sugar moieties in the first modified oligonucleotide are 3'-fluorohexitol sugar moieties.

[0079] Embodiment 9. The oligomeric double helix according to any one of Embodiments 1 to 8, wherein one or more nucleosides of the first modified oligonucleotide are 2'-deoxynucleosides.

[0080] Embodiment 10. The oligomeric double helix according to Embodiment 9, wherein one or more 2'-deoxynucleosides are one or more nucleosides in the region of the sequence of the first modified oligonucleotide between the 5th to the 16th nucleosides counted from the 5' end of the first modified oligonucleotide and including those nucleosides.

[0081] Embodiment 11. The oligomeric double helix according to Embodiment 10, wherein the one or more 2'-deoxynucleosides are located in a region of the sequence of the first modified oligonucleotide that is either the 5th and / or 6th and / or 7th nucleosides counted from the 5' end of the first modified oligonucleotide, or the 14th and / or 15th and / or 16th nucleosides.

[0082] Embodiment 12. The oligomeric double chain according to any one of Embodiments 9 to 11, wherein less than 20% or less than 15% of the nucleoside of the first modified oligonucleotide contains fluorine.

[0083] Embodiment 13. The oligomeric double helix according to any one of Embodiments 9 to 12, wherein the one or more 2'-deoxynucleosides are the 5th and / or 6th and / or 7th nucleosides counted from the 5' end of the first modified oligonucleotide.

[0084] Embodiment 14. The oligomeric double helix according to any one of Embodiments 9 to 13, wherein one or two nucleosides of the first modified oligonucleotide are 2'-deoxynucleosides.

[0085] Embodiment 15. The oligomeric double helix according to Embodiment 14, wherein the two 2'-deoxynucleosides are the 5th and 7th nucleosides, or the 14th and 16th nucleosides, counting from the 5' end of the first modified oligonucleotide.

[0086] Embodiment 16. The oligomeric double helix according to Embodiment 14, wherein the sole 2'-deoxynucleoside is the 6th or 16th nucleoside from the 5' end of the first modified oligonucleotide.

[0087] Embodiment 17. An oligomeric double helix according to any one of Embodiments 1 to 8, wherein none of the nucleosides of the first modified oligonucleotide are 2'-deoxynucleosides.

[0088] Embodiment 18. An oligomeric double helix according to any one of Embodiments 1 to 17, wherein the first oligomeric compound comprises a two-nucleoside overhang including the 3' terminal nucleoside of the first modified oligonucleotide and the nucleoside immediately to the 5' side of the 3' terminal nucleoside.

[0089] Embodiment 19. The oligomeric double helix according to Embodiment 18, wherein the overhang nucleoside is two modified adenosine (AA) nucleosides, two modified uridine (UU) nucleosides, two modified inosine (II) nucleosides, or two modified nucleosides (AI or IA) one of which is inosine and the other is adenosine.

[0090] Embodiment 20. An oligomeric double chain according to any one of Embodiments 1 to 19, wherein one or more of the nucleosides of the first modified oligonucleotide independently comprises a sugar surrogate or a bicyclic sugar moiety.

[0091] Embodiment 21. The oligomeric double chain according to Embodiment 20, wherein the bicyclic sugar portion includes a 2'-4' crosslink selected from -O-CH2- and -O-CH(CH3)-.

[0092] Embodiment 22. The oligomeric double chain according to any one of Embodiments 1 to 21, wherein one or more of the nucleosides of the first modified oligonucleotide contain a 2'-OMe sugar moiety.

[0093] Embodiment 23. The oligomeric double chain according to Embodiment 22, wherein at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, or at least 60% of the nucleoside of the first modified oligonucleotide comprises a 2'-OMe sugar moiety.

[0094] Embodiment 24. An oligomeric double chain according to Embodiment 22 or 23, wherein one or more nucleosides containing a 2'-OMe sugar moiety are located between the 3rd and 21st nucleosides counting from the 5' end of the first modified oligonucleotide and in the sequence region of the first modified oligonucleotide containing them, and / or the first two nucleosides counting from the 5' end of the first modified oligonucleotide and / or the first two nucleosides counting from the 3' end of the first modified oligonucleotide are independently modified nucleosides containing a sugar surrogate or a modified sugar moiety other than the 2'-OMe sugar moiety.

[0095] Embodiment 25. The oligomeric double chain according to Embodiment 22 or 23, wherein the 3'-terminal nucleoside of the first modified oligonucleotide contains a 2'-OMe sugar moiety, and / or the nucleoside immediately 5' to the 3'-terminal nucleoside of the first modified oligonucleotide contains a 2'-OMe sugar moiety.

[0096] Embodiment 26. The oligomeric double chain according to any one of Embodiments 1 to 25, wherein one or more of the nucleosides of the first modified oligonucleotide contain a 2'-MOE sugar moiety.

[0097] Embodiment 27. The oligomeric double chain according to Embodiment 26, wherein the 5'-terminal nucleoside and / or 3'-terminal nucleoside of the first modified oligonucleotide contains a 2'-MOE sugar moiety.

[0098] Embodiment 28. An oligomeric double chain according to any one of Embodiments 1 to 27, wherein the nucleoside immediately 5' of the 3'-terminal nucleoside of the first modified oligonucleotide contains a 2'-MOE sugar moiety.

[0099] Embodiment 29. An oligomeric double chain according to any one of Embodiments 1 to 24 and 26 to 28, wherein the 5'-terminal nucleoside and the 3'-terminal nucleoside of the first modified oligonucleotide contain a 2'-MOE sugar moiety, and the nucleoside immediately 5' of the 3'-terminal nucleoside of the first modified oligonucleotide contains a 2'-MOE sugar moiety.

[0100] Embodiment 30. The oligomeric double chain according to any one of Embodiments 1 to 29, wherein the first oligomeric compound comprises a stabilized phosphate group bonded to the 5' terminal nucleoside of the first modified oligonucleotide.

[0101] Embodiment 31. The oligomeric double chain according to Embodiment 30, wherein the stabilized phosphate group comprises cyclopropylphosphonate or vinylphosphonate.

[0102] Embodiment 32. The oligomeric double chain according to any one of Embodiments 1 to 31, wherein the double chain comprises a conjugate group including a conjugate moiety and a conjugate linker.

[0103] Embodiment 33. The oligomeric double chain according to Embodiment 32, wherein the conjugate group includes a cell-targeting moiety.

[0104] Embodiment 34. The oligomeric double chain according to Embodiment 32, wherein the conjugate portion comprises an active drug substance, an aliphatic chain, a lipid, a peptide, a protein, a hydrocarbon, a polyamine, a polyamide, a polyether, a thioether, an aptamer, an antibody, an antibody fragment, a vitamin, a fatty acid, a carbohydrate, an intercalator, or a reporter molecule.

[0105] Embodiment 35. The oligomer double chain according to Embodiment 32, wherein the conjugate group comprises C22 alkyl, C20 alkyl, C17 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, or C5 alkyl, and the alkyl chain optionally has one or more unsaturated bonds.

[0106] Embodiment 36. The oligomeric double chain according to Embodiment 32, wherein the conjugate group comprises a 6-palmitamide hexyl moiety or a 2-(hydroxymethyl)-6-palmitamide hexyl moiety.

[0107] Embodiment 37. The oligomeric double chain according to Embodiment 32, wherein the conjugate group includes a conjugate portion that binds to a type 1 transferrin receptor (TfR1).

[0108] Embodiment 38. The oligomeric double chain according to Embodiment 37, wherein the conjugate portion is selected from antibodies or fragments thereof, proteins or peptides, and aptamers that can bind to TfR1.

[0109] Embodiment 39. The oligomeric double chain according to Embodiment 38, wherein the conjugate portion is a cyclic protein or a cyclic peptide.

[0110] Embodiment 40. The oligomeric double chain according to Embodiment 37, wherein the conjugate group comprises a bicyclic ligand and a conjugate linker.

[0111] Embodiment 41. The oligomeric double chain according to Embodiment 40, wherein the bicyclic ligand comprises a peptide and molecular skeleton consisting of 13 to 22 linked amino acids or amino acid mimes, and each of the first, second, and third amino acids of the peptide contains a reactive group, each of which separately forms a bond with the molecular skeleton, thereby forming two peptide loops bonded to the molecular skeleton.

[0112] Embodiment 42. The oligomeric double chain according to Embodiment 41, wherein the peptide has an amino acid sequence selected from any one of SEQ ID NOs. 1062 to 1253, and each cysteine ​​forms a covalent bond with the molecular skeleton 1,1',1''-(1,3,5-triazinane-1,3,5-triyl)tris(2-bromoetanone) (TATB) or the molecular skeleton 1,1',1''-(1,3,5-triazinane-1,3,5-triyl)triplop-2-en-1-one (TATA).

[0113] Embodiment 43. The bicyclic ligand or conjugate group has the following structure:

[0114] [ka] The oligomeric double helix according to Embodiment 41, having a salt thereof, wherein Q is N3 (BCY17901, SEQ ID NO: 1045), NH2 (BCY21757, SEQ ID NO: 1202), SH (BCY21758, SEQ ID NO: 1203), a conjugate linker, or a conjugate linker covalently bonded to an oligonucleotide.

[0115] Embodiment 44. The oligomeric double helix according to any one of Embodiments 32 to 43, wherein the conjugate group is conjugated to the second modified oligonucleotide.

[0116] Embodiment 45. The oligomeric double helix according to any one of Embodiments 32 to 43, wherein the conjugate group is bonded to the 5' or 3' end of the second modified oligonucleotide.

[0117] Embodiment 46. The oligomeric double helix according to any one of Embodiments 32 to 43, wherein the conjugate group is bonded to the 5'-terminal nucleoside or the 3'-terminal nucleoside of the second modified oligonucleotide.

[0118] Embodiment 47. The oligomeric double helix according to any one of Embodiments 32 to 43, wherein the conjugate group is bonded to the 5' terminal nucleoside of the second modified oligonucleotide.

[0119] Embodiment 48. The oligomeric double helix according to any one of Embodiments 32 to 43, wherein the conjugate group is bonded to the 3' terminal nucleoside of the second modified oligonucleotide.

[0120] Embodiment 49. An oligomeric double chain according to any one of Embodiments 32 to 48, wherein the conjugate linker of the conjugate group consists of a single bond.

[0121] Embodiment 50. An oligomeric double chain according to any one of Embodiments 32 to 48, wherein the conjugate linker of the conjugate group is cleavable.

[0122] Embodiment 51. The oligomeric double helix according to any one of Embodiments 32 to 50, wherein the conjugate linker comprises 1 to 3 linker-nucleosides.

[0123] Embodiment 52. The oligomeric double chain according to any one of Embodiments 32 to 48, wherein the conjugate linker comprises a (bicyclo[6.1.0]nonine)-formyl (BCN) moiety.

[0124] Embodiment 53. The oligomeric double chain according to any one of Embodiments 32 to 48, wherein the conjugate linker comprises a 6-(BCN-carbamate)-2-(hydroxymethyl)hexylphosphoryl moiety or a 6-(BCN-carbamate)hexylphosphoryl moiety.

[0125] Embodiment 54. The conjugate group has the following structure:

[0126] [ka] An oligomeric double chain according to Embodiment 41, having the features described above.

[0127] Embodiment 55. The conjugate group has the following structure:

[0128] [ka] An oligomeric double chain according to Embodiment 41, having the features described above.

[0129] Embodiment 56. The nucleic acid base sequence of the first modified oligonucleotide is 295-316, 296-317, 297-318, 298-320, 299-320, 300-321, 301-322, 302-324, 303-324, 304-325, 304-326, 305-327, 306-325, 306-328, 307-328, 308-329, 309-330, 310-331, 311-332, 312-333, 313-334, 314-335, 315-336, 316-337, 317-339, 318-339, 3 19-340, 320-341, 321-342, 322-344, 323-345, 324-345, 324-346, 325-345, 325-347, 326-347, 327-348, 328-349, 329-350, 330-351, 331-352, 332-35 3, 333-354, 334-355, 505-526, 506-528, 507-529, 508-530, 509-531, 510-531, 511-532, 512-533, 513-535, 514-535, 514-536, 515-536, 516-535, 516 ~537, 517~538, 518~539, 519~541, 520~541, 521~542, 522~544, 523~544, 524~546, 535~556, 536~557, 537~558, 538~559, 539~560, 540~561, 541~563, 542-563, 543-564, 544-565, 545-566, 546-567, 547-568, 548-570, 549-571, 550-572, 551-572, 552-574, 553-574, 554-575, 555-577, 556-578, 557-5 79, 558~580, 559~580, 560~581, 561~582, 562~583, 563~584, 595~616, 596~618, 597~618, 598~620, 599~621, 600~622, 601~623, 602~623, 603~624, 60 4-625, 605-627, 606-628, 607-628, 608-629, 609-630, 610-631, 611-632, 612-633, 613-635, 665-687, 666-687, 667-689, 668-689, 669-690, 670-691,671-692, 672-694, 673-694, 674-695, 675-696, 676-697, 677-698, 678-700, 679-701, 680-702, 681-703, 682-703, 683-704, 684-705, 685-706, 686 ~708, 687~708, 688~709, 689~710, 690~711, 691~712, 692~714, 693~715, 1675~1696, 1676~1698, 1677~1698, 1678~1699, 1679~1700, 1680~1702, 16 An oligomeric double helix according to any one of Embodiments 1 to 55, wherein the equilength portions within the nucleic acid bases selected from any one of 81-1702, 1682-1703, 1683-1705, 1684-1705, 1685-1706, 1686-1707, 1687-1709, 1688-1709, 1689-1710, 1690-1712, 1691-1713, 1692-1714, or 1693-1714 are at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%, or 100%, complementary to the equilength portions within the nucleic acid bases.

[0130] Embodiment 57. The oligomeric double helix according to any one of Embodiments 1 to 55, wherein the nucleic acid base sequence of the first modified oligonucleotide is at least 80%, at least 85%, at least 90%, at least 95%, or 100% complementary to the isolength portion in the sequence of nucleic acid bases 304-326, 306-325, 324-346, 325-345, 514-536, or 516-535 of SEQ ID NO: 1.

[0131] Embodiment 58. The oligomeric double helix according to any one of Embodiments 1 to 55, wherein the nucleic acid base sequence of the first modified oligonucleotide includes 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 nucleic acid bases from any one of the nucleic acid base sequences of SEQ ID NOs. 3 to 314, 627 to 782, 939 to 976, 1033 to 1038, 1254 to 1255, or 1258 to 1287.

[0132] Embodiment 59. The oligomeric double helix according to any one of Embodiments 1 to 55, wherein the nucleic acid base sequence of the first modified oligonucleotide includes one of the nucleic acid base sequences among SEQ ID NOs: 3-314, 627-782, 939-976, 1033-1038, 1254-1255, or 1258-1287.

[0133] Embodiment 60. The oligomeric double helix according to any one of Embodiments 1 to 55, wherein the nucleic acid base sequence of the first modified oligonucleotide consists of one of the nucleic acid base sequences from SEQ ID NOs: 3-314, 627-782, 939-976, 1033-1038, 1254-1255, or 1258-1287.

[0134] Embodiment 61. The oligomeric double helix according to any one of Embodiments 1 to 55, wherein the nucleic acid base sequence of the first modified oligonucleotide contains at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 consecutive nucleic acid bases from any one of the nucleic acid base sequences of SEQ ID NOs: 29, 171, 176, 967, 968, 971, 972, 974, 975, 1254, 1255, 1033-1038, 1254-1255, or 1258-1287.

[0135] Embodiment 62. The oligomeric double helix according to any one of Embodiments 1 to 55, wherein the nucleic acid base sequence of the first modified oligonucleotide includes one of the nucleic acid base sequences of SEQ ID NOs: 29, 171, 176, 967, 968, 971, 972, 974, 975, 1254, 1255, or 1033-1038, 1254-1255, or 1258-1287.

[0136] Embodiment 63. The oligomer double helix according to any one of Embodiments 1 to 55, wherein the nucleic acid base sequence of the first modified oligonucleotide consists of one of the nucleic acid base sequences of SEQ ID NOs: 29, 171, 176, 967, 968, 971, 972, 974, 975, 1254, 1255, 1033-1038, 1254-1255, or 1258-1287.

[0137] Embodiment 64. An oligomeric double helix according to any one of Embodiments 1 to 63, wherein the first modified oligonucleotide and the second modified oligonucleotide each independently consist of 18-30, 18-25, 18-24, 18-23, 18-22, 18-21, 18-19, 19-30, 19-25, 19-24, 19-23, 19-21, 19-20, 20-30, 20-25, 20-24, 20-23, 20-22, 20-21, 21 and 19, 21 and 20, 23 and 21, 23 and 22, or 22 and 21 linked nucleosides.

[0138] Embodiment 65. The oligomeric double helix according to any one of Embodiments 1 to 64, wherein the first modified oligonucleotide consists of 23, 22, or 21 nucleosides.

[0139] Embodiment 66. The oligomeric double helix according to any one of Embodiments 1 to 65, wherein the second modified oligonucleotide consists of 21 nucleosides.

[0140] Embodiment 67. An oligomeric double helix according to any one of Embodiments 1 to 65, wherein the first modified oligonucleotide consists of 23 nucleosides and the second modified oligonucleotide consists of 21 nucleosides.

[0141] Embodiment 68. An oligomeric double helix according to any one of Embodiments 1 to 65, wherein the first modified oligonucleotide consists of 22 nucleosides and the second modified oligonucleotide consists of 21 nucleosides.

[0142] Embodiment 69. An oligomeric double helix according to any one of Embodiments 1 to 65, wherein the first modified oligonucleotide consists of 21 nucleosides, and the second modified oligonucleotide consists of 21 nucleosides.

[0143] Embodiment 70. The first modified state is efyyydyyyyyyyyyyyyyyyyee,efyyydyyyyyyyyyyyyyyyyy,e[FHE]yyydyyyyyyyyyyyyyyyee,e[FHE]yyydyyyyyyyyyyyyyyyyyy,efyydyyyyyyyyyyyyyyyee,efyydyyyyyyyyyyyyyyyyy,e[FHE]yydydyyyyyyyyyyyyyyyee,e[FHE]yydyyyyyyyyyyyyyyyyyyy,efyyyyyy yyyyyfyfyyyyyyy, efyyyfyyyyyyyfyfyyyyyey, efyyyyyyyyyyyyfyfyyyyyee, efyyyfyyyyyyyfyfyyyyyyy, efyyyyyyyyyyyfyyyyyyyyee, efyyyyyyyyyy yfyyyyyyyyy, e[FHNA]yyyfyyyyyyyfyfyyyyyyy, e[FHNA]yyyfyyyyyyyfyfyyyyyyy, efyyydyyyyyyydydyyyyyy, efyyydyyyyyyydydyyyyyyy, efyydy dyyyyyyfyfyyyyyyy, efyyyfyyyyyyyfyyyyyyyee, efyyyfyyyyyyyfyyyyyy yyy, efyyyyyyyyyyyfyfyyyyyee, efyyyyyyyyyyyfyfyyyyyyy, e[FHNA]yyd ydyyyyfyfyfyyyyyyy, efyyyfyyyyyyyfydyyyyyyy, efyyyfyyyyyyyfydyyyyyee, efyydydyyyyyyfyfyyyyye, efyydydyyyyyyfyfyyyyyy, efyyydyyyyy It has a sugar motif (from 5' to 3') selected from among yyyyyyyyye, efyyydyyyyyyyyyyyyyyy, efyyyyyyyyyyyyyyyyyyy, efyydydyyyyyyyyyyyyyy, efyyydyyyyyyyyyyyyyyy, efyyyyyyyyyyyyyyyyyyyy, efyyyyyyyyyyyyyyyyyyyy, efyyyyyyyyyyyyyyyyyyyyy, and efyyyyyyyyyyyyyyyyyyyy, where each "ut" represents a 2'-deoxyglycol, and each "y" represents,An oligomeric double chain according to any one of Embodiments 1 to 69, wherein each "e" represents the 2'-OMe sugar moiety, each "f" represents the 2'-fluoro sugar moiety, and each "[FHNA]" represents the 3'-fluoro-hexitol sugar moiety.

[0144] Embodiment 71. The first modified state is efyydydyyyyyyyyyyyyyyyee,efyyydyyyyyyyyyyyyyyyee,efyydydyyyyyyyyyyyyyyyy,e[FHE]yydydyyyyyyyyyyyyyyyyy,efyyyyyyyyyyyyyyyyyyyyyy,efyyydyyyyyyyyyyyyyyyyy,efyydydyyyyyyyyyyyyyyyye,efyydydyyyyyyyyyyyyyy An oligomer double chain according to any one of the inventions 1 to 69, having a sugar motif (from 5' to 3') selected from among yyy, efyyydyyyyyyyyyyyyyye, efyyydyyyyyyyyyyyyyyyyy, efyyyyyyyyyyyyyyyyyyyy, efyyydyyyyyyyyyyyyyyyyyy, efyyydyyyyyyyyyyyyyyyyyyyy, and efy

[0145] Embodiment 72. The oligomeric double helix according to any one of Embodiments 1 to 71, wherein the first modified oligonucleotide comprises at least one modified internucleoside bond.

[0146] Embodiment 73. The oligomeric double helix according to Embodiment 72, wherein the at least one modified internucleoside bond is a phosphorothioate or mesylphosphoamidate internucleoside bond.

[0147] Embodiment 74. The oligomeric double helix according to Embodiment 72, wherein less than 50%, less than 40%, less than 30%, less than 20%, or less than 10% of the nucleoside bonds of the first modified oligonucleotide are modified nucleoside bonds.

[0148] Embodiment 75. An oligomeric double helix according to any one of Embodiments 1 to 74, wherein each nucleoside bond of the first modified oligonucleotide is independently selected from phosphodiester nucleoside bonds and phosphorothioate nucleoside bonds.

[0149] Embodiment 76. The oligomeric double helix according to Embodiment 75, wherein the nucleoside bonds between the first and second nucleosides, and between the second and third nucleosides, counting from the 5' end of the first modified oligonucleotide, are modified nucleoside bonds.

[0150] Embodiment 77. The oligomeric double helix according to Embodiment 75, wherein the nucleoside bonds between the first and second nucleosides, and between the second and third nucleosides, counting from the 3' end of the first modified oligonucleotide, are modified nucleoside bonds.

[0151] Embodiment 78. The oligomeric double chain according to Embodiment 75, wherein the nucleoside bonds between the first and second nucleosides counting from the 5' end of the first modified oligonucleotide, and between the second and third nucleosides, and the nucleoside bonds between the first and second nucleosides counting from the 3' end of the first modified oligonucleotide, and between the second and third nucleosides, are modified nucleoside bonds.

[0152] Embodiment 79. The oligomeric double chain according to any one of Embodiments 72 to 78, wherein the modified nucleoside bond is a phosphorothioate nucleoside bond.

[0153] Embodiment 80. The oligomeric double helix according to Embodiment 78 or 79, wherein all other nucleoside bonds in the first modified oligonucleotide are phosphodiester nucleoside bonds.

[0154] Embodiment 81. The first modified endpoint is the nucleoside-to- An oligomer double chain according to Embodiment 80, having a sugar motif (from 5' to 3') selected from yy, wherein each "d" represents a 2'-deoxy sugar moiety, each "y" represents a 2'-OMe sugar moiety, each "e" represents a 2'-MOE sugar moiety, each "f" represents a 2'-fluoro sugar moiety, each "[FHNA]" represents a 3'-fluoro-hexitol sugar moiety, each "o" represents a phosphodiester nucleoside bond, and each "s" represents a phosphorothioate nucleoside bond.

[0155] Embodiment 82.1) The first modified endpoint has a nucleoside-binding motif of ssoooooooooooooooooos, and a sugar motif (from 5' to 3') selected from efyydydyyyyyyfyfyyyyye, efyydydyyyyyyfyfyyyyyy, efyyydyyyyyyyfyfyyyyyye, efyyydyyyyyyyyfyfyyyyyy, efyyyyyyyyyyyyfyfyyyyyy, and efyyyyyyyyyyyyfyfyyyyyy, or 2) the first modified endpoint has ssoooooooooo The oligomer double chain according to Embodiment 72, having an internucleoside linkage motif of oooooooo, and a sugar motif (from 5' to 3') selected from efyydydyyyyyyfyfyyyyy, efyyydyyyyyyyfyfyyyyy, and efyyyyyyyyyyyyfyfyyyyy, wherein each "d" represents a 2'-deoxy sugar moiety, each "y" represents a 2'-OMe sugar moiety, each "e" represents a 2'-MOE sugar moiety, each "f" represents a 2'-fluoro sugar moiety, each "o" represents a phosphodiester internucleoside linkage, and each "s" represents a phosphorothioate internucleoside linkage.

[0156] Embodiment 83. An oligomeric double chain according to any one of Embodiments 1 to 82, wherein less than 30%, less than 25%, less than 20%, less than 15%, less than 14%, less than 13%, less than 12%, less than 10%, or less than 5% of the nucleoside in the second modified oligonucleotide contains fluorine.

[0157] Embodiment 84. An oligomer double chain according to any one of Embodiments 1 to 82, wherein four or fewer nucleosides, three or fewer nucleosides, two or fewer nucleosides, or one or fewer nucleosides in the second modified oligonucleotide contain a fluorine-containing modified sugar moiety or a fluorine-containing sugar surrogate, and optionally, neither the nucleosides before the seventh nucleoside or after the eleventh nucleoside, counting from the 5' end of the second modified oligonucleotide, contain a fluorine-containing modified sugar moiety or a fluorine-containing sugar surrogate.

[0158] Embodiment 85. An oligomeric double chain according to any one of Embodiments 1 to 84, wherein one or more of the 7th, 9th, and 11th nucleosides from the 5' end of the second modified oligonucleotide contains a fluorine-containing modified sugar moiety.

[0159] Embodiment 86. The oligomeric double chain according to Embodiment 85, wherein two or more of the 7th, 9th, and 11th nucleosides from the 5' end of the second modified oligonucleotide contain a fluorine-containing modified sugar moiety.

[0160] Embodiment 87. The oligomeric double chain according to Embodiment 85, wherein the 7th, 9th, and 11th nucleosides from the 5' end of the second modified oligonucleotide contain a fluorine-containing modified sugar moiety.

[0161] Embodiment 88. An oligomeric double chain according to any one of Embodiments 1 to 84, wherein one or both of the 10th and 11th nucleosides from the 5' end of the second modified oligonucleotide contain a fluorine-containing modified sugar moiety.

[0162] Embodiment 89. The oligomer double chain according to any one of Embodiments 84 to 88, wherein the fluorine-containing modified sugar portion is a 2'-fluorosugar portion.

[0163] Embodiment 90. The oligomeric double chain according to any one of Embodiments 1 to 89, wherein less than 30%, less than 25%, less than 20%, less than 15%, less than 14%, less than 13%, less than 12%, less than 10%, less than 5%, or less than 1% of the total nucleosides in the oligomeric double chain contains fluorine.

[0164] Embodiment 91. An oligomeric double chain according to any one of Embodiments 1 to 90, wherein one or more of the nucleosides of the second modified oligonucleotide independently comprises a sugar surrogate or a bicyclic sugar moiety.

[0165] Embodiment 92. The oligomeric double chain according to Embodiment 91, wherein the bicyclic sugar portion includes a 2'-4' crosslink selected from -O-CH2- and -O-CH(CH3)-.

[0166] Embodiment 93. The oligomeric double chain according to any one of Embodiments 1 to 92, wherein one or more of the nucleosides of the second modified oligonucleotide contain a 2'-OMe sugar moiety.

[0167] Embodiment 94. The oligomeric double chain according to Embodiment 93, wherein at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 65%, at least 70%, at least 80%, at least 85%, or at least 90% of the nucleoside of the second modified oligonucleotide contains a 2'-OMe sugar moiety.

[0168] Embodiment 95. An oligomeric double chain according to Embodiment 93 or 94, wherein one or more nucleosides containing a 2'-OMe sugar moiety are located between the 3rd and 19th nucleosides counting from the 5' end of the second modified oligonucleotide, and in the sequence region of the second modified oligonucleotide containing them.

[0169] Embodiment 96. The oligomeric double chain according to Embodiment 93 or 94, wherein the 3'-terminal nucleoside of the second modified oligonucleotide contains a 2'-OMe sugar moiety, and / or the nucleoside immediately 5' to the 3'-terminal nucleoside of the second modified oligonucleotide contains a 2'-OMe sugar moiety.

[0170] Embodiment 97. An oligomeric double chain according to any one of Embodiments 93, 94, and 96, wherein the 5'-terminal nucleoside of the second modified oligonucleotide contains a 2'-OMe sugar moiety, and / or the nucleoside immediately 3' to the 5'-terminal nucleoside of the second modified oligonucleotide contains a 2'-OMe sugar moiety.

[0171] Embodiment 98. The oligomeric double chain according to Embodiment 93 or 94, wherein the 5'-terminal nucleoside, the nucleoside immediately 3' of the 5'-terminal nucleoside, the 3'-terminal nucleoside, and the nucleoside immediately 5' of the 3'-terminal nucleoside of the second modified oligonucleotide contain a 2'-OMe sugar moiety.

[0172] Embodiment 99. The oligomeric double chain according to any one of Embodiments 1 to 98, wherein one or more of the nucleosides of the second modified oligonucleotide contain a 2'-MOE sugar moiety.

[0173] Embodiment 100. An oligomeric double chain according to any one of Embodiments 1 to 95, wherein the 3'-terminal nucleoside of the second modified oligonucleotide contains a 2'-MOE sugar moiety, and / or the nucleoside immediately 5' to the 3'-terminal nucleoside of the second modified oligonucleotide contains a 2'-MOE sugar moiety.

[0174] Embodiment 101. An oligomeric double chain according to any one of Embodiments 1 to 96, 99, and 100, wherein the 5'-terminal nucleoside of the second modified oligonucleotide contains a 2'-MOE sugar moiety, and / or the nucleoside immediately 3' to the 5'-terminal nucleoside of the second modified oligonucleotide contains a 2'-MOE sugar moiety.

[0175] Embodiment 102. An oligomeric double chain according to any one of Embodiments 1 to 95, wherein the 5'-terminal nucleoside, the nucleoside immediately 3' of the 5'-terminal nucleoside, the 3'-terminal nucleoside, and the nucleoside immediately 5' of the 3'-terminal nucleoside of the second modified oligonucleotide contain a 2'-MOE sugar moiety.

[0176] Embodiment 13. The second identified state is eeyyyyyyyyyyyyyyyyyyy, eeyyyyyyyyyyyyyyyyyyyyy, yyyyyyyyyyyyyyyyyyyyyy, yyyyyyyyyyyyyyyyyyyyy, yyyyyyyyyyyyyyyyyyyyyy, eeyyyyyyyyyyyyyyyyyy, eeyyyyyyyyyyyyyyyyyy, yyyyyyyyyyyyyyyyyyyyy, yyyyyyyyyyyyyyyyyyyyy, eeyyyyy yyyffyyyyyyyyee, eeyyyyyyyffyyyyyyyyyy, yyyyyyyyyffyyyyyyyyyyyyyyyyyyyyffyyyyyyyyyy, eeyyyyyffyyyyyyyyyy, eeyy yyyffyyyyyyyyyy, yyyyyyyffyyyyyyyyee, yyyyyyyffyyyyyyyyyy, yyyyyyfyfffyyyyyyyy, eeyyyyfyfffyyyyyyee, eeyyyyfyff fyyyyyyyy, yyyyyyfyfffyyyyyyee, eeyyfyfffyyyyyyyyee, eeyyfyfffyyyyyyyyyy, yyyyfyfffyyyyyyyyyyyyyyyyyyyyyyy yyy, eeyyyyyyyydyyyyyyyyy, eeyyyyyyyydyyyyyyyyyy, yyyyyyyyyydyyyyyyyyyyyyyyyyyyyyydyyyyyyyyyy, eeyyyyyyyyyyyy. An oligomeric double chain according to any one of Embodiments 1 to 102, having a sugar motif (from 5' to 3') selected from yyyyyee, eeyyyyyyyyyyyyyyyyyyy, yyyyyyyyyyyyyyyyyyyyee, and yyyyyyyyyyyyyyyyyyyyyy, wherein each "y" represents a 2'-OMe sugar moiety, each "e" represents a 2'-MOE sugar moiety, each "f" represents a 2'-fluoro sugar moiety, and each "d" represents a 2'-deoxy sugar moiety.

[0177] Embodiment 104. The oligomer double chain according to any one of Embodiments 1 to 102, wherein the second modified oligonucleotide has a sugar motif (from 5' to 3') selected from among eeyyyyyyyffyyyyyyyyy, eeyyyyfyfyyyyyyyyyy, yyyyyyyyyffyyyyyyyyyyy, and yyyyyyfyfyfyyyyyyyyyyy, where each "y" represents a 2'-OMe sugar moiety, each "e" represents a 2'-MOE sugar moiety, and each "f" represents a 2'-fluoro sugar moiety.

[0178] Embodiment 105. An oligomer double helix according to any one of Embodiments 1 to 104, wherein (1) the nucleic acid base of the 3' terminal nucleoside and / or the nucleoside immediately 5' to the 3' terminal nucleoside of the first modified oligonucleotide and / or the second modified oligonucleotide is adenine or thymine, and / or (2) the nucleic acid base of the 5' terminal nucleoside of the first modified oligonucleotide is thymine.

[0179] Embodiment 106. An oligomer double helix according to any one of Embodiments 1 to 104, wherein the nucleic acid base of the 3' terminal nucleoside and the nucleoside immediately 5' to the 3' terminal nucleoside of the first modified oligonucleotide is adenine, the nucleic acid base of the 5' terminal nucleoside of the first modified oligonucleotide is thymine, the nucleic acid base of the 3' terminal nucleoside of the second modified oligonucleotide is adenine, and the nucleic acid base of the nucleoside immediately 5' to the 3' terminal nucleoside of the second modified oligonucleotide is thymine or uracil.

[0180] Embodiment 107. The oligomeric double helix according to any one of Embodiments 1 to 106, wherein the second modified oligonucleotide comprises at least one modified internucleoside bond.

[0181] Embodiment 108. The oligomeric double helix according to Embodiment 107, wherein the at least one modified internucleoside bond is a phosphorothioate or mesylphosphoamidate internucleoside bond.

[0182] Embodiment 109. The oligomeric double helix according to Embodiment 107, wherein less than 50%, less than 40%, less than 30%, less than 20%, or less than 10% of the nucleoside bonds of the second modified oligonucleotide are modified nucleoside bonds.

[0183] Embodiment 110. An oligomeric double helix according to any one of Embodiments 107 to 109, wherein each nucleoside bond of the second modified oligonucleotide is independently selected from phosphodiester nucleoside bonds and phosphorothioate nucleoside bonds.

[0184] Embodiment 111. An oligomeric double helix according to any one of Embodiments 107 to 109, wherein the internucleoside bonds between the first and second nucleosides and between the second and third nucleosides, counting from the 5' end of the second modified oligonucleotide, are modified internucleoside bonds.

[0185] Embodiment 112. An oligomeric double helix according to any one of Embodiments 107 to 109 and 111, wherein the nucleoside bonds between the first and second nucleosides and between the second and third nucleosides, counting from the 3' end of the second modified oligonucleotide, are modified nucleoside bonds.

[0186] Embodiment 113. An oligomeric double helix according to any one of Embodiments 107 to 109, wherein the nucleoside bonds between the first and second nucleosides and between the second and third nucleosides counting from the 5' end of the second modified oligonucleotide, and the nucleoside bonds between the first and second nucleosides and between the second and third nucleosides counting from the 3' end of the second modified oligonucleotide are modified nucleoside bonds.

[0187] Embodiment 114. The oligomeric double helix according to any one of Embodiments 107 to 113, wherein the modified nucleoside bond is a phosphorothioate nucleoside bond.

[0188] Embodiment 115. The oligomeric double helix according to Embodiment 114, wherein all other nucleoside bonds in the second modified oligonucleotide are phosphodiester nucleoside bonds.

[0189] Embodiment 116. The oligomeric double chain according to Embodiment 115, wherein the second modified oligonucleotide has a nucleoside-linking motif of ssooooooooooooooooss and a sugar motif (from 5' to 3') selected from eeyyyyyyyffyyyyyyyyyee, eeyyyyfyfyyyyyyyyyyee, yyyyyyyyyffyyyyyyyyyyy, and yyyyyyfyfyyyyyyyyyyyy, where each "y" represents a 2'-OMe sugar moiety, each "e" represents a 2'-MOE sugar moiety, each "f" represents a 2'-fluoro sugar moiety, each "o" represents a phosphodiester nucleoside linkage, and each "s" represents a phosphorothioate nucleoside linkage.

[0190] Embodiment 117. The oligomeric double helix according to any one of Embodiments 1 to 116, wherein the nucleic acid base sequence of the second modified oligonucleotide contains 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 nucleic acid bases from any one of the nucleic acid base sequences of SEQ ID NOs. 315-626, 783-938, 977-1016, 1027-1032, 1256-1257, or 1288-1290.

[0191] Embodiment 118. The oligomeric double helix according to any one of Embodiments 1 to 116, wherein the nucleic acid base sequence of the second modified oligonucleotide includes one of the nucleic acid base sequences of SEQ ID NOs: 315-626, 783-938, 977-1016, 1027-1032, 1256-1257, or 1288-1290.

[0192] Embodiment 119. The oligomeric double helix according to any one of Embodiments 1 to 116, wherein the nucleic acid base sequence of the second modified oligonucleotide consists of one of the nucleic acid base sequences of SEQ ID NOs: 315-626, 783-938, 977-1016, 1027-1032, 1256-1257, or 1288-1290.

[0193] Embodiment 120. The oligomeric double helix according to any one of Embodiments 1 to 116, wherein the nucleic acid base sequence of the second modified oligonucleotide contains at least 16 consecutive nucleic acid bases from any one of the nucleic acid base sequences of SEQ ID NOs. 341, 483, 488, 1011-1016, 1027-1032, 1256-1257, or 1288-1290.

[0194] Embodiment 121. The oligomeric double helix according to any one of Embodiments 1 to 116, wherein the nucleic acid base sequence of the second modified oligonucleotide includes one of the nucleic acid base sequences of SEQ ID NOs: 341, 483, 488, 1011-1016, 1027-1032, 1256-1257, or 1288-1290.

[0195] Embodiment 122. The oligomeric double helix according to any one of Embodiments 1 to 116, wherein the nucleic acid base sequence of the second modified oligonucleotide consists of one of the nucleic acid base sequences of SEQ ID NOs: 341, 483, 488, 1011-1016, 1027-1032, 1256-1257, or 1288-1290.

[0196] Embodiment 123. An oligomeric double chain, (1) Sequence numbers 1: 295-316, 296-317, 297-318, 298-320, 299-320, 300-321, 301-322, 302-324, 303-324, 304-325, 304-326, 305-327, 306-325, 306-328, 307- 328, 308~329, 309~330, 310~331, 311~332, 312~333, 313~334, 314~335, 315~336, 316~337, 317~339, 318~339, 319~340, 320~341, 321~342, 322~344, 3 23-345, 324-345, 324-346, 325-345, 325-347, 326-347, 327-348, 328-345, 328-349, 329-350, 330-351, 331-352, 332-353, 333-354, 334-355, 505-52 6, 506~528, 507~529, 508~530, 509~531, 510~531, 511~532, 512~533, 513~535, 514~535, 514~536, 515~536, 516~535, 516~537, 517~538, 518~539, 519 ~541, 520~541, 521~542, 522~544, 523~544, 524~546, 535~556, 536~557, 537~558, 538~559, 539~560, 540~561, 541~563, 542~563, 543~564, 544~565, 545~566, 546~567, 547~568, 548~570, 549~571, 550~572, 551~572, 552~574, 553~574, 554~575, 555~577, 556~578, 557~579, 558~580, 559~580, 560~5 81, 561~582, 562~583, 563~584, 595~616, 596~618, 597~618, 598~620, 599~621, 600~622, 601~623, 602~623, 603~624, 604~625, 605~627, 606~628, 60 7-628, 608-629, 609-630, 610-631, 611-632, 612-633, 613-635, 665-687, 666-687, 667-689, 668-689, 669-690, 670-691, 671-692, 672-694, 673-694,674~695, 675~696, 676~697, 677~698, 678~700, 679~701, 680~702, 681~703, 682~703, 683~704, 684~705, 685~706, 686~708, 687~708, 688~709, 689~7 10, 690~711, 691~712, 692~714, 693~715, 1675~1696, 1676~1698, 1677~1698, 1678~1699, 1679~1700, 1680~1702, 1681~1702, 1682~1703, 1683~1705, 1 A first oligomer compound comprising a first modified oligonucleotide consisting of 18 to 30 consecutively linked nucleosides that are at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% complementary, or 100% complementary, to an isolength portion of a nucleic acid base selected from any one of 684-1705, 1685-1706, 1686-1707, 1687-1709, 1688-1709, 1689-1710, 1690-1712, 1691-1713, 1692-1714, or 1693-1714, (2) A second oligomer compound comprising a second modified oligonucleotide consisting of 16 to 28 consecutively linked nucleosides that are at least 90% complementary to the equilength portion of the first modified oligonucleotide, During the ceremony, (a) Each of the nucleosides of the first modified oligonucleotide and each of the nucleosides of the second modified oligonucleotide comprises a modified sugar moiety or sugar surrogate, (b) At least one of the modified sugar moieties or sugar surrogates of the first modified oligonucleotide contains fluorine, (c) an oligomeric double chain in which less than 40% of the nucleoside of the first modified oligonucleotide contains fluorine.

[0197] Embodiment 124. An oligomeric double hemisphere comprising (1) a first modified oligonucleotide comprising 18 to 30 consecutively linked nucleosides, wherein the nucleic acid base sequence of the first modified oligonucleotide is 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 nucleic acid base sequences from any one of the nucleic acid base sequences of SEQ ID NOs: 3 to 314, 627 to 782, 939 to 976, 1033 to 1038, 1254 to 1255, or 1258 to 1287 An oligomeric double helix comprising (1) a first oligomeric compound containing a nucleic acid base, and (2) a second oligomeric compound comprising a second modified oligonucleotide consisting of 16 to 28 consecutively linked nucleosides that are at least 90% complementary to the isolength portion of the first modified oligonucleotide, wherein (a) each of the nucleosides of the first modified oligonucleotide and each of the nucleosides of the second modified oligonucleotide contains a modified sugar moiety or sugar surrogate, (b) at least one of the modified sugar moieties or sugar surrogates of the first modified oligonucleotide contains fluorine, and (c) less than 40% of the nucleosides of the first modified oligonucleotide contain fluorine.

[0198] Embodiment 125. The oligomer double chain according to Embodiment 124, wherein each nucleoside of the oligomer double chain comprises (i) a modified sugar moiety, or (ii) independently a sugar moiety selected from the 2'-F sugar moiety, 2'-MOE sugar moiety, 2'-OMe sugar moiety, 2'-deoxy sugar moiety, and 3'-fluorohexitol sugar moiety.

[0199] Embodiment 126. The oligomeric double helix according to Embodiment 124, wherein the nucleic acid base sequence of the first modified oligonucleotide includes or consists of one of the nucleic acid base sequences of SEQ ID NOs: 3-314, 627-782, 939-976, 1033-1038, 1254-1255, or 1258-1287.

[0200] Embodiment 127. The oligomeric double helix according to Embodiment 124, wherein the nucleic acid base sequence of the first modified oligonucleotide contains 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 nucleic acid bases in any one of the nucleic acid base sequences of SEQ ID NOs. 29, 171, 176, 967, 968, 971, 972, 974, 975, 1033-1038, 1254-1255, or 1258-1287.

[0201] Embodiment 128. The oligomeric double helix according to Embodiment 124, wherein the nucleic acid base sequence of the first modified oligonucleotide includes one of the nucleic acid base sequences of SEQ ID NOs: 29, 171, 176, 967, 968, 971, 972, 974, 975, 1033-1038, 1254-1255, or 1258-1287.

[0202] Embodiment 129. The oligomer double helix according to Embodiment 124, wherein the nucleic acid base sequence of the first modified oligonucleotide consists of one of the nucleic acid base sequences of SEQ ID NOs: 29, 171, 176, 967, 968, 971, 972, 974, 975, 1033-1038, 1254-1255, or 1258-1287.

[0203] Embodiment 130. The oligomeric double helix according to Embodiment 124, wherein the nucleic acid base sequence of the second modified oligonucleotide contains 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 nucleic acid bases from any one of the nucleic acid base sequences of SEQ ID NOs. 315-626, 783-938, 977-1016, 1027-1032, 1256-1257, or 1288-1290.

[0204] Embodiment 131. The oligomeric double helix according to Embodiment 126, wherein the nucleic acid base sequence of the second modified oligonucleotide includes one of the nucleic acid base sequences of SEQ ID NOs: 315-626, 783-938, 977-1016, 1027-1032, 1256-1257, or 1288-1290.

[0205] Embodiment 132. The oligomer double helix according to Embodiment 126, wherein the nucleic acid base sequence of the second modified oligonucleotide consists of one of the nucleic acid base sequences of SEQ ID NOs: 315-626, 783-938, 977-1016, 1027-1032, 1256-1257, or 1288-1290.

[0206] Embodiment 133. The oligomeric double helix according to Embodiment 127, wherein the nucleic acid base sequence of the second modified oligonucleotide contains 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 nucleic acid bases from any one of the nucleic acid base sequences of SEQ ID NOs. 341, 483, 488, 1011-1016, 1027-1032, 1256-1257, or 1288-1290.

[0207] Embodiment 134. The oligomeric double helix according to Embodiment 128, wherein the nucleic acid base sequence of the second modified oligonucleotide includes one of the nucleic acid base sequences of SEQ ID NOs: 341, 483, 488, 1011-1016, 1027-1032, 1256-1257, or 1288-1290.

[0208] Embodiment 135. The oligomeric double helix according to Embodiment 129, wherein the nucleic acid base sequence of the second modified oligonucleotide consists of one of the nucleic acid base sequences of SEQ ID NOs: 341, 483, 488, 1011-1016, 1027-1032, 1256-1257, or 1288-1290.

[0209] Embodiment 136. An oligomeric double helix according to any one of Embodiments 123 to 135, wherein (1) the nucleic acid base of the 3' terminal nucleoside and / or the nucleoside immediately 5' to the 3' terminal nucleoside of the first modified oligonucleotide and / or the second modified oligonucleotide is adenine or thymine, and / or (2) the nucleic acid base of the 5' terminal nucleoside of the first modified oligonucleotide is thymine.

[0210] Embodiment 137. An oligomeric double helix according to any one of Embodiments 123 to 135, wherein the nucleic acid base of the 3' terminal nucleoside and the nucleoside immediately 5' to the 3' terminal nucleoside of the first modified oligonucleotide is adenine, the nucleic acid base of the 5' terminal nucleoside of the first modified oligonucleotide is thymine, the nucleic acid base of the 3' terminal nucleoside of the second modified oligonucleotide is adenine, and the nucleic acid base of the nucleoside immediately 5' to the 3' terminal nucleoside of the second modified oligonucleotide is thymine or uracil.

[0211] Embodiment 138. An oligomeric double helix according to any one of Embodiments 123 to 135, wherein the first oligomeric compound comprises a two-nucleoside overhang including the 3' terminal nucleoside of the first modified oligonucleotide and the nucleoside immediately to the 5' side of the 3' terminal nucleoside.

[0212] Embodiment 139. The oligomeric double helix according to Embodiment 138, wherein the overhang nucleoside is two modified adenosine (AA) nucleosides, two modified uridine (UU) nucleosides, two modified inosine (II) nucleosides, or two modified nucleosides (AI or IA) one of which is inosine and the other is adenosine.

[0213] Embodiment 140. The oligomeric double chain according to any one of Embodiments 123 to 139, wherein neither the modified sugar moiety nor the sugar surrogate of the nucleoside of the second modified oligonucleotide is fluorine-free.

[0214] Embodiment 141. At least one of the modified sugar moieties or sugar surrogates of the second modified oligonucleotide contains fluorine, and less than 40%, less than 30%, less than 25%, less than 20%, less than 15%, less than 14%, less than 13%, less than 12%, less than 10%, or less than 5% of the nucleoside of the second modified oligonucleotide contains fluorine, and / or The oligomeric double chain according to any one of Embodiments 123 to 139, wherein less than 30%, less than 25%, less than 20%, less than 15%, less than 14%, less than 13%, less than 12%, less than 10%, or less than 5% of the total nucleosides in the oligomeric double chain contains fluorine.

[0215] Embodiment 142. An oligomer double chain according to any one of Embodiments 123 to 139, wherein two, three, or four of the nucleosides of the second modified oligonucleotide independently contain a fluorine-containing modified sugar moiety or a fluorine-containing sugar surrogate, or four or fewer nucleosides, three or fewer nucleosides, two or fewer nucleosides, or one or fewer nucleosides of the second modified oligonucleotide contain a fluorine-containing modified sugar moiety or a fluorine-containing sugar surrogate.

[0216] Embodiment 143. An oligomeric double chain according to any one of Embodiments 123 to 142, wherein two, three, or four of the nucleosides of the first modified oligonucleotide independently contain a fluorine-containing modified sugar moiety or a fluorine-containing sugar surrogate, or four or fewer nucleosides, three or fewer nucleosides, two or fewer nucleosides, or one or fewer nucleosides of the first modified oligonucleotide contain a fluorine-containing modified sugar moiety or a fluorine-containing sugar surrogate.

[0217] Embodiment 144. An oligomeric double chain according to any one of Embodiments 123 to 143, wherein the space between the 3rd and 21st nucleosides from the 5' end of the modified oligonucleotide, and one or fewer nucleosides, two or fewer nucleosides, or three or fewer nucleosides in the sequence of the first modified oligonucleotide containing them, comprises a fluorine-containing modified sugar moiety or a fluorine-containing sugar surrogate.

[0218] Embodiment 145. One or more nucleosides containing a fluorine-containing modified sugar moiety or a fluorine-containing sugar surrogate of the first modified oligonucleotide independently i. The second nucleoside from the 5' end, ii. The 14th and 16th nucleosides counting from the 5' end, or iii. Selected from the 2nd, 14th, and 16th nucleosides counting from the 5' end, The oligomeric double chain according to any one of embodiments 123 to 144, wherein each of the fluorine-containing modified sugar moieties or fluorine-containing sugar surrogates is independently a 2'-fluorosugar moiety or a 3'-fluoro-hexitol sugar moiety.

[0219] Embodiment 146. An oligomeric double helix according to any one of Embodiments 123 to 145, wherein none of the nucleosides of the second modified oligonucleotide are 2'-deoxynucleosides, and / or none of the nucleosides of the first modified oligonucleotide are 2'-deoxynucleosides.

[0220] Embodiment 147. An oligomeric double chain according to any one of Embodiments 123 to 146, wherein all of the nucleosides of the second modified oligonucleotide contain a modified ribosyl sugar moiety.

[0221] Embodiment 148. An oligomeric double helix according to any one of Embodiments 123 to 145 and 147, wherein one, two, or three of the nucleosides of the first modified oligonucleotide are 2'-deoxynucleosides, or three or fewer, two or fewer, or one or fewer nucleosides of the first modified oligonucleotide are 2'-deoxynucleosides, or only three, two or one nucleosides of the first modified oligonucleotide are 2'-deoxynucleosides.

[0222] Embodiment 149. The oligomeric double helix according to Embodiment 148, wherein the 5th and 7th nucleosides counted from the 5' end of the first modified oligonucleotide are 2'-deoxynucleosides, or the 6th nucleoside counted from the 5' end of the first modified oligonucleotide is a 2'-deoxynucleoside.

[0223] Embodiment 150. (a) The 5'-terminal nucleoside and 3'-terminal nucleoside of the second modified oligonucleotide, the nucleoside immediately 3' to the 5'-terminal nucleoside, and the nucleoside immediately 5' to the 3'-terminal nucleoside contain a 2'-MOE sugar moiety and / or (b) The 5'-terminal nucleoside and the 3'-terminal nucleoside of the first modified oligonucleotide, and the nucleoside immediately 5' to the 3'-terminal nucleoside, contain a 2'-MOE sugar moiety and / or (c) The oligomeric double chain according to any one of Embodiments 123 to 149, wherein any nucleoside in the first and second modified oligonucleotides that do not contain fluorine or a 2'-MOE sugar moiety contains a 2'-OMe sugar moiety.

[0224] Embodiment 151. An oligomeric double chain according to any one of Embodiments 123 to 149, wherein the 3'-terminal nucleoside of the first modified oligonucleotide contains a 2'-OMe sugar moiety, and / or the nucleoside immediately 5' to the 3'-terminal nucleoside of the first modified oligonucleotide contains a 2'-OMe sugar moiety, and optionally, the 5'-terminal nucleoside of the first modified oligonucleotide contains a 2'-MOE sugar moiety.

[0225] Embodiment 152. The oligomeric double chain according to any one of Embodiments 123 to 151, wherein the first oligomeric compound comprises a stabilized phosphate group bonded to the 5' terminal nucleoside of the first modified oligonucleotide.

[0226] Embodiment 153. The oligomeric double chain according to Embodiment 152, wherein the stabilized phosphate group comprises cyclopropylphosphonate or vinylphosphonate.

[0227] Embodiment 154. An oligomeric double chain according to any one of Embodiments 123 to 153, wherein four or fewer of the nucleosides of the first modified oligonucleotide contain a fluorine-containing modified sugar moiety or a fluorine-containing sugar surrogate.

[0228] Embodiment 155. The first modified state is efyyyyyyyyyyyyyyyyyyyyy,efyyyyyyyyyyyyyyyyyyyy,e[FHNE]yyyyyyyyyyyyyyyyyyyy,e[FHNE]yyyyyyyyyyyyyyyyyyyyy,e[FHNE]yyyyyyyyyyyyyyyyyyyyy,efyyyyyyyyyyyyyyyyyyyyyyy,e[FHNE]yydydyyyyyyyyyyyyyy An oligomeric double chain according to Embodiment 154, having a sugar motif (from 5' to 3') selected from yy and efyyyfyyyyyyyfyfyyyyee, where each "d" represents a 2'-deoxy sugar moiety, each "y" represents a 2'-OMe sugar moiety, each "e" represents a 2'-MOE sugar moiety, each "f" represents a 2'-fluoro sugar moiety, and each "[FHNA]" represents a 3'-fluoro-hexitol sugar moiety.

[0229] Embodiment 156. An oligomeric double chain according to any one of Embodiments 123 to 153, wherein three or fewer of the nucleosides of the first modified oligonucleotide contain a fluorine-containing modified sugar moiety or a fluorine-containing sugar surrogate.

[0230] Embodiment 157. The first modified state is efyyydyyyyyyyyyyyyyyyyee,efyyydyyyyyyyyyyyyyyyyy,e[FHE]yyydyyyyyyyyyyyyyyee,e[FHE]yyydyyyyyyyyyyyyyyyyyy,efyydydyyyyyyyyyyyyyyyee,efyydydyyyyyyyyyyyyyyyyy,e[FH NA]yydydyyyyyyfyfyyyyyee, e[FHNA]yydyyyyyyfyfyyyyyyy, efyyyyyyyyyyyfyfyyyyyyy, efyyyfyyyyyyyyyyy yyyyyyy, efyyyfyyyyyyyfydyyyyyee, efyyyfyyyyyyyfydyyyyyyy, efyyyfyyyyyyyfydyyyyyee, efyyyfyyyyyyyf ydyyyyyyy, efyydydyyyyyyfyfyyyyye, efyydydyyyyyyfyfyyyyyy, efyyydyyyyyyyfyfyyyyye, efyyydyyyyyyyf yfyyyyyy, efyyyyyyyyyyyfyfyyyyye, efyyyyyyyyyyyyfyfyyyyyy, efyydydyyyyyyfyfyyyyy, efyyydyyyyyyyfyfy An oligomer double chain according to Embodiment 156, having a sugar motif (from 5' to 3') selected from yyyy and efyyyyyyyyyyyfyfyyyyyy, where each "d" represents a 2'-deoxy sugar moiety, each "y" represents a 2'-OMe sugar moiety, each "e" represents a 2'-MOE sugar moiety, each "f" represents a 2'-fluoro sugar moiety, and each "[FHNA]" represents a 3'-fluoro-hexitol sugar moiety.

[0231] Embodiment 158. An oligomeric double chain according to any one of Embodiments 123 to 153, wherein two or fewer of the nucleosides of the first modified oligonucleotide contain a fluorine-containing modified sugar moiety or a fluorine-containing sugar surrogate.

[0232] Embodiment 159. The oligomer double chain according to Embodiment 158, wherein the first modified oligonucleotide has a sugar motif (from 5' to 3') selected from efyyyyyyyyyyyfyyyyyyyyee, efyyyyyyyyyyyyfyyyyyyyyy, e[FHNA]yyyyyyyyyyy[FHNA]yyyyyyyee, and e[FHNA]yyyyyyyyyyy[FHNA]yyyyyyyyy, where each "y" represents a 2'-OMe sugar moiety, each "e" represents a 2'-MOE sugar moiety, each "f" represents a 2'-fluoro sugar moiety, and each "[FHNA]" represents a 3'-fluoro-hexitol sugar moiety.

[0233] Embodiment 160. An oligomeric double chain according to any one of Embodiments 123 to 153, wherein only one of the nucleosides of the first modified oligonucleotide contains a fluorine-containing modified sugar moiety or a fluorine-containing sugar surrogate.

[0234] Embodiment 161. The oligomer double chain according to Embodiment 160, wherein the first modified oligonucleotide has a sugar motif (from 5' to 3') selected from efyyydyyyyyyyydydyyyyyy, efyyydyyyyyyyyydydyyyyyee, e[FHNA]yyydyyyyyyyyyyyyy, and e[FHNA]yyydyyyyyyyyyyyyyee, where each "d" represents a 2'-deoxy sugar moiety, each "y" represents a 2'-OMe sugar moiety, each "e" represents a 2'-MOE sugar moiety, each "f" represents a 2'-fluoro sugar moiety, and each "[FHNA]" represents a 3'-fluoro-hexitol sugar moiety.

[0235] Embodiment 162. The oligomeric double helix according to any one of Embodiments 123 to 158 and 160, wherein two or fewer of the nucleosides of the first modified oligonucleotide are 2'-deoxynucleosides.

[0236] Embodiment 163. The first modified state is efyydydyyyyyyyfyfyyyyyyee, efyydydyyyyyyyfyfyyyyyyy, e[FHE]yydydyyyyyyyfyfyyyyyyee, e[FHE]yydydyyyyyyyfyfyyyyyyy, efyydydyyyyyyyyyyyyye, efyydydyyyyyyyyyyyyyy, and An oligomer double chain according to Embodiment 162, having a sugar motif (from 5' to 3') selected from efyydydyyyyyyfyfyyyyy, where each "d" represents a 2'-deoxy sugar moiety, each "y" represents a 2'-OMe sugar moiety, each "e" represents a 2'-MOE sugar moiety, each "f" represents a 2'-fluoro sugar moiety, and each "[FHNA]" represents a 3'-fluoro-hexitol sugar moiety.

[0237] Embodiment 164. The oligomeric double helix according to any one of Embodiments 123-154, 156, 158, and 160, wherein only one of the nucleosides of the first modified oligonucleotide is a 2'-deoxynucleoside.

[0238] Embodiment 165. The first modified state is efyyydyyyyyyyyyyyyyyyyee,efyyydyyyyyyyyyyyyyyyyy,e[FHE]yyydyyyyyyyyyyyyyyyee,e[FHE]yyydyyyyyyyyyyyyyyyyyy,eyyyyyyyyyyyyyyyyyyy,efyyyyyyyyyyyyyyyyyyyy,eyyy[FHE]yyyyyyyyyyyyyyyy,e[FHE]yyyyyyyyyyyyyyyyy An oligomer double chain according to Embodiment 164, having a sugar motif (from 5' to 3') selected from yyee, efyyydyyyyyyyfyfyyyyyye, efyyydyyyyyyyfyfyyyyyy, and efyyydyyyyyyyfyfyyyyy, wherein each "d" represents a 2'-deoxy sugar moiety, each "y" represents a 2'-OMe sugar moiety, each "e" represents a 2'-MOE sugar moiety, each "f" represents a 2'-fluoro sugar moiety, and each "[FHNA]" represents a 3'-fluoro-hexitol sugar moiety.

[0239] Embodiment 165a. The first modified state is efyyydyyyyyyyyyyyyyyyyee, efyyydyyyyyyyyyyyyyyyyyy, e[FHE]yyydyyyyyyyyyyyyyyyee, e[FHE]yyydyyyyyyyyyyyyyyyyyy, eyyyyyyyyyyyyyyyyyyyy, efyyyyyyyyyyyyyyyyyyee, efyyy[FHE]yyyyyyyyyyyyyyyy, e[FHE]yyyyyyyyyyyyyyyyyyye An oligomer double chain according to Embodiment 164, having a sugar motif (from 5' to 3') selected from e, efyyydyyyyyyyfyfyyyyye, efyyydyyyyyyyfyfyyyyyy, and efyyydyyyyyyyfyfyyyyy, wherein each "d" represents a 2'-deoxy sugar moiety, each "y" represents a 2'-OMe sugar moiety, each "e" represents a 2'-MOE sugar moiety, each "f" represents a 2'-fluoro sugar moiety, and each "[FHNA]" represents a 3'-fluoro-hexitol sugar moiety.

[0240] Embodiment 166. An oligomeric double chain according to any one of Embodiments 123 to 154, wherein none of the nucleosides of the first modified oligonucleotide contain a 2'-deoxy sugar moiety.

[0241] Embodiment 167. The oligomer double chain according to Embodiment 166, wherein the first modified oligonucleotide has a sugar motif (from 5' to 3') selected from efyyyyyyyyyyyfyfyyyyyyee, efyyyfyyyyyyyyyyfyyyyyyy, efyyyyyyyyyyyyfyfyyyyyye, efyyyyyyyyyyyyfyfyyyyyy, and efyyyyyyyyyyyyfyfyyyyy, where each "y" represents a 2'-OMe sugar moiety, each "e" represents a 2'-MOE sugar moiety, and each "f" represents a 2'-fluoro sugar moiety.

[0242] Embodiment 168. An oligomeric double chain according to any one of Embodiments 123-139 and 141-167, wherein four or fewer of the nucleosides of the second modified oligonucleotide contain a fluorine-containing modified sugar moiety or a fluorine-containing sugar surrogate.

[0243] Embodiment 169. The oligomer double chain according to Embodiment 168, wherein the second modified oligonucleotide has a sugar motif (from 5' to 3') selected from among yyyyyyfyfffyyyyyyyyy, eeyyyyfyfffyyyyyyyyy, yyyyyfyfffyyyyyyyyy, eeyyyyfyfffyyyyyyyyy, yyyyfyfffyyyyyyyyyy, and eeyyfyfffyyyyyyyyyy, where each "y" represents a 2'-OMe sugar moiety, each "e" represents a 2'-MOE sugar moiety, and each "f" represents a 2'-fluoro sugar moiety.

[0244] Embodiment 170. An oligomeric double chain according to any one of Embodiments 123-139 and 141-167, wherein three or fewer of the nucleosides of the second modified oligonucleotide contain a fluorine-containing modified sugar moiety or a fluorine-containing sugar surrogate.

[0245] Embodiment 171. The oligomeric double chain according to Embodiment 170, wherein the second modified oligonucleotide has a sugar motif (from 5' to 3') selected from eeyyyyfyfyyfyyyyyyyyee and yyyyyyfyfyfyyyyyyyyyy, where each "y" represents a 2'-OMe sugar moiety, each "e" represents a 2'-MOE sugar moiety, and each "f" represents a 2'-fluoro sugar moiety.

[0246] Embodiment 172. An oligomeric double chain according to any one of Embodiments 123-139 and 141-167, wherein two or fewer of the nucleosides of the second modified oligonucleotide contain a fluorine-containing modified sugar moiety or a fluorine-containing sugar surrogate.

[0247] Embodiment 173. The oligomeric double chain according to Embodiment 172, wherein the second modified oligonucleotide has a sugar motif (from 5' to 3') selected from among eeyyyyyyyffyyyyyyyyee, yyyyyyyyffyyyyyyyyyyy, eeyyyyyffyyyyyyyyyee, and yyyyyyyffyyyyyyyyyyy, where each "y" represents a 2'-OMe sugar moiety, each "e" represents a 2'-MOE sugar moiety, and each "f" represents a 2'-fluoro sugar moiety.

[0248] Embodiment 174. An oligomeric double chain according to any one of Embodiments 123 to 167, wherein none of the nucleosides of the second modified oligonucleotide contain a fluorine-containing modified sugar moiety or a fluorine-containing sugar surrogate, and the second modified oligonucleotide has a sugar motif (from 5' to 3') selected from yyyyyyyyyyyyyyyyyyyyyy, eeyyyyyyyyyyyyyyyyyyyyy, yyyyyyyyyyydyyyyyyyyyyy, and eeyyyyyyyyydyyyyyyyyyy, where each "y" represents a 2'-OMe sugar moiety, each "e" represents a 2'-MOE sugar moiety, and each "d" represents a 2'-deoxy sugar moiety.

[0249] Embodiment 175. An oligomeric double helix according to any one of Embodiments 123 to 174, wherein one or more of the nucleoside bonds of the first modified oligonucleotide are modified nucleoside bonds, and / or less than 50%, less than 40%, less than 30%, less than 20%, or less than 10% of the nucleoside bonds of the first modified oligonucleotide are modified nucleoside bonds.

[0250] Embodiment 176. An oligomeric double helix according to any one of Embodiments 123 to 175, wherein the internucleoside bonds between the first and second nucleosides counting from the 5' end of the first modified oligonucleotide, and between the second and third nucleosides, and the internucleoside bonds between the first and second nucleosides counting from the 3' end of the first modified oligonucleotide, and between the second and third nucleosides, are phosphorothioate internucleoside bonds.

[0251] Embodiment 177. The oligomeric double helix according to any one of Embodiments 123 to 175, wherein the first modified oligonucleotide has an internucleoside linking motif (from 5' to 3') selected from ssooooooooooooooooooss, ssooosoooooooooooooooss, ssoooooooooooooooooooss, ssoooooooooooooooooo, and ssooooooooooooooooss, where each "o" represents a phosphodiester internucleoside linkage and each "s" represents a phosphorothioate internucleoside linkage.

[0252] Embodiment 178. An oligomeric double helix according to any one of Embodiments 123 to 177, wherein one or more of the nucleoside bonds of the second modified oligonucleotide are modified nucleoside bonds.

[0253] Embodiment 179. An oligomeric double helix according to any one of Embodiments 123 to 178, wherein less than 50%, less than 40%, less than 30%, less than 20%, or less than 10% of the nucleoside bonds of the second modified oligonucleotide are modified nucleoside bonds.

[0254] Embodiment 180. An oligomeric double helix according to any one of Embodiments 123 to 179, wherein the internucleoside bonds between the first and second nucleosides counting from the 5' end of the second modified oligonucleotide, and between the second and third nucleosides, and the internucleoside bonds between the first and second nucleosides counting from the 3' end of the second modified oligonucleotide, and between the second and third nucleosides, are phosphorothioate internucleoside bonds.

[0255] Embodiment 181. The second modified oligonucleotide has a nucleoside linkage motif (from 5' to 3') selected from ssooooooooooooooooss, ssooooooosooooooooss, ssoooooozozoooooooss, and ssooooooooooooooss, wherein each "o" represents a phosphodiester nucleoside linkage, each "s" represents a phosphorothioate nucleoside linkage, and each "z" represents a mesylphosphoramidate nucleoside linkage. The oligomer duplex according to any one of Embodiments 123 to 180.

[0256] Embodiment 182. The first modified oligonucleotide has a first sugar motif (1 st ), and the second modified oligonucleotide has a second sugar motif (2 nd ), and the first and second sugar motifs are in the following combinations (from 5' to 3'): 1 st : efyydydyyyyyyfyfyyyyyee and 2 nd : eeyyyyfyfyfyyyyyyyyee, 1 st : efyydydyyyyyyfyfyyyyyyy and 2 nd : yyyyyyfyfyfyyyyyyyyyy, 1 st : efyydydyyyyyyfyfyyyyyee and 2 nd : yyyyyyfyfyfyyyyyyyyyy, 1 st : efyydydyyyyyyfyfyyyyyyy and 2 nd : eeyyyyfyfyfyyyyyyyyee, 1 st : efyyyyyyyyyyyfyfyyyyyee and 2 nd : eeyyyyyyyffyyyyyyyyee, 1 st : efyyyyyyyyyyyfyfyyyyyyy and 2 nd : yyyyyyyyyffyyyyyyyyyy, 1 st : efyyyyyyyyyyyfyfyyyyyee and 2 nd : yyyyyyyyyffyyyyyyyyyy, 1 st: emiyyyyyyyyyyyyyyyyyyyyy and 2 nd :eeyyyyyyyffyyyyyyyyy, 1 st :efyyydyyyyyyyfyfyyyyyee and 2 nd :eeyyyyyyyffyyyyyyyyy, 1 st :efyyydyyyyyyydatayyyyyyyy and 2 nd :yyyyyyyyyfyyyyyyyyyy, 1 st :efyyydyyyyyyyfyfyyyyyee and 2 nd :yyyyyyyyyfyyyyyyyyyy, 1 st :efyyydyyyyyyydataydatayyyyyyy and 2 nd :eeyyyyyyyffyyyyyyyyy, 1 st :efyydydyyyyyyfyfyyyyyee and 2 nd :eeyyyyyyyffyyyyyyyyy, 1 st :efyydydyyyyyyfyfyyyyyyy and 2 nd :yyyyyyyyyfyyyyyyyyyy, 1 st :efyydydyyyyyyfyfyyyyyee and 2 nd :yyyyyyyyyfyyyyyyyyyy, 1 st :efyydydyyyyyyfyfyyyyyyy and 2 nd :eeyyyyyyyffyyyyyyyyy, 1 st :efyyydyyyyyyyfyfyyyyyee and 2 nd :eeyyyyyyyyyyyyyyyyyy, 1 st :efyyydyyyyyyydataydatayyyyyyy and 2 nd :yyyyyyyyyyyyyyyyyyyyy, 1 st :efyyydyyyyyyyfyfyyyyyee and 2 nd :yyyyyyyyyyyyyyyyyyyyy, 1 st :efyyydyyyyyyydataydatayyyyyyy and 2 nd :eeyyyyyyyyyyyyyyyyyy, 1 st:efyyyyyyyyyyyyyyyyyyee and 2 nd :eeyyyyyyyyyyyyyyyyyy, 1 st : emiyyyyyyyyyyyyyyyyyyyyy and 2 nd :yyyyyyyyyyyyyyyyyyyyy, 1 st :efyyyyyyyyyyyyyyyyyyee and 2 nd :yyyyyyyyyyyyyyyyyyyyy, 1 st : emiyyyyyyyyyyyyyyyyyyyyy and 2 nd :eeyyyyyyyyyyyyyyyyyy, 1 st :eyyyyyyyyyyyyyyyyyye and 2 nd :eeyyyyyyyffyyyyyyyyy, 1 st : emiyyyyyyyyyyyyyyyyyyyy and 2 nd :yyyyyyyyyfyyyyyyyyyy, 1 st :eyyyyyyyyyyyyyyyyyye and 2 nd :yyyyyyyyyfyyyyyyyyyy, 1 st : emiyyyyyyyyyyyyyyyyyyyy and 2 nd :eeyyyyyyyffyyyyyyyyy, 1 st :eyyyyyyyyyyyyyyyyyye and 2 nd :eeyyyyyyyyyyyyyyyyyy, 1 st : emiyyyyyyyyyyyyyyyyyyyy and 2 nd :yyyyyyyyyyyyyyyyyyyyy, 1 st :eyyyyyyyyyyyyyyyyyye and 2 nd :yyyyyyyyyyyyyyyyyyyyy, 1 st : emiyyyyyyyyyyyyyyyyyyyy and 2 nd :eeyyyyyyyyyyyyyyyyyy, 1 st :efyydydyyyyyyfyfyyyyye and 2 nd :eeyyyyyyyyyyyyyyyyyy, 1 st: efyydydyyyyyyfyfyyyyyy and 2 nd : yyyyyyfyfyfyyyyyyyyyy, 1 st : efyydydyyyyyyfyfyyyyye and 2 nd : yyyyyyfyfyfyyyyyyyyyy, 1 st : efyydydyyyyyyfyfyyyyyy and 2 nd : eeyyyyfyfyfyyyyyyyyee, 1 st : efyydydyyyyyyfyfyyyyye and 2 nd : eeyyyyyyyffyyyyyyyyee, 1 st : efyydydyyyyyyfyfyyyyyy and 2 nd : yyyyyyyyyffyyyyyyyyyy, 1 st : efyydydyyyyyyfyfyyyyye and 2 nd : yyyyyyyyyffyyyyyyyyyy, 1 st : efyydydyyyyyyfyfyyyyyy and 2 nd : eeyyyyyyyffyyyyyyyyee, 1 st : efyyydyyyyyyyfyfyyyyye and 2 nd : eeyyyyyyyffyyyyyyyyee, 1 st : efyyydyyyyyyyfyfyyyyyy and 2 nd : yyyyyyyyyffyyyyyyyyyy, 1 st : efyyydyyyyyyyfyfyyyyye and 2 nd : yyyyyyyyyffyyyyyyyyyy, 1 st : efyyydyyyyyyyfyfyyyyyy and 2 nd : eeyyyyyyyffyyyyyyyyee, 1 st : efyyydyyyyyyyfyfyyyyye and 2 nd : eeyyyyfyfyfyyyyyyyyee, 1 st : efyyydyyyyyyyfyfyyyyyy and 2 nd : yyyyyyfyfyfyyyyyyyyyy, 1 st: efyyydyyyyyyyfyfyyyyye and 2 nd : yyyyyyfyfyfyyyyyyyyyy, 1 st : efyyydyyyyyyyfyfyyyyyy and 2 nd : eeyyyyfyfyfyyyyyyyyee, 1 st : efyyyyyyyyyyyfyfyyyyy and 2 nd : eeyyyyyyyffyyyyyyyyee, 1 st : efyyyyyyyyyyyfyfyyyyy and 2 nd : yyyyyyyyyffyyyyyyyyyy, 1 st : efyyyyyyyyyyyfyfyyyyy and 2 nd : eeyyyyfyfyfyyyyyyyyee, 1 st : efyyyyyyyyyyyfyfyyyyy and 2 nd : yyyyyyfyfyfyyyyyyyyyy, 1 st : efyydydyyyyyyfyfyyyyy and 2 nd : eeyyyyfyfyfyyyyyyyyee, 1 st : efyydydyyyyyyfyfyyyyy and 2 nd : yyyyyyfyfyfyyyyyyyyyy, 1 st : efyydydyyyyyyfyfyyyyy and 2 nd : eeyyyyyyyffyyyyyyyyee, 1 st : efyydydyyyyyyfyfyyyyy and 2 nd : yyyyyyyyyffyyyyyyyyyy, 1 st : efyyydyyyyyyyfyfyyyyy and 2 nd : eeyyyyyyyffyyyyyyyyee, 1 st : efyyydyyyyyyyfyfyyyyy and 2 nd : yyyyyyyyyffyyyyyyyyyy, 1 st : efyyydyyyyyyyfyfyyyyy and 2 nd : eeyyyyfyfyfyyyyyyyyee, 1 st:efyyydyyyyyyyydatayyyyyy and 2 nd An oligomeric double chain according to any one of Embodiments 1-4, 12, 18, 19, 30-69, 72, 80, 105-115, 117-139, 152, 153, and 175-181, wherein the formula is selected from :yyyyyyfyfyfyyyyyyyyy, where each "y" represents a 2'-OMe sugar moiety, each "e" represents a 2'-MOE sugar moiety, each "f" represents a 2'-fluoro sugar moiety, and each "d" represents a 2'-deoxy sugar moiety.

[0257] Embodiment 183. The first modified oligonucleotide is a first sugar motif (1 st ) has the second modified oligonucleotide, and the second sugar motif (2 nd )) and the first and second sugar motifs are in the following combination (from 5' to 3'): 1 st :efyydydyyyyyyfyfyyyyyee and 2 nd :eeyyyyfyfffyyyyyyyyy, 1 st :efyydydyyyyyyfyfyyyyyyy and 2 nd :yyyyyyyy5vyyyyyyyyyy,1 st :efyydydyyyyyyfyfyyyyyee and 2 nd :yyyyyyyy5vyyyyyyyyyy,1 st :efyydydyyyyyyfyfyyyyyyy and 2 nd :eeyyyyfyfffyyyyyyyyy, 1 st :efyyyyyyyyyyyyyyyyyyee and 2 nd :eeyyyyfyfffyyyyyyyyy, 1 st : emiyyyyyyyyyyyyyyyyyyyyy and 2 nd :yyyyyyyy5vyyyyyyyyyy,1 st :efyyyyyyyyyyyyyyyyyyee and 2 nd :yyyyyyyy5vyyyyyyyyyy,1 st : emiyyyyyyyyyyyyyyyyyyyyy and 2nd :eeyyyyfyfffyyyyyyyyy, 1 st :efyyyyyyyyyyyyyyyyyyee and 2 nd :eeyyyyyyyffyyyyyyyyy, 1 st : emiyyyyyyyyyyyyyyyyyyyyy and 2 nd :yyyyyyyyyfyyyyyyyyyy, 1 st :efyyyyyyyyyyyyyyyyyyee and 2 nd :yyyyyyyyyfyyyyyyyyyy, 1 st : emiyyyyyyyyyyyyyyyyyyyyy and 2 nd :eeyyyyyyyffyyyyyyyyy, 1 st :efyyyyyyyyyyyyyyyyyyee and 2 nd :eeyyyyyyyyyyyyyyyyyy, 1 st : emiyyyyyyyyyyyyyyyyyyyyy and 2 nd :yyyyyyyyyyyyyyyyyyyyy, 1 st :efyyyyyyyyyyyyyyyyyyee and 2 nd :yyyyyyyyyyyyyyyyyyyyy, 1 st : emiyyyyyyyyyyyyyyyyyyyyy and 2 nd :eeyyyyyyyyyyyyyyyyyy, 1 st : emiyyyyyyyyyyyyyyyyyyyyyy and 2 nd :yyyyyyyyyfyyyyyyyyyy, 1 st :efyyyfyyyyyyyyyyyyyyyee and 2 nd :eeyyyyyyyffyyyyyyyyy, 1 st : emiyyyyyyyyyyyyyyyyyyyyyy and 2 nd :eeyyyyyyyffyyyyyyyyy, 1 st :efyyyfyyyyyyyyyyyyyyyee and 2 nd :yyyyyyyyyfyyyyyyyyyy, 1 st : emiyyyyyyyyyyyyyyyyyyyyyy and 2nd :yyyyyyyyyyyyyyyyyyyyy, 1 st :efyyyfyyyyyyyyyyyyyyyee and 2 nd :eeyyyyyyyyyyyyyyyyyy, 1 st : emiyyyyyyyyyyyyyyyyyyyyyy and 2 nd :eeyyyyyyyyyyyyyyyyyy, 1 st :efyyyfyyyyyyyyyyyyyyyee and 2 nd :yyyyyyyyyyyyyyyyyyyyy, 1 st :efyyyfyyyyyyyyyfyyyyee and 2 nd :eeyyyyfyfffyyyyyyy, 1 st : efyyyfyyyyyyyyyyyyyyy and 2 nd :yyyyyyyy5vyyyyyyyy, 1 st :efyyyfyyyyyyyyyfyyyyee and 2 nd :yyyyyyyy5vyyyyyyyy, 1 st : efyyyfyyyyyyyyyyyyyyy and 2 nd :eeyyyyfyfffyyyyyyy, 1 st :efyyyfyyyyyyyyyfyyyyee and 2 nd :eeyyyyffyyyyyyyyy, 1 st : efyyyfyyyyyyyyyyyyyyy and 2 nd :yyyyyyfyyyyyyyyyy, 1 st :efyyyfyyyyyyyyyfyyyyee and 2 nd :yyyyyyfyyyyyyyyyy, 1 st : efyyyfyyyyyyyyyyyyyyy and 2 nd :eeyyyyffyyyyyyyyy, 1 st :e[FHNA]yydydyyyyfyfyfyyyyyee and 2 nd :eeyyyyfyfffyyyyyyyyy, 1 st :efyyyfyyyyyyyyyyyyyyyey and 2 nd:eeyyyyfyfffyyyyyyyyy, 1 st :efyyyfyyyyyyyyyyyyyyyey and 2 nd :yyyyyyyy5vyyyyyyyyyy,1 st :e[FHNA]yydydyyyyfyfyfyyyyyyy and 2 nd :yyyyyyyy5vyyyyyyyyyy,1 st :e[FHNA]yydydyyyyfyfyfyyyyyee and 2 nd :yyyyyyyy5vyyyyyyyyyy,1 st :e[FHNA]yydydyyyyfyfyfyyyyyyy and 2 nd :eeyyyyfyfffyyyyyyyyy, 1 st :e[FHNA]yydydyyyyfyfyfyyyyyee and 2 nd :eeyyyyyyyyyyyyyyyyyy, 1 st :e[FHNA]yydydyyyyfyfyfyyyyyyy and 2 nd :yyyyyyyyyyyyyyyyyyyyy, 1 st :e[FHNA]yydydyyyyfyfyfyyyyyee and 2 nd :yyyyyyyyyyyyyyyyyyyyyy, next to 1 st :e[FHNA]yydydyyyyfyfyfyyyyyyy and 2 nd An oligomeric double chain according to any one of Embodiments 1-4, 12, 18, 19, 30-69, 72, 80, 105-115, 117-139, 152, 153, and 175-181, wherein the formula is selected from :eeyyyyfyfyfyyyyyyyyy, where each "y" represents a 2'-OMe sugar moiety, each "e" represents a 2'-MOE sugar moiety, each "f" represents a 2'-fluoro sugar moiety, each "[FHNA]" represents a 3'-fluoro-hexitol sugar moiety, and each "d" represents a 2'-deoxy sugar moiety.

[0258] Embodiment 184. The first modified oligonucleotide is a first sugar motif (1 st) has the second modified oligonucleotide, and the second sugar motif (2 nd )) and the first and second sugar motifs are in the following combination (from 5' to 3'): 1 st : emiyyyyyyyyyyyyyyyyyyyyyy and 2 nd :yyyyyyyy5vyyyyyyyyyy,1 st :efyyyfyyyyyyyyyyyyyyyee and 2 nd :eeyyyyfyfffyyyyyyyyy, 1 st :efyyyfyyyyyyyyyyyyyyyee and 2 nd :yyyyyyfyffyyyyyyyyyy, next to 1 st : emiyyyyyyyyyyyyyyyyyyyyyy and 2 nd An oligomeric double chain according to any one of embodiments 1-4, 12, 18, 19, 30-69, 72, 80, 105-115, 117-139, 152, 153, and 175-181, wherein the formula is selected from :eeyyyyfyfffyyyyyyyyy, where each "y" represents a 2'-OMe sugar moiety, each "e" represents a 2'-MOE sugar moiety, and each "f" represents a 2'-fluoro sugar moiety.

[0259] Embodiment 185. The first modified oligonucleotide is a first sugar motif (1 st ) has the second modified oligonucleotide, and the second sugar motif (2 nd )) and the first and second sugar motifs are in the following combination (from 5' to 3'): 1 st : emiyyyyyyyyyyyyyyyyyyyyyy and 2 nd :yyyyyyyyyyyyyyyyyyyyy, 1 st :efyyyfyyyyyyyyyyyyyyyee and 2 nd :eeyyyyyyyyyyyyyyyyyy, 1 st : emiyyyyyyyyyyyyyyyyyyyyyy and 2 nd :eeyyyyyyyyyyyyyyyyyy, 1 st:efyyyfyyyyyyyyyyyyyyyee and 2 nd :yyyyyyyyyyyyyyyyyyyyy, 1 st : emiyyyyyyyyyyyyyyyyyyyyyy and 2 nd :yyyyyyyyyydyyyyyyyyyy, 1 st :efyyyfyyyyyyyyyyyyyyyee and 2 nd :eeyyyyyyyydyyyyyyyyy, 1 st : emiyyyyyyyyyyyyyyyyyyyyyy and 2 nd :eeyyyyyyyydyyyyyyyyy, 1 st :efyyyfyyyyyyyyyyyyyyyee and 2 nd :yyyyyyyyyydyyyyyyyyyy, 1 st :efyyyyyyyyyyydatayyyyyyyee and 2 nd :eeyyyyfyfffyyyyyyyyy, 1 st : eiyyyyyyyyyyydatayyyyyyyyy and 2 nd :yyyyyyyy5vyyyyyyyyyy,1 st :efyyyyyyyyyyydatayyyyyyyee and 2 nd :yyyyyyyy5vyyyyyyyyyy,1 st : eiyyyyyyyyyyydatayyyyyyyyy and 2 nd :eeyyyyfyfffyyyyyyyyy, 1 st :efyyyyyyyyyyydatayyyyyyyee and 2 nd :eeyyyyyyyyyyyyyyyyyy, 1 st : eiyyyyyyyyyyydatayyyyyyyyy and 2 nd :yyyyyyyyyyyyyyyyyyyyy, 1 st :efyyyyyyyyyyydatayyyyyyyee and 2 nd :yyyyyyyyyyyyyyyyyyyyy, 1 st : eiyyyyyyyyyyydatayyyyyyyyy and 2 nd :eeyyyyyyyyyyyyyyyyyy, 1 st:efyyydyyyyyyyfyfyyyyyee and 2 nd :eeyyyyfyfffyyyyyyyyy, 1 st :efyyydyyyyyyydataydatayyyyyyy and 2 nd :yyyyyyyy5vyyyyyyyyyy,1 st :efyyydyyyyyyyfyfyyyyyee and 2 nd :yyyyyyyy5vyyyyyyyyyy,1 st :efyyydyyyyyyydataydatayyyyyyy and 2 nd :eeyyyyfyfffyyyyyyyyy, 1 st :efyyyfyyyyyyyyyfyyyyee and 2 nd :eeyyfyfffyyyyyyyyy, 1 st : efyyyfyyyyyyyyyyyyyyy and 2 nd :yyyyyy5vyyyyyyyyyy, 1 st :efyyyfyyyyyyyyyfyyyyee and 2 nd :yyyyyy5vyyyyyyyyyy, 1 st : efyyyfyyyyyyyyyyyyyyy and 2 nd :eeyyfyfffyyyyyyyyy, 1 st :efyyyfyyyyyyyyyydyyyyyee and 2 nd :eeyyyyfyfffyyyyyyyyy, 1 st :efyyydatayyyyyyyyyydyyyyyyy and 2 nd :yyyyyyyy5vyyyyyyyyyy,1 st :efyyyfyyyyyyyyyydyyyyyee and 2 nd :yyyyyyyy5vyyyyyyyyyy,1 st :efyyydatayyyyyyyyyydyyyyyyy and 2 nd :eeyyyyfyfffyyyyyyyyy, 1 st :e[FHCE]yyyfyyyyyyyyyyyyyyyee and 2 nd :eeyyyyfyfffyyyyyyyyy, 1 st:e[FHCE]yyyfyyyyyyyyyyyyyyyyy and 2 nd :yyyyyyyy5vyyyyyyyyyy,1 st :e[FHCE]yyyfyyyyyyyyyyyyyyyee and 2 nd :yyyyyyfyffyyyyyyyyyy, next to 1 st :e[FHCE]yyyfyyyyyyyyyyyyyyyyy and 2 nd An oligomeric double chain according to any one of Embodiments 1-4, 12, 18, 19, 30-69, 72, 80, 105-115, 117-139, 152, 153, and 175-181, wherein the formula is selected from :eeyyyyfyfffyyyyyyyyy, where each "y" represents a 2'-OMe sugar moiety, each "e" represents a 2'-MOE sugar moiety, each "f" represents a 2'-fluoro sugar moiety, each "[FHNA]" represents a 3'-fluoro-hexitol sugar moiety, and each "d" represents a 2'-deoxy sugar moiety.

[0260] Embodiment 186. The first modified oligonucleotide is a first sugar motif (1 st ) has the second modified oligonucleotide, and the second sugar motif (2 nd )) and the first and second sugar motifs are in the following combination (from 5' to 3'): 1 st :efyyyyyyyyyyydatayyyyyyyee and 2 nd :eeyyyyyyyffyyyyyyyyy, 1 st : eiyyyyyyyyyyydatayyyyyyyyy and 2 nd :yyyyyyyyyfyyyyyyyyyy, 1 st :efyyyyyyyyyyydatayyyyyyyee and 2 nd :yyyyyyyyyfyyyyyyyyyy, 1 st : eiyyyyyyyyyyydatayyyyyyyyy and 2 nd :eeyyyyyyyffyyyyyyyyy, 1 st :efyyyyyyyyyyyyyyyyyyee and 2 nd:eeyyyyfyfffyyyyyyyyy, 1 st : emiyyyyyyyyyyyyyyyyyyyyy and 2 nd :yyyyyyyy5vyyyyyyyyyy,1 st :efyyyyyyyyyyyyyyyyyyee and 2 nd :yyyyyyyy5vyyyyyyyyyy,1 st : emiyyyyyyyyyyyyyyyyyyyyy and 2 nd :eeyyyyfyfffyyyyyyyyy, 1 st :efyyyyyyyyyyyyyyyyyyee and 2 nd :eeyyyyyyyffyyyyyyyyy, 1 st : emiyyyyyyyyyyyyyyyyyyyyy and 2 nd :yyyyyyyyyfyyyyyyyyyy, 1 st :efyyyyyyyyyyyyyyyyyyee and 2 nd :yyyyyyfyffyyyyyyyyyy, next to 1 st : emiyyyyyyyyyyyyyyyyyyyyy and 2 nd An oligomeric double chain according to any one of embodiments 1-4, 12, 18, 19, 30-69, 72, 80, 105-115, 117-139, 152, 153, and 175-181, wherein the formula is selected from :eeyyyyfyfffyyyyyyyyy, where each "y" represents a 2'-OMe sugar moiety, each "e" represents a 2'-MOE sugar moiety, and each "f" represents a 2'-fluoro sugar moiety.

[0261] Embodiment 187. An oligomeric double chain according to any one of Embodiments 123 to 186, wherein the nucleoside bonds between the first and second nucleosides counting from the 5' end of the first modified oligonucleotide, and between the second and third nucleosides, and the nucleoside bonds between the first and second nucleosides counting from the 3' end of the first modified oligonucleotide, and between the second and third nucleosides, are phosphorothioate nucleoside bonds, and all other nucleoside bonds of the first modified oligonucleotide are phosphodiester nucleoside bonds.

[0262] Embodiment 188. An oligomeric double chain according to any one of Embodiments 123 to 187, wherein the nucleoside bonds between the first and second nucleosides counting from the 5' end of the second modified oligonucleotide, and between the second and third nucleosides, and the nucleoside bonds between the first and second nucleosides counting from the 3' end of the second modified oligonucleotide, and between the second and third nucleosides, are phosphorothioate nucleoside bonds, and all other nucleoside bonds of the second modified oligonucleotide are phosphodiester nucleoside bonds.

[0263] Embodiment 189. An oligomeric double helix according to any one of Embodiments 123 to 188, wherein the nucleic acid base sequence of the first modified oligonucleotide includes or consists of any one of the nucleic acid base sequences of SEQ ID NOs: 967, 968, 971, 972, 974, 975, 1033-1038, 1254-1255, or 1258-1287.

[0264] Embodiment 190. The oligomeric double helix according to any one of Embodiments 1 to 189, wherein the cytosine nucleic acid base in the first and / or second modified oligonucleotide is optionally 5-methylcytosine.

[0265] Embodiment 191. The oligomer double chain according to any one of Embodiments 123 to 190, wherein the oligomer double chain comprises a conjugate group including a conjugate moiety and a conjugate linker.

[0266] Embodiment 192. The oligomeric double chain according to Embodiment 191, wherein the conjugate portion comprises an active drug substance, an aliphatic chain, a lipid, a peptide, a protein, a hydrocarbon, a polyamine, a polyamide, a polyether, a thioether, an aptamer, an antibody, an antibody fragment, a vitamin, a fatty acid, a carbohydrate, an intercalator, or a reporter molecule.

[0267] Embodiment 193. The oligomer double chain according to Embodiment 191, wherein the conjugate group comprises C22 alkyl, C20 alkyl, C17 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, or C5 alkyl, and the alkyl chain optionally has one or more unsaturated bonds.

[0268] Embodiment 194. The oligomeric double chain according to Embodiment 191, wherein the conjugate group comprises a 6-palmitamide hexyl moiety or a 2-(hydroxymethyl)-6-palmitamide hexyl moiety.

[0269] Embodiment 195. The oligomeric double chain according to Embodiment 191, wherein the oligomeric double chain includes a conjugate portion that binds to a type 1 transferrin receptor (TfR1).

[0270] Embodiment 196. The oligomeric double chain according to Embodiment 195, wherein the conjugate portion is selected from antibodies or fragments thereof, proteins or peptides, and aptamers that can bind to TfR1.

[0271] Embodiment 197. The oligomeric double chain according to Embodiment 196, wherein the conjugate portion is a cyclic protein or a cyclic peptide.

[0272] Embodiment 198. The oligomeric double chain according to Embodiment 195, wherein the conjugate group comprises a bicyclic ligand and a conjugate linker.

[0273] Embodiment 199. The oligomeric double chain according to Embodiment 198, wherein the bicyclic ligand comprises a peptide and molecular skeleton consisting of 13 to 22 linked amino acids or amino acid mimes, and each of the first, second, and third amino acids of the peptide contains a reactive group, each of which separately forms a bond with the molecular skeleton, thereby forming two peptide loops bonded to the molecular skeleton.

[0274] Embodiment 200. The oligomeric double chain according to Embodiment 199, wherein the bicyclic ligand comprises an amino acid sequence selected from any one of SEQ ID NOs: 1062 to 1253.

[0275] Embodiment 201. An oligomeric double chain according to any one of Embodiments 198 to 200, wherein the conjugate linker comprises a (bicyclo[6.1.0]nonine)-formyl (BCN) moiety.

[0276] Embodiment 202. The oligomeric double chain according to any one of Embodiments 198 to 200, wherein the conjugate linker comprises a 6-(BCN-carbamate)-2-(hydroxymethyl)hexylphosphoryl moiety or a 6-(BCN-carbamate)hexylphosphoryl moiety.

[0277] Embodiment 203. An oligomeric double chain according to any one of Embodiments 123 to 190, comprising a conjugate group consisting of a conjugate moiety and a conjugate linker, wherein the conjugate linker comprises a 6-(BCN-carbamate)-2-(hydroxymethyl)hexylphosphoryl moiety or a 6-(BCN-carbamate)hexylphosphoryl moiety.

[0278] Embodiment 204. An oligomeric double chain according to any one of Embodiments 123 to 190, comprising a bicyclic ligand containing a peptide having an amino acid sequence selected from any one of SEQ ID NOs. 1062 to 1253, wherein each cysteine ​​forms a covalent bond with the molecular skeleton 1,1',1''-(1,3,5-triazinane-1,3,5-triyl)tris(2-bromoetanone) (TATB), or the molecular skeleton is 1,1',1''-(1,3,5-triazinane-1,3,5-triyl)triplop-2-en-1-one (TATA).

[0279] Embodiment 205. Chemical notation below: vPT es U fs U yo A yo A yo G do A yo U yo G yo A yo G yo A yo C yo A fo G yo A fo A yo A yo U yo U yo G ys A es A e An oligomeric compound comprising an oligonucleotide modified by (SEQ ID NO: 1033), wherein, A = adenine nucleic acid base, C = cytosine nucleic acid base, G = guanine nucleic acid base, T=thymine nucleobase, U = uracil nucleic acid base, d = 2'-deoxy sugar portion, e=2'-MOE sugar moiety, f = 2'-fluorosugar portion, y=2'-OMe sugar moiety, o = phosphodiester nucleoside interbonding, s = phosphorothioate nucleoside bond, and An oligomeric compound with a vP=5' vinylphosphonate group.

[0280] Embodiment 206. Chemical notation below: m C es A es A yo U yo U yo U yo C yo U yo G yo U fo C fo U yo C yo A yo U yo C yo U yo U yo A ys A es A e An oligomeric compound comprising an oligonucleotide modified by (SEQ ID NO: 1027), wherein the formula, A = adenine nucleic acid base, m C=5-methylcytosine nucleic acid base, C = cytosine nucleic acid base, G = guanine nucleic acid base, U = uracil nucleic acid base, e=2'-MOE sugar moiety, f = 2'-fluorosugar portion, y=2'-OMe sugar moiety, o = phosphodiester nucleoside bond, and An oligomeric compound in which s = phosphorothioate nucleoside bond.

[0281] Embodiment 207. Chemical notation below: [X] n - m C es A es A yo U yo U yo U yo C yo U yo G yo U fo C fo U yo C yo A yo U yo Cyo U yo U yo A ys A es A e -[X] k An oligomeric compound comprising a conjugated modified oligonucleotide according to (SEQ ID NO: 1039), wherein the formula is: m C=5-methylcytosine nucleic acid base, C = cytosine nucleic acid base, A = adenine nucleic acid base, G = guanine nucleic acid base, U = uracil nucleic acid base, e=2'-MOE sugar moiety, f = 2'-fluorosugar portion, y=2'-OMe sugar moiety, o = phosphodiester nucleoside interbonding, s = phosphorothioate nucleoside interbonding, [X] = a conjugate group containing a bicyclic ligand, and An oligomeric compound in which n and k are either 0 or 1, where k=0 when n=1, and k=1 when n=0.

[0282] Embodiment 208. An oligomeric double chain comprising the oligomeric compound described in Embodiment 205 and the oligomeric compound described in Embodiment 206.

[0283] Embodiment 209. An oligomeric double chain comprising the oligomeric compound described in Embodiment 205 and the oligomeric compound described in Embodiment 207.

[0284] Embodiment 210. Chemical notation below: vP-T es U fs U yo A yo A do G yo A do U yo G yo A yo G yo A yo C yo A fo Gyo A fo A yo A yo U yo U yo G ys A es A e An oligomeric compound comprising an oligonucleotide modified by (SEQ ID NO: 1034), wherein, A = adenine nucleic acid base, C = cytosine nucleic acid base, G = guanine nucleic acid base, T=thymine nucleobase, U = uracil nucleic acid base, d = 2'-deoxy sugar portion, e=2'-MOE sugar moiety, f = 2'-fluorosugar portion, y=2'-OMe sugar moiety, o = phosphodiester nucleoside interbonding, s = phosphorothioate nucleoside bond, and An oligomeric compound with a vP=5' vinylphosphonate group.

[0285] Embodiment 211. Chemical notation below: C es A es A yo U yo U yo U yo C fo U yo G fo U yo C fo U yo C yo A yo U yo C yo U yo U yo A ys A es A e An oligomeric compound comprising an oligonucleotide modified by (SEQ ID NO: 1028), wherein the formula, A = adenine nucleic acid base, C = cytosine nucleic acid base, G = guanine nucleic acid base, U = uracil nucleic acid base, e=2'-MOE sugar moiety, f = 2'-fluorosugar portion, y=2'-Ome sugar moiety, o = phosphodiester nucleoside bond, and An oligomeric compound in which s = phosphorothioate nucleoside bond.

[0286] Embodiment 212. Chemical notation below: [X] n -C es A es A yo U yo U yo U yo C fo U yo G fo U yo C fo U yo C yo A yo U yo C yo U yo U yo A ys A es A e -[X] k An oligomeric compound comprising a conjugated modified oligonucleotide according to (SEQ ID NO: 1040), wherein, C = cytosine nucleic acid base, A = adenine nucleic acid base, G = guanine nucleic acid base, U = uracil nucleic acid base, e=2'-MOE sugar moiety, f = 2'-fluorosugar portion, y=2'-Ome sugar moiety, o = phosphodiester nucleoside interbonding, s = phosphorothioate nucleoside interbonding, [X] = a conjugate group containing a bicyclic ligand, and An oligomeric compound in which n and k are either 0 or 1, where k=0 when n=1, and k=1 when n=0.

[0287] Embodiment 213. An oligomeric double chain comprising the oligomeric compound described in Embodiment 210 and the oligomeric compound described in Embodiment 211.

[0288] Embodiment 214. An oligomeric double chain comprising the oligomeric compound described in Embodiment 210 and the oligomeric compound described in Embodiment 212.

[0289] Embodiment 215. Chemical notation below: vPT es A fs U yo A yo A yo A do U yo A yo G yo A yo U yo U yo C yo U fo G yo U fo A yo G yo C yo U yo U ys A es A e An oligomeric compound comprising an oligonucleotide modified by (SEQ ID NO: 1035), wherein, A = adenine nucleic acid base, C = cytosine nucleic acid base, G = guanine nucleic acid base, T=thymine nucleobase, U = uracil nucleic acid base, d = 2'-deoxy sugar portion, e=2'-MOE sugar moiety, f = 2'-fluorosugar portion, y=2'-OMe sugar moiety, o = phosphodiester nucleoside interbonding, s = phosphorothioate nucleoside bond, and An oligomeric compound with a vP=5' vinylphosphonate group.

[0290] Embodiment 216. Chemical notation below: A es A esG yo C yo U yo A yo C yo A yo G yo A fo A fo U yo C yo U yo A yo U yo U yo U yo A ys T es A e An oligomeric compound comprising an oligonucleotide modified by (SEQ ID NO: 1029), wherein the formula, A = adenine nucleic acid base, C = cytosine nucleic acid base, G = guanine nucleic acid base, T=thymine nucleobase, U = uracil nucleic acid base, e=2'-MOE sugar moiety, f = 2'-fluorosugar portion, y=2'-OMe sugar moiety, o = phosphodiester nucleoside bond, and An oligomeric compound in which s = phosphorothioate nucleoside bond.

[0291] Embodiment 217. Chemical notation below: [X] n -A es A es G yo C yo U yo A yo C yo A yo G yo A fo A fo U yo C yo U yo A yo U yo U yo U yo A ys T es A e -[X] kAn oligomeric compound comprising a conjugated modified oligonucleotide according to (SEQ ID NO: 1041), wherein the formula, C = cytosine nucleic acid base, A = adenine nucleic acid base, G = guanine nucleic acid base, T=thymine nucleobase, U = uracil nucleic acid base, e=2'-MOE sugar moiety, f = 2'-fluorosugar portion, y=2'-OMe sugar moiety, o = phosphodiester nucleoside interbonding, s = phosphorothioate nucleoside interbonding, [X] = a conjugate group containing a bicyclic ligand, and An oligomeric compound in which n and k are either 0 or 1, where k=0 when n=1, and k=1 when n=0.

[0292] Embodiment 218. An oligomeric double chain comprising the oligomeric compound described in Embodiment 215 and the oligomeric compound described in Embodiment 216.

[0293] Embodiment 219. An oligomer compound comprising the oligomer compound described in Embodiment 215 and the oligomer compound described in Embodiment 217.

[0294] Embodiment 220. Chemical notation below: vPT es A fs U yo A yo A do A yo T do A yo G yo A yo U yo U yo C yo U fo G yo U fo A yo G yo C yo U yo U ys A es A eAn oligomeric compound comprising an oligonucleotide modified by (SEQ ID NO: 1036), wherein, A = adenine nucleic acid base, C = cytosine nucleic acid base, G = guanine nucleic acid base, T=thymine nucleobase, U = uracil nucleic acid base, d = 2'-deoxy sugar portion, e=2'-MOE sugar moiety, f = 2'-fluorosugar portion, y=2'-OMe sugar moiety, o = phosphodiester nucleoside interbonding, s = phosphorothioate nucleoside bond, and An oligomeric compound with a vP=5' vinylphosphonate group.

[0295] Embodiment 221. Chemical notation below: A es A es G yo C yo U yo A yo C fo A yo G fo A yo A fo U yo C yo U yo A yo U yo U yo U yo A ys U es A e An oligomeric compound comprising an oligonucleotide modified by (SEQ ID NO: 1030), wherein the formula, A = adenine nucleic acid base, C = cytosine nucleic acid base, G = guanine nucleic acid base, U = uracil nucleic acid base, e=2'-MOE sugar moiety, f = 2'-fluorosugar portion, y=2'-OMe sugar moiety, o = phosphodiester nucleoside bond, and An oligomeric compound in which s = phosphorothioate nucleoside bond.

[0296] Embodiment 222. Chemical notation below: [X] n -A es A es G yo C yo U yo A yo C fo A yo G fo A yo A fo U yo C yo U yo A yo U yo U yo U yo A ys U es A e -[X] k An oligomeric compound comprising a conjugated modified oligonucleotide according to (SEQ ID NO: 1042), wherein, C = cytosine nucleic acid base, A = adenine nucleic acid base, G = guanine nucleic acid base, U = uracil nucleic acid base, e=2'-MOE sugar moiety, f = 2'-fluorosugar portion, y=2'-OMe sugar moiety, o = phosphodiester nucleoside interbonding, s = phosphorothioate nucleoside interbonding, [X] = a conjugate group containing a bicyclic ligand, and An oligomeric compound in which n and k are either 0 or 1, where k=0 when n=1, and k=1 when n=0.

[0297] Embodiment 223. An oligomeric double chain comprising the oligomeric compound described in Embodiment 220 and the oligomeric compound described in Embodiment 221.

[0298] Embodiment 224. An oligomeric double chain comprising the oligomeric compound described in Embodiment 220 and the oligomeric compound described in Embodiment 222.

[0299] Embodiment 225. Chemical notation below: vPT es U fs A yo A yo G yo T do U yo U yo U yo A yo G yo U yo C yo U fo U yo A fo A yo U yo C yo U yo U ys A es A e An oligomeric compound comprising an oligonucleotide modified by (SEQ ID NO: 1037), wherein the formula, A = adenine nucleic acid base, C = cytosine nucleic acid base, G = guanine nucleic acid base, T=thymine nucleobase, U = uracil nucleic acid base, d = 2'-deoxy sugar portion, e=2'-MOE sugar moiety, f = 2'-fluorosugar portion, y=2'-OMe sugar moiety, o = phosphodiester nucleoside interbonding, s = phosphorothioate nucleoside bond, and An oligomeric compound with a vP=5' vinylphosphonate group.

[0300] Embodiment 226. Chemical notation below: A es A es G yo A yo U yo U yo A yo A yo G yo Afo C fo U yo A yo A yo A yo A yo C yo U yo U ys A es A e An oligomeric compound comprising an oligonucleotide modified by (SEQ ID NO: 1031), wherein the formula, A = adenine nucleic acid base, C = cytosine nucleic acid base, G = guanine nucleic acid base, U = uracil nucleic acid base, e=2'-MOE sugar moiety, f = 2'-fluorosugar portion, y=2'-OMe sugar moiety, o = phosphodiester nucleoside bond, and An oligomeric compound in which s = phosphorothioate nucleoside bond.

[0301] Embodiment 227. Chemical notation below: [X] n -A es A es G yo A yo U yo U yo A yo A yo G yo A fo C fo U yo A yo A yo A yo A yo C yo U yo U ys A es A e -[X] k An oligomeric compound comprising a conjugated modified oligonucleotide according to (SEQ ID NO: 1043), wherein, C = cytosine nucleic acid base, A = adenine nucleic acid base, G = guanine nucleic acid base, U = uracil nucleic acid base, e=2'-MOE sugar moiety, f = 2'-fluorosugar portion, y=2'-OMe sugar moiety, o = phosphodiester nucleoside interbonding, s = phosphorothioate nucleoside interbonding, [X] = a conjugate group containing a bicyclic ligand, and An oligomeric compound in which n and k are either 0 or 1, where k=0 when n=1, and k=1 when n=0.

[0302] Embodiment 228. An oligomeric double hemisphere comprising the modified oligonucleotide described in Embodiment 225 and the modified oligonucleotide described in Embodiment 226.

[0303] Embodiment 229. An oligomeric double helix comprising the modified oligonucleotide described in Embodiment 225 and the conjugate described in Embodiment 227.

[0304] Embodiment 230. Chemical notation below: vPT es U fs A yo A yo G do U yo T do U yo U yo A yo G yo U yo C yo U fo U yo A fo A yo U yo C yo U yo U ys A es A e An oligomeric compound comprising an oligonucleotide modified by (SEQ ID NO: 1038), wherein the formula, A = adenine nucleic acid base, C = cytosine nucleic acid base, G = guanine nucleic acid base, T=thymine nucleobase, U = uracil nucleic acid base, d = 2'-deoxy sugar portion, e=2'-MOE sugar moiety, f = 2'-fluorosugar portion, y=2'-OMe sugar moiety, o = phosphodiester nucleoside interbonding, s = phosphorothioate nucleoside bond, and An oligomeric compound with a vP=5' vinylphosphonate group.

[0305] Embodiment 231. Chemical notation below: A es A es G yo A yo U yo U yo A fo A yo G fo A yo C fo U yo A yo A yo A yo A yo C yo U yo U ys A es A e An oligomeric compound comprising an oligonucleotide modified by (SEQ ID NO: 1032), wherein the formula, A = adenine nucleic acid base, C = cytosine nucleic acid base, G = guanine nucleic acid base, U = uracil nucleic acid base, e=2'-MOE sugar moiety, f = 2'-fluorosugar portion, y=2'-OMe sugar moiety, o = phosphodiester nucleoside bond, and An oligomeric compound in which s = phosphorothioate nucleoside bond.

[0306] Embodiment 232. Chemical notation below: [X] n -A es A es G yo A yo Uyo U yo A fo A yo G fo A yo C fo U yo A yo A yo A yo A yo C yo U yo U ys A es A e -[X] k An oligomeric compound comprising a conjugated modified oligonucleotide according to (SEQ ID NO: 1044), wherein, C = cytosine nucleic acid base, A = adenine nucleic acid base, G = guanine nucleic acid base, U = uracil nucleic acid base, e=2'-MOE sugar moiety, f = 2'-fluorosugar portion, y=2'-OMe sugar moiety, o = phosphodiester nucleoside interbonding, s = phosphorothioate nucleoside interbonding, [X] = a conjugate group containing a bicyclic ligand, and An oligomeric compound in which n and k are either 0 or 1, where k=0 when n=1, and k=1 when n=0.

[0307] Embodiment 233. An oligomeric double chain comprising the oligomeric compound described in Embodiment 230 and the oligomeric compound described in Embodiment 231.

[0308] Embodiment 234. An oligomeric double chain comprising the oligomeric compound described in Embodiment 230 and the oligomeric compound described in Embodiment 232.

[0309] Embodiment 235. Chemical notation below: vPT es A fs U yo A yo A yo A yo Uyo A yo G yo A yo U yo U yo C yo U fo G yo U fo A yo G yo C yo U yo U ys A es A e An oligomeric compound comprising an oligonucleotide modified by (SEQ ID NO: 1255), wherein, A = adenine nucleic acid base, C = cytosine nucleic acid base, G = guanine nucleic acid base, T=thymine nucleobase, U = uracil nucleic acid base, e=2'-MOE sugar moiety, f = 2'-fluorosugar portion, y=2'-OMe sugar moiety, o = phosphodiester nucleoside interbonding, s = phosphorothioate nucleoside bond, and An oligomeric compound with a vP=5' vinylphosphonate group.

[0310] Embodiment 236. Chemical notation below: A es A es G yo C yo U yo A yo C yo A yo G yo A fo A fo U yo C yo U yo A yo U yo U yo U yo A ys T es A e An oligomeric compound comprising an oligonucleotide modified by (SEQ ID NO: 1029), wherein the formula, A = adenine nucleic acid base, C = cytosine nucleic acid base, G = guanine nucleic acid base, U = uracil nucleic acid base, T=thymine nucleobase, e=2'-MOE sugar moiety, f = 2'-fluorosugar portion, y=2'-OMe sugar moiety, o = phosphodiester nucleoside bond, and An oligomeric compound in which s = phosphorothioate nucleoside bond.

[0311] Embodiment 237. Chemical notation below: [X] n -A es A es G yo C yo U yo A yo C yo A yo G yo A fo A fo U yo C yo U yo A yo U yo U yo U yo A ys T es A e -[X] k An oligomeric compound comprising a conjugated modified oligonucleotide according to (SEQ ID NO: 1041), wherein the formula, C = cytosine nucleic acid base, A = adenine nucleic acid base, G = guanine nucleic acid base, U = uracil nucleic acid base, T=thymine nucleobase, e=2'-MOE sugar moiety, f = 2'-fluorosugar portion, y=2'-OMe sugar moiety, o = phosphodiester nucleoside interbonding, s = phosphorothioate nucleoside interbonding, [X] = a conjugate group containing a bicyclic ligand, and An oligomeric compound in which n and k are either 0 or 1, where k=0 when n=1, and k=1 when n=0.

[0312] Embodiment 238. An oligomeric double chain comprising the oligomeric compound described in Embodiment 235 and the oligomeric compound described in Embodiment 236.

[0313] Embodiment 239. An oligomeric double chain comprising the oligomeric compound described in Embodiment 235 and the oligomeric compound described in Embodiment 237.

[0314] Embodiment 240. Structure below:

[0315] [ka] An oligomeric double helix according to any one of Embodiments 123 to 190, 209, 214, 219, 224, 229, 234, 239, or an oligomeric compound according to any one of Embodiments 207, 212, 217, 222, 227, 232, or 237, comprising a bicyclic ligand or conjugate group having a salt thereof (wherein Q is N3 (BCY17901, SEQ ID NO: 1045), NH2 (BCY21757, SEQ ID NO: 1202), SH (BCY21758, SEQ ID NO: 1203), or a conjugate linker, or a conjugate linker covalently bonded to an oligonucleotide).

[0316] Embodiment 241. The oligomeric double chain or oligomeric compound according to Embodiment 240, wherein Q is N3 or a conjugate linker.

[0317] Embodiment 242. The following structure:

[0318] [ka] An oligomeric double chain according to any one of embodiments 123 to 190, 209, 214, 219, 224, 229, 234, 239, or an oligomeric double chain according to any one of embodiments 207, 212, 217, 222, 227, 232, or 237, comprising a conjugate group having .

[0319] Embodiment 243. The following structure:

[0320] [ka] An oligomeric double chain according to any one of embodiments 123 to 190, 209, 214, 219, 224, 229, 234, 239, or an oligomeric double chain according to any one of embodiments 207, 212, 217, 222, 227, 232, or 237, comprising a conjugate group having .

[0321] Embodiment 244. An oligomeric double-chain or oligomeric compound according to any one of Embodiments 191 to 243, wherein the conjugate group is bonded to the second modified oligonucleotide.

[0322] Embodiment 245. An oligomeric double chain or compound according to any one of Embodiments 191 to 243, wherein the conjugate group is bonded to the 5' or 3' end of the second modified oligonucleotide.

[0323] Embodiment 246. The oligomeric double-chain or oligomeric compound according to any one of Embodiments 191 to 243, wherein the conjugate group is bonded to the 5' terminal nucleoside of the second modified oligonucleotide.

[0324] Embodiment 247. The following chemical structure:

[0325] [ka]

[0326] [ka]

[0327] [ka] Oligomer double chains, such as those specified by (SEQ ID NO: 1033 and SEQ ID NO: 1027) or their salts.

[0328] Embodiment 248. The oligomeric double chain according to Embodiment 247, wherein the double chain is a sodium salt or a potassium salt.

[0329] Embodiment 249. The following chemical structure:

[0330] [ka]

[0331] [ka]

[0332] [ka] Oligomer double helix (according to Sequence ID No. 1033 and Sequence ID No. 1027).

[0333] Embodiment 250. The following chemical structure:

[0334] [ka]

[0335] [ka]

[0336] [ka] Oligomer double chains, such as those formed by (SEQ ID NOs. 1033 and 1039) or their salts.

[0337] Embodiment 251. The oligomeric double chain according to Embodiment 250, wherein the double chain is a sodium salt or a potassium salt.

[0338] Embodiment 252. The following chemical structure:

[0339] [ka]

[0340] [ka]

[0341] [ka] Oligomer double helix (according to Sequence ID No. 1033 and Sequence ID No. 1039).

[0342] Embodiment 253. The following chemical structure:

[0343] [ka]

[0344] [ka]

[0345] [ka] Oligomer double helixes, such as those specified by (SEQ ID NO: 1034 and SEQ ID NO: 1028) or their salts.

[0346] Embodiment 254. The oligomeric double chain according to Embodiment 253, wherein the double chain is a sodium salt or a potassium salt.

[0347] Embodiment 255. The following chemical structure:

[0348] [ka]

[0349] [ka]

[0350] [ka] Oligomer double helix (according to Sequence ID No. 1034 and Sequence ID No. 1028).

[0351] Embodiment 256. The following chemical structure:

[0352] [ka]

[0353] [ka]

[0354] [ka] Oligomeric double chains, based on (SEQ ID NOs. 1034 and 1040) or their salts.

[0355] Embodiment 257. The oligomeric double chain according to Embodiment 256, wherein the double chain is a sodium salt or a potassium salt.

[0356] Embodiment 258. The following chemical structure:

[0357] [ka]

[0358] [ka]

[0359] [ka] Oligomer double helix (according to Sequence ID No. 1034 and Sequence ID No. 1040).

[0360] Embodiment 259. The following chemical structure:

[0361] [ka]

[0362] [ka]

[0363] [ka] Oligomer double chains, such as those specified by (SEQ ID NO: 1035 and SEQ ID NO: 1029) or their salts.

[0364] Embodiment 260. The oligomeric double chain according to Embodiment 259, wherein the double chain is a sodium salt or a potassium salt.

[0365] Embodiment 261. The following chemical structure:

[0366] [ka]

[0367] [ka]

[0368] [ka] Oligomer double helix (according to Sequence ID No. 1035 and Sequence ID No. 1029).

[0369] Embodiment 262. The following chemical structure:

[0370] [ka]

[0371] [ka]

[0372] [ka] Oligomer double chains, such as those specified by (SEQ ID NO: 1035 and SEQ ID NO: 1041) or their salts.

[0373] Embodiment 263. The oligomeric double chain according to Embodiment 262, wherein the double chain is a sodium salt or a potassium salt.

[0374] Embodiment 264. The following chemical structure:

[0375] [ka]

[0376] [ka]

[0377] [ka] Oligomer double helix (according to Sequence ID No. 1035 and Sequence ID No. 1041).

[0378] Embodiment 265. The following chemical structure:

[0379] [ka]

[0380] [ka]

[0381] [ka] Oligomeric double chains, based on (SEQ ID NOs. 1036 and 1030) or their salts.

[0382] Embodiment 266. The oligomeric double chain according to Embodiment 265, wherein the double chain is a sodium salt or a potassium salt.

[0383] Embodiment 267. The following chemical structure:

[0384] [ka]

[0385] [ka]

[0386] [ka] Oligomer double helix (according to Sequence ID No. 1036 and Sequence ID No. 1030).

[0387] Embodiment 268. The following chemical structure:

[0388] [ka]

[0389] [ka]

[0390] [ka] Oligomer double chains, such as those in SEQ ID NOs. 1036 and 1042, or their salts.

[0391] Embodiment 269. The oligomeric double chain according to Embodiment 268, wherein the double chain is a sodium salt or a potassium salt.

[0392] Embodiment 270. The following chemical structure:

[0393] [ka]

[0394] [ka]

[0395] [ka] Oligomer double helix (according to Sequence ID No. 1036 and Sequence ID No. 1042).

[0396] Embodiment 271. The following chemical structure:

[0397] [ka]

[0398] [ka]

[0399] [ka] Oligomer double chains, such as those formed by (SEQ ID NO: 1037 and SEQ ID NO: 1031) or their salts.

[0400] Embodiment 272. The oligomeric double chain according to Embodiment 271, wherein the double chain is a sodium salt or a potassium salt.

[0401] Embodiment 273. The following chemical structure:

[0402] [ka]

[0403] [ka]

[0404] [ka] Oligomer double helix (according to Sequence ID No. 1037 and Sequence ID No. 1031).

[0405] Embodiment 274. The following chemical structure:

[0406] [ka]

[0407] [ka]

[0408] [ka] Oligomer double chains, such as those specified in SEQ ID NOs. 1037 and 1043, or their salts.

[0409] Embodiment 275. The oligomeric double chain according to Embodiment 274, wherein the double chain is a sodium salt or a potassium salt.

[0410] Embodiment 276. The following chemical structure:

[0411] [ka]

[0412] [ka]

[0413] [ka] Oligomer double helix (according to Sequence ID No. 1037 and Sequence ID No. 1043).

[0414] Embodiment 277. The following chemical structure:

[0415] [ka]

[0416] [ka]

[0417] [ka] Oligomer double chains, such as those formed by (SEQ ID NOs. 1038 and 1032) or their salts.

[0418] Embodiment 278. The oligomeric double chain according to Embodiment 277, wherein the double chain is a sodium salt or a potassium salt.

[0419] Embodiment 279. The following chemical structure:

[0420] [ka]

[0421] [ka]

[0422] [ka] Oligomer double helix (according to Sequence ID No. 1038 and Sequence ID No. 1032).

[0423] Embodiment 280. The following chemical structure:

[0424] [ka]

[0425] [ka]

[0426] [ka] Oligomer double chains, such as those specified by (SEQ ID NO: 1038 and SEQ ID NO: 1044) or their salts.

[0427] Embodiment 281. The oligomeric double chain according to Embodiment 280, wherein the double chain is a sodium salt or a potassium salt.

[0428] Embodiment 282. The following chemical structure:

[0429] [ka]

[0430] [ka]

[0431] [ka] Oligomer double helix (according to Sequence ID No. 1038 and Sequence ID No. 1044).

[0432] Embodiment 283. The following chemical structure:

[0433] [ka]

[0434] [ka]

[0435] [ka] Oligomer double chains, such as those specified by (SEQ ID NO: 1255 and SEQ ID NO: 1029) or their salts.

[0436] Embodiment 284. The oligomeric double chain according to Embodiment 283, wherein the double chain is a sodium salt or a potassium salt.

[0437] Embodiment 285. The following chemical structure:

[0438] [ka]

[0439] [ka]

[0440] [ka] Oligomer double helix (according to Sequence ID No. 1255 and Sequence ID No. 1029).

[0441] Embodiment 286. The following chemical structure:

[0442] [ka]

[0443] [ka]

[0444] [ka] Oligomer double chains, such as those formed by (SEQ ID NO: 1255 and SEQ ID NO: 1041) or their salts.

[0445] Embodiment 287. The oligomeric double chain according to Embodiment 286, wherein the double chain is a sodium salt or a potassium salt.

[0446] Embodiment 288. The following chemical structure:

[0447] [ka]

[0448] [ka]

[0449] [ka] Oligomer double helix (according to Sequence ID No. 1255 and Sequence ID No. 1041).

[0450] Embodiment 289. A group of oligomeric double chains or oligomeric compounds according to any one of Embodiments 1 to 288, wherein the group is concentrated with respect to a first and / or second modified oligonucleotide having at least one specific phosphorothioate nucleoside bond having a specific stereochemical configuration.

[0451] Embodiment 290. The population according to Embodiment 289, wherein the population is enriched with respect to a first and / or second modified oligonucleotide comprising at least one specific phosphorothioate nucleoside linkage having a (Sp) or (Rp) configuration.

[0452] Embodiment 291. An oligomeric double-chain or oligomeric compound according to any one of Embodiments 1 to 288, wherein the first modified oligonucleotide consists of 23 linked nucleosides, and the second modified oligonucleotide consists of 21 linked nucleosides.

[0453] Embodiment 292. An antisense compound comprising or consisting of an oligomeric double chain or oligomeric compound described in any one of Embodiments 1 to 288.

[0454] Embodiment 293. The antisense compound according to Embodiment 292, wherein the antisense compound is an RNAi agent capable of reducing the amount of PLN nucleic acid through the activation of RISC / Ago2.

[0455] Embodiment 294. A pharmaceutical composition comprising an oligomeric double-chain or oligomeric compound according to any one of Embodiments 1 to 288 or 291, a group according to any one of Embodiments 289 to 290, or an antisense compound according to Embodiment 292 or 293, and a pharmaceutically acceptable diluent or carrier.

[0456] Embodiment 295. The pharmaceutical composition according to Embodiment 294, wherein the pharmaceutically acceptable diluent is water or phosphate-buffered saline.

[0457] Embodiment 296. The pharmaceutical composition according to Embodiment 295, wherein the pharmaceutical composition essentially consists of an oligomeric double chain, an oligomeric compound, or an antisense compound, and water or phosphate-buffered saline.

[0458] Embodiment 297. A method for reducing the amount of PLN RNA and / or PLN protein in cells, tissues, organs, or subjects, comprising contacting the cells, tissues, organs, or subjects with an oligomeric double-strand or oligomeric compound described in any one of Embodiments 1 to 288 or 291, a population described in any one of Embodiments 289 to 290, an antisense compound described in Embodiment 292 or 293, or a pharmaceutical composition described in any one of Embodiments 294 to 296.

[0459] Embodiment 298. The method according to Embodiment 297, wherein the cells are muscle cells and / or cardiac cells.

[0460] Embodiment 299. A method comprising administering to a subject an oligomeric double-chain or oligomeric compound according to any one of Embodiments 1 to 288 or 291, a population according to any one of Embodiments 289 to 290, an antisense compound according to Embodiment 292 or 293, or a pharmaceutical composition according to any one of Embodiments 294 to 296, wherein the subject has or is at risk of developing a cardiovascular or cardiac injury, disease, condition or disorder, cardiomyopathy, cardiac arrhythmia, and / or heart failure.

[0461] Embodiment 300. A method for preventing or treating a disease, disorder, condition, or injury related to cardiac calcium misregulation, or a method for delaying the symptoms of a disease, disorder, or condition related to an injured, weakened, and / or overworked heart, comprising administering to a subject having or at risk of having a disease, disorder, or condition related to cardiac calcium misregulation a therapeutically effective amount of an oligomeric double-chain or oligomeric compound according to any one of Embodiments 1 to 288 or 291, a population according to any one of Embodiments 289 to 290, an antisense compound according to Embodiment 292 or 293, or a pharmaceutical composition according to any one of Embodiments 294 to 296, wherein the disease, disorder, condition, or injury is selected from cardiac or cardiovascular diseases, disorders, conditions, or injuries, cardiomyopathy, cardiac arrhythmias, and / or heart failure.

[0462] Embodiment 301. A method for preventing or treating a heart or cardiovascular disease, disorder, condition, or injury related to heart failure, or a method for delaying the symptoms of heart failure, comprising administering to a subject who has or is at risk of having a heart or cardiovascular disease, disorder, condition, or injury, an effective amount of an oligomeric double-chain or oligomeric compound according to any one of Embodiments 1 to 288 or 291, a population according to any one of Embodiments 289 to 290, an antisense compound according to Embodiment 292 or 293, or a pharmaceutical composition according to any one of Embodiments 294 to 296, wherein the disease, disorder, condition, or injury is cardiomyopathy, cardiac arrhythmia, and / or heart failure.

[0463] Embodiment 302. A method for reducing the amount of PLN RNA and / or PLN protein in the heart of a subject having or at risk of developing a disease, disorder, or condition related to an injured, weakened, and / or overworked heart, comprising administering to a subject having or at risk of developing a disease, disorder, or condition related to an injured, weakened, and / or overworked heart, a therapeutically effective amount of an oligomeric double-strand or oligomeric compound according to any one of Embodiments 1 to 288 or 291, a population according to any one of Embodiments 289 to 290, an antisense compound according to Embodiment 292 or 293, or a pharmaceutical composition according to any one of Embodiments 294 to 296, wherein the disease, disorder, condition, or injury is cardiomyopathy, cardiac arrhythmia, and / or heart failure.

[0464] Embodiment 303. The method according to any one of Embodiments 297 to 302, wherein the amount of PLN RNA and / or PLN protein in the target myocardium is reduced.

[0465] Embodiment 304. The method according to any one of Embodiments 297 to 302, wherein the disease, disorder, or condition is cardiomyopathy or arrhythmia.

[0466] Embodiment 305. The method according to Embodiment 304, wherein the cardiomyopathy is a hereditary cardiomyopathy.

[0467] Embodiment 306. The method according to Embodiment 305, wherein the hereditary cardiomyopathy is associated with a PLN p.Arg14del, Arg9Cys(R9C), or Arg25Cys(R25C) gene mutation.

[0468] Embodiment 307. The method according to Embodiment 304, wherein the cardiomyopathy is dilated cardiomyopathy (DCM).

[0469] Embodiment 308. The method according to Embodiment 307, wherein the DCM is a hereditary DCM.

[0470] Embodiment 309. The method according to Embodiment 308, wherein the hereditary DCM is associated with a TTN, LMNA, RBM20, SCN5A, MYH7, TNNT2, or TPM1 mutation.

[0471] Embodiment 310. The method according to Embodiment 307, wherein the DCM is an arrhythmogenic DCM.

[0472] Embodiment 311. The method according to any one of Embodiments 299 to 303, wherein the heart failure is heart failure with maintained ejection fraction (HFpEF), heart failure with reduced ejection fraction (HFrEF), acute heart failure, or exacerbation of chronic heart failure.

[0473] Embodiment 312. The method according to Embodiment 304, wherein the arrhythmia is ventricular tachycardia (VTAC) or ventricular fibrillation (VFIB).

[0474] Embodiment 313. The method according to Embodiment 300 or 301, wherein the symptoms of a disease, disorder, or condition associated with an injured, weakened, and / or overworked heart, or heart failure, are reduced myocardial contractility and / or impaired cardiac relaxation.

[0475] Embodiment 314. The method according to any one of Embodiments 299 to 313, wherein the method prevents or delays the effects of an injured, weakened, and / or overworked heart and / or the progression of heart failure.

[0476] Embodiment 315. The method according to any one of Embodiments 299 to 313, wherein administration of an oligomeric double-chain or oligomeric compound according to any one of Embodiments 1 to 288 or 291, a population according to any one of Embodiments 289 to 290, an antisense compound according to Embodiment 292 or 293, or a pharmaceutical composition according to any one of Embodiments 294 to 296 improves cardiac function, cardiovascular death, cardiomegaly, cardiac 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 flow profile, left ventricular (LV) strain, left ventricular (LV) strain rate, infarct size, hospitalization due to heart failure, 6-minute walk test (6MWT), Kansas City Cardiomyopathy Questionnaire score (KCCQS), heart rate, or rhythm in a subject.

[0477] Embodiment 316. The method according to any one of Embodiments 297 to 315, wherein the oligomeric double chain or oligomeric compound according to any one of Embodiments 1 to 288 or 291, the group according to any one of Embodiments 289 to 290, the antisense compound according to Embodiment 292 or 293, or the pharmaceutical composition according to any one of Embodiments 294 to 296 comprises a conjugate moiety having affinity for a transferrin receptor.

[0478] Embodiment 317. The method according to any one of Embodiments 297 to 315, wherein the oligomeric double chain or oligomeric compound described in any one of Embodiments 1 to 288 or 291, the group described in any one of Embodiments 289 to 290, the antisense compound described in Embodiment 292 or 293, or the pharmaceutical composition described in any one of Embodiments 294 to 296 comprises a bicyclic ligand having affinity for a transferrin receptor.

[0479] Embodiment 318. An oligomeric double-chain or oligomeric compound according to any one of Embodiments 1 to 288 or 291, a group according to any one of Embodiments 289 to 290, or an antisense compound according to Embodiment 292 or 293, or a pharmaceutical composition according to any one of Embodiments 294 to 296, for use in treating or preventing diseases, disorders, or conditions associated with an injured, weakened, and / or overworked heart, or heart failure.

[0480] Embodiment 319. Use of an oligomeric double-chain or oligomeric compound according to any one of Embodiments 1 to 288 or 291, a group according to any one of Embodiments 289 to 290, an antisense compound according to Embodiment 292 or 293, or a pharmaceutical composition according to any one of Embodiments 294 to 296 for the treatment or prevention of a disease, disorder, or condition associated with an injured, weakened, and / or overworked heart or heart failure.

[0481] Embodiment 320. Use of an oligomeric double-chain or oligomeric compound according to any one of Embodiments 1 to 288 or 291, a group according to any one of Embodiments 289 to 290, an antisense compound according to Embodiment 292 or 293, or a pharmaceutical composition according to any one of Embodiments 294 to 296 in the manufacture of a pharmaceutical for the treatment or prevention of a disease, disorder, or condition associated with an injured, weakened, and / or overworked heart or heart failure.

[0482] Embodiment 321. Use according to any one of Embodiments 318 to 320, wherein the disease, disorder, or condition relating to or relating to a damaged, weakened, and / or overworked heart is cardiomyopathy, cardiac arrhythmia, and / or heart failure.

[0483] Embodiment 322. The use described in Embodiment 321, wherein the cardiomyopathy is a hereditary cardiomyopathy.

[0484] Embodiment 323. The use described in Embodiment 322, wherein the hereditary cardiomyopathy is associated with a PLN p.Arg14del, Arg9Cys(R9C), or Arg25Cys(R25C) gene mutation.

[0485] Embodiment 324. The use according to Embodiment 321, wherein the cardiomyopathy is dilated cardiomyopathy (DCM).

[0486] Embodiment 325. The use described in Embodiment 324, wherein the DCM is a hereditary DCM.

[0487] Embodiment 326. The use according to Embodiment 325, wherein the hereditary DCM is associated with a TTN, LMNA, RBM20, SCN5A, MYH7, TNNT2, or TPM1 mutation.

[0488] Embodiment 327. The use according to Embodiment 324, wherein the DCM is an arrhythmogenic DCM.

[0489] Embodiment 328. The use according to Embodiment 321, wherein the heart failure is heart failure with maintained ejection fraction (HFpEF), heart failure with reduced ejection fraction (HFrEF), acute heart failure, or exacerbation of chronic heart failure.

[0490] Embodiment 329. The use according to Embodiment 321, wherein the arrhythmia is ventricular tachycardia (VTAC) or ventricular fibrillation (VFIB).

[0491] Embodiment A1. An oligomeric double chain comprising a first oligomeric compound and a second oligomeric compound, (1) The first oligomer compound comprises a modified oligonucleotide consisting of 8 to 50 linked nucleosides, wherein the nucleic acid base 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 nucleic acid bases from any of the nucleic acid base sequences of SEQ ID NOs. 3 to 314, 627 to 782, 939 to 976, 1033 to 1038, and 1254 to 1255, wherein each of the nucleosides of the first modified oligonucleotide comprises a modified sugar moiety or sugar surrogate, and at least one modified nucleoside of the first modified oligonucleotide and less than 40% of the nucleosides contain fluorine. (2) An oligomeric double helix, wherein the second oligomeric compound comprises a modified oligonucleotide consisting of 8 to 50 consecutively linked nucleosides, the nucleic acid base 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 nucleic acid bases from any of the nucleic acid base sequences of SEQ ID NOs. 315 to 626, 783 to 938, 977 to 1016, and 1027 to 1032, each of the nucleosides of the second modified oligonucleotide comprises a modified sugar moiety or sugar surrogate, and less than 40% of the nucleosides of the second modified oligonucleotide contain fluorine.

[0492] Embodiment A2. The oligomeric double helix according to Embodiment A1, wherein the first modified oligonucleotide is at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% complementary to the isolength portion of the PLN nucleic acid, and the PLN nucleic acid has the nucleic acid base sequence of SEQ ID NO: 1 or SEQ ID NO: 2.

[0493] Embodiment A3. An oligomeric double chain according to Embodiment A1 or A2, wherein each of the nucleosides of the first modified oligonucleotide independently comprises a modified sugar moiety or sugar surrogate independently selected from 2'-F, 2'-MOE, 2'-OMe, 2'-deoxyribosyl, and FHNA, and the second modified oligonucleotide independently comprises a modified sugar moiety or sugar surrogate independently selected from 2'-F, 2'-MOE, 2'-OMe, 2'-deoxyribosyl, and FHNA.

[0494] Embodiment A4. An oligomeric double chain according to any one of Embodiments A1 to A3, wherein less than 35%, less than 30%, less than 25%, less than 20%, less than 15%, less than 14%, less than 13%, less than 12%, less than 10%, less than 5%, or less than 1% of the nucleoside in the first modified oligonucleotide contains fluorine.

[0495] Embodiment A5. An oligomer double chain according to any one of Embodiments A1 to A4, wherein one or fewer nucleosides, two or fewer nucleosides, three or fewer nucleosides, or four or fewer nucleosides in the first modified oligonucleotide contain a fluorine-containing modified sugar moiety or sugar surrogate.

[0496] Embodiment A6. An oligomer double chain according to any one of Embodiments A1 to A5, wherein the space between the 3rd and 21st nucleosides from the 5' end of the modified oligonucleotide, and one or fewer nucleosides, two or fewer nucleosides, or three or fewer nucleosides in the sequence of the first modified oligonucleotide containing them, contain a fluorine-containing modified sugar moiety or sugar surrogate.

[0497] Embodiment A7. A nucleoside containing a fluorine-containing modified sugar moiety or sugar surrogate of the first modified oligonucleotide is independently, i. The second nucleoside from the 5' end, ii. The 14th and 16th nucleosides counting from the 5' end, or iii. Select one of the 2nd, 14th, and 16th nucleosides counting from the 5' end, The oligomer double chain according to any one of Embodiments A1 to A6, wherein each of the fluorine-containing modified sugar moieties or sugar surrogates is independently a 2'-fluorosugar moiety or a 3'-fluorohexitol sugar moiety.

[0498] Embodiment A8. An oligomeric double chain according to any one of Embodiments A1 to A7, wherein one or fewer of the fluorine-containing modified sugar moieties and / or sugar surrogates in the first modified oligonucleotide is a 3'-fluorohexitol sugar moiety.

[0499] Embodiment A9. The oligomeric double helix according to any one of Embodiments A1 to A8, wherein one or more nucleosides of the first modified oligonucleotide are 2'-deoxynucleosides.

[0500] Embodiment A10. The oligomeric double helix according to Embodiment A9, wherein one or more 2'-deoxynucleosides are one or more nucleosides in the region of the sequence of the first modified oligonucleotide between the 5th to the 16th nucleosides counted from the 5' end of the first modified oligonucleotide and including those nucleosides.

[0501] Embodiment A11. The oligomeric double helix according to Embodiment A10, wherein the one or more 2'-deoxynucleosides are located in a region of the sequence of the first modified oligonucleotide that is the 5th, 6th, and / or 7th nucleoside counted from the 5' end of the first modified oligonucleotide, or the 14th, 15th, and / or 16th nucleoside.

[0502] Embodiment A12. The oligomeric double chain according to any one of Embodiments A9 to A11, wherein less than 20% or less than 15% of the nucleoside of the first modified oligonucleotide contains fluorine.

[0503] Embodiment A13. The oligomeric double helix according to any one of Embodiments A9 to A12, wherein the one or more 2'-deoxynucleosides are the 5th, 6th, and / or 7th nucleosides counted from the 5' end of the first modified oligonucleotide.

[0504] Embodiment A14. The oligomeric double helix according to any one of Embodiments A9 to A13, wherein only two nucleosides of the first modified oligonucleotide are 2'-deoxynucleosides.

[0505] Embodiment A15. The oligomeric double helix according to Embodiment A14, wherein the two 2'-deoxynucleosides are the 5th and 7th nucleosides, or the 14th and 16th nucleosides, counting from the 5' end of the first modified oligonucleotide.

[0506] Embodiment A16. The oligomeric double helix according to Embodiment A14, wherein the two 2'-deoxynucleosides are the 5th or 7th nucleosides from the 5' end of the first modified oligonucleotide.

[0507] Embodiment A17. The oligomeric double helix according to any one of Embodiments A9 to A13, wherein only one of the nucleosides of the first modified oligonucleotide is a 2'-deoxynucleoside.

[0508] Embodiment A18. The oligomeric double helix according to Embodiment A17, wherein the 2'-deoxynucleoside is the 6th or 16th nucleoside from the 5' end of the first modified oligonucleotide.

[0509] Embodiment A19. The oligomeric double helix according to Embodiment A17, wherein the 2'-deoxynucleoside is the sixth nucleoside from the 5' end of the first modified oligonucleotide.

[0510] Embodiment A20. An oligomeric double chain according to any one of Embodiments A1 to A19, wherein one or more of the nucleosides of the first modified oligonucleotide independently contain a sugar surrogate or a bicyclic sugar moiety.

[0511] Embodiment A21. The oligomeric double chain according to Embodiment A20, wherein the bicyclic sugar portion includes a 2'-4' crosslink selected from -O-CH2- and -O-CH(CH3)-.

[0512] Embodiment A22. An oligomeric double chain according to any one of Embodiments A1 to A21, wherein one or more of the nucleosides of the first modified oligonucleotide contain a 2'-OMe sugar moiety.

[0513] Embodiment A23. The oligomeric double chain according to Embodiment A22, wherein at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, or at least 60% of the nucleoside of the first modified oligonucleotide comprises a 2'-OMe sugar moiety.

[0514] Embodiment A24. An oligomeric double chain according to Embodiment A22 or A23, wherein one or more nucleosides containing a 2'-OMe sugar moiety are located between the 3rd and 21st nucleosides counting from the 5' end of the first modified oligonucleotide, and in the sequence region of the first modified oligonucleotide containing them.

[0515] Embodiment A25. An oligomeric double chain according to Embodiment A22 or A23, wherein the 3'-terminal nucleoside of the first modified oligonucleotide contains a 2'-OMe sugar moiety, and / or the nucleoside immediately 5' to the 3'-terminal nucleoside of the first modified oligonucleotide contains a 2'-OMe sugar moiety.

[0516] Embodiment A26. An oligomeric double chain according to any one of Embodiments A1 to A25, wherein one or more of the nucleosides of the first modified oligonucleotide contain a 2'-MOE sugar moiety.

[0517] Embodiment A27. The oligomeric double chain according to Embodiment A26, wherein the 5'-terminal nucleoside and / or 3'-terminal nucleoside of the first modified oligonucleotide comprises a 2'-MOE sugar moiety.

[0518] Embodiment A28. An oligomeric double chain according to any one of Embodiments A1 to A27, wherein the nucleoside immediately 5' of the 3'-terminal nucleoside of the first modified oligonucleotide contains a 2'-MOE sugar moiety.

[0519] Embodiment A29. An oligomer double chain according to any one of Embodiments A1 to A24 and A26 to A28, wherein the 5'-terminal nucleoside and the 3'-terminal nucleoside of the first modified oligonucleotide contain a 2'-MOE sugar moiety, and the nucleoside immediately 5' of the 3'-terminal nucleoside of the first modified oligonucleotide contains a 2'-MOE sugar moiety.

[0520] Embodiment A30. The oligomeric double helix according to any one of Embodiments A1 to A29, wherein the first modified oligonucleotide comprises a stabilized phosphate group bonded to the 5' terminal nucleoside.

[0521] Embodiment A31. The oligomeric double chain according to Embodiment A30, wherein the stabilized phosphate group comprises cyclopropylphosphonate or vinylphosphonate.

[0522] Embodiment A32. The oligomeric double chain according to any one of Embodiments A1 to A31, wherein the double chain comprises a conjugate group including a conjugate moiety and a conjugate linker.

[0523] Embodiment A33. The oligomeric double helix according to Embodiment A32, wherein the conjugate group includes a cell-targeting moiety.

[0524] Embodiment A34. The oligomeric double chain according to Embodiment A32, wherein the conjugate portion comprises an active drug substance, an aliphatic chain, a lipid, a peptide, a protein, a hydrocarbon, a polyamine, a polyamide, a polyether, a thioether, an aptamer, an antibody or antibody fragment, a vitamin, a fatty acid, a carbohydrate, an intercalator, or a reporter molecule.

[0525] Embodiment A35. The oligomer double chain according to Embodiment A32, wherein the conjugate group comprises C22 alkyl, C20 alkyl, C17 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, or C5 alkyl, and the alkyl chain optionally has one or more unsaturated bonds.

[0526] Embodiment A36. The oligomeric double chain according to Embodiment A32, wherein the conjugate group comprises a 6-palmitamide hexyl moiety or a 2-(hydroxymethyl)-6-palmitamide hexyl moiety.

[0527] Embodiment A37. The oligomeric double helix according to Embodiment A32, wherein the double helix includes a conjugate portion that binds to a type 1 transferrin receptor (TfR1).

[0528] Embodiment A38. The oligomeric double chain according to Embodiment A37, wherein the conjugate portion is selected from an antibody or fragment thereof, a protein or peptide, or an aptamer that can bind to TfR1.

[0529] Embodiment A39. The oligomeric double chain according to Embodiment A38, wherein the conjugate portion is a cyclic protein or a cyclic peptide.

[0530] Embodiment A40. The oligomeric double chain according to Embodiment A37, wherein the conjugate group consists of a bicyclic ligand and a conjugate linker.

[0531] Embodiment A41. The oligomeric double chain according to Embodiment A40, wherein the bicyclic compound comprises a polypeptide and a molecular skeleton consisting of 13 to 22 linked amino acids or amino acid mimes, and each of the first, second, and third amino acids of the polypeptide contains a reactive group, each of which separately forms a bond with the molecular skeleton, thereby forming two polypeptide loops bonded to the molecular skeleton.

[0532] Embodiment A42. The peptide of the bicyclic compound has the following chemical notation: It has Ac-CP[HyP]DAYLGC[tBuGly]SYCEPW[K(N3)]-NH2 (Sequence ID 1045), in which, Ac=acetylester C = cysteine, P = proline, D = aspartic acid, A = Alanine, Y = tyrosine, L = leucine, G = glycine, S = serine, E = glutamic acid, W = tryptophan, [HyP] = trans-4-hydroxy-L-proline, [tBuGly] = t-butyl-glycine, [K N3 )] = 6-azidridine, The oligomeric double chain according to Embodiment A41, wherein each cysteine ​​forms a covalent bond with the molecular skeleton 1,1',1''-(1,3,5-triazinan-1,3,5-triyl)tris(2-bromoetanone) (TATB).

[0533] Embodiment A43. The bicyclic compound has the following structure:

[0534] [ka] The oligomeric double chain according to Embodiment A41, having a salt thereof, wherein Q is N3 (BCY17901, SEQ ID NO: 1045), NH2 (BCY21757, SEQ ID NO: 1202), SH (BCY21758, SEQ ID NO: 1203), a conjugate linker, or a conjugate linker covalently bonded to an oligonucleotide.

[0535] Embodiment A44. An oligomeric double helix according to any one of Embodiments A32 to A43, wherein the second oligomeric compound comprises a conjugated group conjugated to the second modified oligonucleotide.

[0536] Embodiment A45. An oligomeric double helix according to any one of Embodiments A32 to A43, wherein the conjugate group is conjugated to the 5' or 3' end of the second modified oligonucleotide.

[0537] Embodiment A46. An oligomeric double helix according to any one of Embodiments A32 to A43, wherein the conjugate group is bonded to the 5'-terminal nucleoside or the 3'-terminal nucleoside of the second modified oligonucleotide.

[0538] Embodiment A47. An oligomeric double helix according to any one of Embodiments A32 to A43, wherein the conjugate group is bonded to the 5' terminal nucleoside of the second modified oligonucleotide.

[0539] Embodiment A48. An oligomeric double helix according to any one of Embodiments A32 to A43, wherein the conjugate group is bonded to the 3' terminal nucleoside of the second modified oligonucleotide.

[0540] Embodiment A49. An oligomeric double chain according to any one of Embodiments A32 to A48, wherein the conjugate linker of the conjugate group consists of a single bond.

[0541] Embodiment A50. An oligomeric double chain according to any one of Embodiments A32 to A48, wherein the conjugate linker of the conjugate group is cleavable.

[0542] Embodiment A51. An oligomeric double helix according to any one of Embodiments A32 to A50, wherein the conjugate linker comprises 1 to 3 linker-nucleosides.

[0543] Embodiment A52. An oligomeric double chain according to any one of Embodiments A32 to A48, wherein the conjugate linker includes a (bicyclo[6.1.0]nonine)-formyl (BCN) moiety.

[0544] Embodiment A53. The oligomeric double chain according to Embodiment A52, wherein the conjugate linker comprises a 6-(BCN-carbamate)-2-(hydroxymethyl)hexylphosphoryl moiety or a 6-(BCN-carbamate)hexylphosphoryl moiety.

[0545] Embodiment A54. The oligomeric double chain according to Embodiment A53, wherein the conjugate group has the following structure.

[0546] [ka]

[0547] Embodiment A55. The oligomeric double chain according to Embodiment A53, wherein the conjugate group has the following structure.

[0548] [ka]

[0549] Embodiment A56. The nucleic acid base sequence of the first modified oligonucleotide is the nucleic acid bases 295-316, 296-317, 297-318, 298-320, 299-320, 300-321, 301-322, 302-324, 303-324, 304-325, 304-326, 305-327, 306-325, 306-328, 307-328, 308-329, 309-330, 310-331, 311-332, 312-333, 313-334, 314-335, 315-336, 316-337, 317-339, 318-339, 3 19-340, 320-341, 321-342, 322-344, 323-345, 324-345, 324-346, 325-345, 325-347, 326-347, 327-348, 328-349, 329-350, 330-351, 331-352, 332-3 53, 333~354, 334~355, 505~526, 506~528, 507~529, 508~530, 509~531, 510~531, 511~532, 512~533, 513~535, 514~535, 514~536, 515~536, 516~535, 5 16-537, 517-538, 518-539, 519-541, 520-541, 521-542, 522-544, 523-544, 524-546, 535-556, 536-557, 537-558, 538-559, 539-560, 540-561, 541- 563, 542~563, 543~564, 544~565, 545~566, 546~567, 547~568, 548~570, 549~571, 550~572, 551~572, 552~574, 553~574, 554~575, 555~577, 556~578, 557~579, 558~580, 559~580, 560~581, 561~582, 562~583, 563~584, 595~616, 596~618, 597~618, 598~620, 599~621, 600~622, 601~623, 602~623, 603~ 624, 604~625, 605~627, 606~628, 607~628, 608~629, 609~630, 610~631, 611~632, 612~633, 613~635, 665~687, 666~687, 667~689, 668~689, 669~690,670~691, 671~692, 672~694, 673~694, 674~695, 675~696, 676~697, 677~698, 678~700, 679~701, 680~702, 681~703, 682~703, 683~704, 684~705, 685~706, 686~708, 687~708, 688~709, 689~710, 690~711, 691~712, 692~714, 693~715, 1675~1696, 1676~1698, 1677~1698, 1678~1699, 16 An oligomeric double chain according to any one of Embodiments A1 to A55, wherein the equilength portions within 79-1700, 1680-1702, 1681-1702, 1682-1703, 1683-1705, 1684-1705, 1685-1706, 1686-1707, 1687-1709, 1688-1709, 1689-1710, 1690-1712, 1691-1713, 1692-1714, and 1693-1714 are at least 80%, at least 85%, at least 90%, at least 95%, or 100% complementary.

[0550] Embodiment A57. An oligomeric double helix according to any one of Embodiments A1 to A55, wherein the nucleic acid base sequence of the first modified oligonucleotide is at least 80%, at least 85%, at least 90%, at least 95%, or 100% complementary to the equilength portions within nucleic acid bases 304-326, 306-325, 324-346, 325-345, 514-536, or 516-535 of SEQ ID NO: 1.

[0551] Embodiment A58. The oligomeric double helix according to any one of Embodiments A1 to A55, wherein the nucleic acid base sequence of the first modified oligonucleotide contains 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 nucleic acid bases from any of the nucleic acid base sequences of SEQ ID NOs. 3 to 314, 627 to 782, 939 to 976, 1033 to 1038, and 1254 to 1255.

[0552] Embodiment A59. The oligomeric double helix according to any one of Embodiments A1 to A55, wherein the nucleic acid base sequence of the first modified oligonucleotide includes one of the nucleic acid base sequences among SEQ ID NOs: 3-314, 627-782, 939-976, 1033-1038, and 1254-1255.

[0553] Embodiment A60. An oligomer double helix according to any one of Embodiments A1 to A55, wherein the nucleic acid base sequence of the first modified oligonucleotide consists of any of the nucleic acid base sequences of SEQ ID NOs: 3-314, 627-782, 939-976, 1033-1038, and 1254-1255.

[0554] Embodiment A61. An oligomeric double helix according to any one of Embodiments A1 to A55, wherein the nucleic acid base sequence of the first modified oligonucleotide contains 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 nucleic acid bases from the nucleic acid base sequences of SEQ ID NOs. 29, 171, 176, 967, 968, 971, 972, 974, 975, 1254, 1255, and 1033 to 1038.

[0555] Embodiment A62. An oligomeric double helix according to any one of Embodiments A1 to A55, wherein the nucleic acid base sequence of the first modified oligonucleotide includes any of the nucleic acid base sequences of SEQ ID NOs: 29, 171, 176, 967, 968, 971, 972, 974, 975, 1254, 1255, and 1033-1038.

[0556] Embodiment A63. An oligomer double helix according to any one of Embodiments A1 to A55, wherein the nucleic acid base sequence of the first modified oligonucleotide consists of one of the nucleic acid base sequences of SEQ ID NOs: 29, 171, 176, 967, 968, 971, 972, 974, 975, 1254, 1255, and 1033-1038.

[0557] Embodiment A64. An oligomeric double helix according to any one of Embodiments A1 to A55, wherein the first modified oligonucleotide and the second modified oligonucleotide each independently consist of 18-30, 18-25, 18-24, 18-23, 18-22, 18-21, 18-19, 19-30, 19-25, 19-24, 19-23, 19-21, 19-20, 20-30, 20-25, 20-24, 20-23, 20-22, and 20-21 linked nucleosides.

[0558] Embodiment A65. The oligomeric double helix according to any one of Embodiments A1 to A55, wherein the first modified oligonucleotide consists of 23 nucleosides.

[0559] Embodiment A66. The first modified state is efyyydyyyyyyyyyyyyyyyyee,efyyydyyyyyyyyyyyyyyyyy,e[FHE]yyydyyyyyyyyyyyyyyyee,e[FHE]yyydyyyyyyyyyyyyyyyyy,efyydydyyyyyyyyyyyyyyyee,efyydydyyyyyyyyyyyyyyyyy,e[FHE]yydydyyyyyyyyyyyyyyee,e[FHE]yydyyyyyyyyyyyyy yyyyyyy, efyyyfyyyyyyfyfyyyyyyy, efyyyfyyyyyyyfyfyyyyyy, efyyyyyyyyyyyfyfyyyyyy, efyyyfyyyyyyyfyfyyyyyyee, efyyyyyy yyyyyfyyyyyyyyyyyyyyyyyyyyyyyyfyyyyyyyyy, e[FHNA]yyyfyyyyyyyfyfyyyyyyee, e[FHNA]yyyfyyyyyyyfyfyyyyyyy, efyyydyyyyyyydy dyyyyyee, efyyydyyyyyyydydyyyyyyy, efyydydyyyyyyfyfyyyyyyy, efyyyfyyyyyyyfyyyyyyyy, efyyyfyyyyyyyfyyyyyyyyy, efyyyyy yyyyyyfyfyyyyyy, efyyyyyyyyyyyyfyfyyyyyyy, e[FHNA]yydydyyyyfyfyfyyyyyyy, efyyyfyyyyyyyfydyyyyyyyy, efyyyfyyyyyyyfydyyy An oligomeric double chain according to any one of Embodiments A1 to A65, having a sugar motif (from 5' to 3') selected from yyee, efyyyfyyyyyyyfyfyyyyee, and efyyyfyyyyyyyyfyfyyyyy, 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, each "f" represents a 2'-fluoro sugar moiety, and each "[FHNA]" represents a 3'-fluoro-hexitol sugar moiety.

[0560] Embodiment A67. An oligomeric double chain according to any one of Embodiments A1 to A65, wherein the first modified oligonucleotide has a sugar motif (from 5' to 3') selected from efyydydyyyyyyfyfyyyyyee, efyyydyyyyyyyfyfyyyyyyee, efyydydyyyyyyfyfyyyyyyy, e[FHNA]yydydyyyyfyfyfyyyyyyy, and efyyydyyyyyyyfyfyyyyyyy.

[0561] Embodiment A68. The oligomeric double helix according to any one of Embodiments A1 to A67, wherein the first modified oligonucleotide comprises at least one modified internucleoside bond.

[0562] Embodiment A69. The oligomeric double helix according to Embodiment A68, wherein the at least one modified internucleoside bond is a phosphorothioate or mesylphosphoamidate internucleoside bond.

[0563] Embodiment A70. The oligomeric double helix according to Embodiment A68, wherein less than 50%, less than 40%, less than 30%, less than 20%, or less than 10% of the nucleoside bonds of the first modified oligonucleotide are modified nucleoside bonds.

[0564] Embodiment A71. An oligomeric double helix according to any one of Embodiments A1 to A70, wherein each nucleoside bond of the first modified oligonucleotide is independently selected from phosphodiester nucleoside bonds and phosphorothioate nucleoside bonds.

[0565] Embodiment A72. The oligomeric double helix according to Embodiment A71, wherein the nucleoside bonds between the first and second nucleosides, and between the second and third nucleosides, counting from the 5' end of the first modified oligonucleotide, are modified nucleoside bonds.

[0566] Embodiment A73. The oligomeric double helix according to Embodiment A71, wherein the nucleoside bonds between the first and second nucleosides, and between the second and third nucleosides, counting from the 3' end of the first modified oligonucleotide, are modified nucleoside bonds.

[0567] Embodiment A74. An oligomer double helix according to Embodiment A72, wherein the nucleoside bonds between the first and second nucleosides counting from the 5' end of the first modified oligonucleotide, and between the second and third nucleosides, and the nucleoside bonds between the first and second nucleosides counting from the 3' end of the first modified oligonucleotide, and between the second and third nucleosides, are modified nucleoside bonds.

[0568] Embodiment A75. The oligomeric double helix according to any one of Embodiments A71 to A74, wherein the modified nucleoside bond is a phosphorothioate nucleoside bond.

[0569] Embodiment A76. The oligomeric double helix according to Embodiment A74 or A75, wherein all other nucleoside bonds in the first modified oligonucleotide are phosphodiester nucleoside bonds.

[0570] Embodiment A77. The first modified endpoint is a nucleoside-linking motif of ssooooooooooooooooooooss, and a sugar motif (5' to ) selected from efyydydyyyyyyfyfyyyyyee, efyyydyyyyyyyfyfyyyyyyee, efyydydyyyyyyfyfyyyyyyy, e[FHNA]yydydyyyyfyfyfyyyyyyy, and efyyydyyyyyyyfyfyyyyyyyy An oligomer double chain according to Embodiment A76, having 3') in the formula, where 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, each "f" represents a 2'-fluoro sugar moiety, each "[FHNA]" represents a 3'-fluoro-hexitol sugar moiety, each "o" represents a phosphodiester nucleoside bond, and each "s" represents a phosphorothioate nucleoside bond.

[0571] Embodiment A78. An oligomeric double chain according to any one of Embodiments A1 to A77, wherein less than 30%, less than 25%, less than 20%, less than 15%, less than 14%, less than 13%, less than 12%, less than 10%, or less than 5% of the nucleoside in the second modified oligonucleotide contains fluorine.

[0572] Embodiment A79. An oligomer double chain according to any one of Embodiments A1 to A77, wherein four or fewer nucleosides, three or fewer nucleosides, two or fewer nucleosides, or one or fewer nucleosides in the second modified oligonucleotide contain a fluorine-containing modified sugar moiety.

[0573] Embodiment A80. An oligomeric double chain according to any one of Embodiments A1 to A77, wherein neither the nucleoside before the 7th nucleoside or after the 11th nucleoside, counting from the 5' end of the second modified oligonucleotide, contains a fluorine-containing modified sugar moiety.

[0574] Embodiment A81. An oligomeric double chain according to any one of Embodiments A1 to A77, wherein one or more of the 7th, 9th, and 11th nucleosides from the 5' end of the second modified oligonucleotide contains a fluorine-containing modified sugar moiety.

[0575] Embodiment A82. The oligomeric double chain according to Embodiment A81, wherein two or more of the 7th, 9th, and 11th nucleosides from the 5' end of the second modified oligonucleotide contain a fluorine-containing modified sugar moiety.

[0576] Embodiment A83. The oligomeric double chain according to Embodiment A81, wherein the 7th, 9th, and 11th nucleosides from the 5' end of the second modified oligonucleotide contain a fluorine-containing modified sugar moiety.

[0577] Embodiment A84. An oligomeric double chain according to any one of Embodiments A1 to A80, wherein one or both of the 10th and 11th nucleosides from the 5' end of the second modified oligonucleotide contain a fluorine-containing modified sugar moiety.

[0578] Embodiment A85. An oligomeric double chain according to any one of Embodiments A77 to A84, wherein the fluorine-containing modified sugar portion is a 2'-fluorosugar portion.

[0579] Embodiment A86. An oligomeric double chain according to any one of Embodiments A1 to A85, wherein less than 30%, less than 25%, less than 20%, less than 15%, less than 14%, less than 13%, less than 12%, less than 10%, less than 5%, or less than 1% of the total nucleosides in the compound contains fluorine.

[0580] Embodiment A87. An oligomeric double chain according to any one of Embodiments A1 to A86, wherein one or more of the nucleosides of the second modified oligonucleotide independently comprises a sugar surrogate or a bicyclic sugar moiety.

[0581] Embodiment A88. The oligomeric double chain according to Embodiment A87, wherein the bicyclic sugar portion includes a 2'-4' crosslink selected from -O-CH2- and -O-CH(CH3)-.

[0582] Embodiment A89. An oligomeric double chain according to any one of Embodiments A1 to A88, wherein one or more of the nucleosides of the second modified oligonucleotide contain a 2'-OMe sugar moiety.

[0583] Embodiment A90. The oligomeric double chain according to Embodiment A89, wherein at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, or at least 60%, or at least 65%, or at least 70%, or at least 80%, or at least 85%, or at least 90% of the nucleoside of the second modified oligonucleotide contains a 2'-OMe sugar moiety.

[0584] Embodiment A91. An oligomeric double helix according to Embodiment A89 or A90, wherein one or more nucleosides containing a 2'-OMe sugar moiety are located between the 3rd and 19th nucleosides counting from the 5' end of the second modified oligonucleotide, and in the sequence region of the second modified oligonucleotide containing them.

[0585] Embodiment A92. An oligomer double helix according to Embodiment A89 or A90, wherein the 3'-terminal nucleoside of the second modified oligonucleotide contains a 2'-OMe sugar moiety, and / or the nucleoside immediately 5' to the 3'-terminal nucleoside of the second modified oligonucleotide contains a 2'-OMe sugar moiety.

[0586] Embodiment A93. An oligomeric double chain according to any one of Embodiments A89, A90, and A92, wherein the 5'-terminal nucleoside of the second modified oligonucleotide contains a 2'-OMe sugar moiety, and / or the nucleoside immediately 3' to the 5'-terminal nucleoside of the second modified oligonucleotide contains a 2'-OMe sugar moiety.

[0587] Embodiment A94. The oligomeric double chain according to Embodiment A89 or A90, wherein the 5'-terminal nucleoside, the nucleoside immediately 3' to the 5'-terminal nucleoside, the 3'-terminal nucleoside, and the nucleoside immediately 5' to the 3'-terminal nucleoside of the second modified oligonucleotide contain a 2'-OMe sugar moiety.

[0588] Embodiment A95. An oligomeric double chain according to any one of Embodiments A1 to A94, wherein one or more of the nucleosides of the second modified oligonucleotide contain a 2'-MOE sugar moiety.

[0589] Embodiment A96. An oligomer double chain according to any one of Embodiments A1 to A93, wherein the 3'-terminal nucleoside of the second modified oligonucleotide contains a 2'-MOE sugar moiety, and / or the nucleoside immediately 5' to the 3'-terminal nucleoside of the second modified oligonucleotide contains a 2'-MOE sugar moiety.

[0590] Embodiment A97. An oligomer double chain according to any one of Embodiments A1 to A93, A95, and A96, wherein the 5'-terminal nucleoside of the second modified oligonucleotide contains a 2'-MOE sugar moiety, and / or the nucleoside immediately 3' to the 5'-terminal nucleoside of the second modified oligonucleotide contains a 2'-MOE sugar moiety.

[0591] Embodiment A98. An oligomeric double chain according to any one of Embodiments A1 to A91, wherein the 5'-terminal nucleoside, the nucleoside immediately 3' to the 5'-terminal nucleoside, the 3'-terminal nucleoside, and the nucleoside immediately 5' to the 3'-terminal nucleoside of the second modified oligonucleotide contain a 2'-MOE sugar moiety.

[0592] Invention A99. Herein the second analyzed state is eeyyyyyyyyyyyyyyyyyy,eeyyyyyyyyyyyyyyyyyy,yyyyyyyyyyyyyyyyyyyy,yyyyyyyyyyyyyyyyyyyy,yyyyyyyyyyyyyyyyyyyyy,eeyyyyyyyyyyyyyyyyy,eeyyyyyyyyyyyyyyyy,eeyyyyyyyyyyyyyyyyyy,yyyyyyyyyyyyyyyyyyy,yyyyyyyyyyyyyyyyyyy,eeyyyyyyyyyyyyyy yyyyyee, eeyyyyyyyffyyyyyyyyyy, yyyyyyyyyffyyyyyyyyyyyyyyyyyyyffyyyyyyyyyy, eeyyyyyffyyyyyyyyyyyyyyyyyyyyyyyyyyy yyyyyyy, yyyyyyyffyyyyyyyyee, yyyyyyyffyyyyyyyyyy, yyyyyyfyfffyyyyyyyy, eeyyyyfyfffyyyyyyee, eeyyyyfyfffyyyyyyy eey yyyyyyydyyyyyyyyy, eeyyyyyyyydyyyyyyyyyy, yyyyyyyyyydyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyy, eeyyyyyyyyyyyyyyyyyyy An oligomer double chain according to any one of Embodiments A1 to A98, having a sugar motif (from 5' to 3') selected from, eeyyyyyyyyyyyyyyyyyyyy, yyyyyyyyyyyyyyyyyyyyee, and yyyyyyyyyyyyyyyyyyyyyy, wherein each "y" represents a 2'-OMe sugar moiety, each "e" represents a 2'-MOE sugar moiety, each "f" represents a 2'-fluoro sugar moiety, and each "d" represents a 2'-β-D-deoxyribosyl sugar moiety.

[0593] Embodiment A100. An oligomer double chain according to any one of Embodiments A1 to A98, wherein the second modified oligonucleotide has a sugar motif (from 5' to 3') selected from eeyyyyyyyffyyyyyyyyy, eeyyyyfyfyyyyyyyyyy, yyyyyyyyyffyyyyyyyyyyy, and yyyyyyfyfyfyyyyyyyyyyy, where each "y" represents a 2'-OMe sugar moiety, each "e" represents a 2'-MOE sugar moiety, and each "f" represents a 2'-fluoro sugar moiety.

[0594] Embodiment A101. An oligomeric double helix according to any one of Embodiments A1 to A100, wherein the nucleic acid base of the 3' terminal nucleoside and / or the nucleoside immediately 5' to the 3' terminal nucleoside of the second modified oligonucleotide is adenine.

[0595] Embodiment A102. An oligomeric double helix according to any one of Embodiments A1 to A100, wherein the nucleic acid base of the 3' terminal nucleoside of the second modified oligonucleotide is adenine, and the nucleic acid base of the nucleoside immediately to the 5' side of the 3' terminal nucleoside is thymine or uracil.

[0596] Embodiment A103. The oligomeric double helix according to any one of Embodiments A1 to A100, wherein the second modified oligonucleotide comprises at least one modified internucleoside bond.

[0597] Embodiment A104. The oligomeric double helix according to Embodiment A103, wherein the at least one modified internucleoside bond is a phosphorothioate or mesylphosphoamidate internucleoside bond.

[0598] Embodiment A105. The oligomeric double helix according to Embodiment A103, wherein less than 50%, less than 40%, less than 30%, less than 20%, or less than 10% of the nucleoside bonds of the first modified oligonucleotide are modified nucleoside bonds.

[0599] Embodiment A106. An oligomeric double helix according to any one of Embodiments A103 to A105, wherein each nucleoside bond of the second modified oligonucleotide is independently selected from phosphodiester nucleoside bonds and phosphorothioate nucleoside bonds.

[0600] Embodiment A107. An oligomeric double helix according to any one of Embodiments A103 to A105, wherein the nucleoside bonds between the first and second nucleosides and between the second and third nucleosides, counting from the 5' end of the second modified oligonucleotide, are modified nucleoside bonds.

[0601] Embodiment A108. An oligomeric double helix according to any one of Embodiments A103 to A105 and A107, wherein the nucleoside bonds between the first and second nucleosides and between the second and third nucleosides, counting from the 3' end of the first modified oligonucleotide, are modified nucleoside bonds.

[0602] Embodiment A109. An oligomer double helix according to any one of Embodiments A103 to A105, wherein the nucleoside bonds between the first and second nucleosides counting from the 5' end of the second modified oligonucleotide, and between the second and third nucleosides, and the nucleoside bonds between the first and second nucleosides counting from the 3' end of the second modified oligonucleotide, and between the second and third nucleosides, are modified nucleoside bonds.

[0603] Embodiment A110. An oligomeric double helix according to any one of Embodiments A103 to A109, wherein the modified nucleoside bond is a phosphorothioate nucleoside bond.

[0604] Embodiment A111. The oligomeric double helix according to Embodiment A110, wherein all other nucleoside bonds in the second modified oligonucleotide are phosphodiester nucleoside bonds.

[0605] Embodiment A112. The oligomeric double chain according to Embodiment A111, wherein the second modified oligonucleotide has a nucleoside-linking motif of ssooooooooooooooooss and a sugar motif (5' to 3') selected from eeyyyyyyyffyyyyyyyyyee, eeyyyyfyfyyyyyyyyyyee, yyyyyyyyyffyyyyyyyyyyy, and yyyyyyfyfyyyyyyyyyyyy, where each "y" represents a 2'-OMe sugar moiety, each "e" represents a 2'-MOE sugar moiety, each "f" represents a 2'-fluoro sugar moiety, each "o" represents a phosphodiester nucleoside linkage, and each "s" represents a phosphorothioate nucleoside linkage.

[0606] Embodiment A113. The oligomeric double helix according to any one of Embodiments A1 to A112, wherein the nucleic acid base sequence of the second modified oligonucleotide contains 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 nucleic acid bases from any of the nucleic acid base sequences among SEQ ID NOs. 315 to 626, 783 to 938, 977 to 1016, and 1027 to 1032.

[0607] Embodiment A114. The oligomeric double helix according to any one of Embodiments A1 to A112, wherein the nucleic acid base sequence of the second modified oligonucleotide includes any of the nucleic acid base sequences of SEQ ID NOs: 315-626, 783-938, 977-1016, and 1027-1032.

[0608] Embodiment A115. The oligomeric double helix according to any one of Embodiments A1 to A112, wherein the nucleic acid base sequence of the second modified oligonucleotide consists of any of the nucleic acid base sequences of SEQ ID NOs. 315-626, 783-938, 977-1016, and 1027-1032.

[0609] Embodiment A116. The oligomeric double helix according to any one of Embodiments A1 to A112, wherein the nucleic acid base sequence of the second modified oligonucleotide contains 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 nucleic acid bases from the nucleic acid base sequences of SEQ ID NOs. 341, 483, 488, 1011-1016, and 1027-1032.

[0610] Embodiment A117. The oligomeric double helix according to any one of Embodiments A1 to A112, wherein the nucleic acid base sequence of the second modified oligonucleotide includes any of the nucleic acid base sequences of SEQ ID NOs. 341, 483, 488, 1011-1016, and 1027-1032.

[0611] Embodiment A118. The oligomeric double helix according to any one of Embodiments A1 to A112, wherein the nucleic acid base sequence of the second modified oligonucleotide consists of any of the nucleic acid base sequences of SEQ ID NOs. 341, 483, 488, 1011-1016, and 1027-1032.

[0612] Embodiment A119. An oligomeric double chain, (1) Nucleic acid bases of SEQ ID NO: 1, 295-316, 296-317, 297-318, 298-320, 299-320, 300-321, 301-322, 302-324, 303-324, 304-325, 304-326, 305-327, 306-325, 306-328, 307-328, 308-329, 309-330, 310-331, 311-332, 312-333, 313-334, 314-335, 315-336, 316-337, 317-339, 318-339, 319-340, 320-341, 321-342, 322- 344, 323~345, 324~345, 324~346, 325~345, 325~347, 326~347, 327~348, 328~349, 329~350, 330~351, 331~352, 332~353, 333~354, 334~355, 505~526, 506-528, 507-529, 508-530, 509-531, 510-531, 511-532, 512-533, 513-535, 514-535, 514-536, 515-536, 516-535, 516-537, 517-538, 518-539, 519-5 41, 520~541, 521~542, 522~544, 523~544, 524~546, 535~556, 536~557, 537~558, 538~559, 539~560, 540~561, 541~563, 542~563, 543~564, 544~565, 5 45-566, 546-567, 547-568, 548-570, 549-571, 550-572, 551-572, 552-574, 553-574, 554-575, 555-577, 556-578, 557-579, 558-580, 559-580, 560-58 1, 561~582, 562~583, 563~584, 595~616, 596~618, 597~618, 598~620, 599~621, 600~622, 601~623, 602~623, 603~624, 604~625, 605~627, 606~628, 607 ~628, 608~629, 609~630, 610~631, 611~632, 612~633, 613~635, 665~687, 666~687, 667~689, 668~689, 669~690, 670~691, 671~692, 672~694, 673~694,674~695, 675~696, 676~697, 677~698, 678~700, 679~701, 680~702, 681~703, 682~703, 683~704, 684~705, 685~706, 686~708, 687~708, 688~709, 689~710, 690~711, 691~712, 692~714, 693~715, 1675~1696, 1676~1698, 1677~1698, 1678~1699, 1679~1700, 1680~1702, 1681~1702, 1682~1 A first oligomer compound comprising a first modified oligonucleotide consisting of 18 to 30 consecutively linked nucleosides that are at least 85%, at least 90%, at least 95%, or at least 95% complementary, or 100% complementary, to the equilength portions within 703, 1683-1705, 1684-1705, 1685-1706, 1686-1707, 1687-1709, 1688-1709, 1689-1710, 1690-1712, 1691-1713, 1692-1714, and 1693-1714, (2) A second oligomer compound comprising a second modified oligonucleotide consisting of 16 to 28 consecutively linked nucleosides that are at least 90% complementary to the equilength portion of the first modified oligonucleotide, During the ceremony, (a) Each of the nucleosides of the first modified oligonucleotide and each of the nucleosides of the second modified oligonucleotide comprises a modified sugar moiety or sugar surrogate, (b) At least one of the modified sugar moieties or sugar surrogates of the first modified oligonucleotide contains fluorine, (c) an oligomeric double chain in which less than 40% of the nucleoside of the first modified oligonucleotide contains fluorine.

[0613] Embodiment A120. The oligomeric double helix according to Embodiment A119, wherein the nucleic acid base sequence of the first modified oligonucleotide contains 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 nucleic acid bases from any of the nucleic acid base sequences of SEQ ID NOs. 3-314, 627-782, 939-976, 1033-1038, and 1254-1255.

[0614] Embodiment A121. The oligomeric double helix according to Embodiment A119, wherein the nucleic acid base sequence of the first modified oligonucleotide includes any of the nucleic acid base sequences of SEQ ID NOs: 3-314, 627-782, 939-976, 1033-1038, and 1254-1255.

[0615] Embodiment A122. The oligomer double helix according to Embodiment A119, wherein the nucleic acid base sequence of the first modified oligonucleotide consists of any of the nucleic acid base sequences of SEQ ID NOs: 3-314, 627-782, 939-976, 1033-1038, and 1254-1255.

[0616] Embodiment A123. The oligomeric double helix according to Embodiment A119, wherein the nucleic acid base sequence of the first modified oligonucleotide contains 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 nucleic acid bases from any of the nucleic acid base sequences of SEQ ID NOs. 29, 171, 176, 967, 968, 971, 972, 974, 975, 1254, 1255, and 1033-1038.

[0617] Embodiment A124. The oligomeric double helix according to Embodiment A119, wherein the nucleic acid base sequence of the first modified oligonucleotide includes any of the nucleic acid base sequences of SEQ ID NOs: 29, 171, 176, 967, 968, 971, 972, 974, 975, 1254, 1255, and 1033-1038.

[0618] Embodiment A125. The oligomeric double helix according to Embodiment A119, wherein the nucleic acid base sequence of the first modified oligonucleotide consists of any of the nucleic acid base sequences of SEQ ID NOs: 29, 171, 176, 967, 968, 971, 972, 974, 975, 1254, 1255, and 1033-1038.

[0619] Embodiment A126. The oligomeric double helix according to Embodiment A120, wherein the nucleic acid base sequence of the second modified oligonucleotide contains 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 nucleic acid bases from any of the nucleic acid base sequences among SEQ ID NOs. 315-626, 783-938, 977-1016, and 1027-1032.

[0620] Embodiment A127. The oligomeric double helix according to Embodiment A121, wherein the nucleic acid base sequence of the second modified oligonucleotide includes any of the nucleic acid base sequences of SEQ ID NOs. 315-626, 783-938, 977-1016, and 1027-1032.

[0621] Embodiment A128. The oligomeric double helix according to Embodiment A122, wherein the nucleic acid base sequence of the second modified oligonucleotide consists of any of the nucleic acid base sequences of SEQ ID NOs. 315-626, 783-938, 977-1016, and 1027-1032.

[0622] Embodiment A129. The oligomeric double helix according to Embodiment A123, wherein the nucleic acid base sequence of the second modified oligonucleotide contains 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 nucleic acid bases from any of the nucleic acid base sequences of SEQ ID NOs. 341, 483, 488, 1011-1016, and 1027-1032.

[0623] Embodiment A130. The oligomeric double helix according to Embodiment A124, wherein the nucleic acid base sequence of the second modified oligonucleotide includes any of the nucleic acid base sequences of SEQ ID NOs. 341, 483, 488, 1011-1016, and 1027-1032.

[0624] Embodiment A131. The oligomeric double helix according to Embodiment A125, wherein the nucleic acid base sequence of the second modified oligonucleotide consists of any of the nucleic acid base sequences of SEQ ID NOs. 341, 483, 488, 1011-1016, and 1027-1032.

[0625] Embodiment A132. An oligomeric double chain according to any one of Embodiments A119 to A131, wherein none of the modified sugar portions of the nucleoside of the second modified oligonucleotide are fluorine-free.

[0626] Embodiment A133. An oligomeric double chain according to any one of Embodiments A119 to A131, wherein at least one of the modified sugar moieties of the second modified oligonucleotide contains fluorine, and less than 40% of the nucleosides of the second modified oligonucleotide contain fluorine.

[0627] Embodiment A134. An oligomeric double chain according to any one of Embodiments A119 to A131, wherein two, three, or four of the nucleosides of the second modified oligonucleotide contain a fluorine-containing modified sugar moiety.

[0628] Embodiment A135. An oligomeric double chain according to any one of Embodiments A119 to A134, wherein two, three, or four of the nucleosides of the first modified oligonucleotide contain a fluorine-containing modified sugar moiety.

[0629] Embodiment A136. An oligomeric double helix according to any one of Embodiments A119 to A135, wherein none of the nucleosides of the second modified oligonucleotide are 2'-deoxynucleosides.

[0630] Embodiment A137. An oligomeric double helix according to any one of Embodiments A119 to A135, wherein all of the nucleosides of the second modified oligonucleotide contain a modified ribosyl sugar moiety.

[0631] Embodiment A138. An oligomeric double helix according to any one of Embodiments A119 to A137, wherein one, two, or three of the nucleosides of the first modified oligonucleotide are 2'-deoxynucleosides.

[0632] Embodiment A139. (a) The 5'-terminal nucleoside and 3'-terminal nucleoside of the second modified oligonucleotide, the nucleoside directly adjacent to the 5'-terminal nucleoside, and the nucleoside directly adjacent to the 3'-terminal nucleoside contain a 2'-MOE sugar moiety, (b) The 5'-terminal nucleoside and the 3'-terminal nucleoside of the first modified oligonucleotide, and the nucleoside immediately 5' to the 3'-terminal nucleoside, contain a 2'-MOE sugar moiety and / or (b) The oligomeric double chain according to any one of Embodiments A119 to A138, wherein any nucleoside in the first and second modified oligonucleotides that do not contain fluorine or a 2'-MOE sugar moiety contains a 2'-OMe sugar moiety.

[0633] Embodiment A140. An oligomeric double chain according to any one of Embodiments A119 to A139, wherein four or fewer of the nucleosides of the first modified oligonucleotide contain a fluorine-containing modified sugar moiety.

[0634] Embodiment A141. The first modified state language is efyyyyyyyyyyyyyyyyyyyyyee, efyyyyyyyyyyyyyyyyyyyyyy, e[FHNE]yyyyyyyyyyyyyyyyyyee, e[FHNE]yyyyyyyyyyyyyyyyyyyyyyy, efyyyyyyyyyyyyyyyyyyyyyyy, e[FHNE]yydydyyyyyyyyyyyyyyyyyyy, and efy An oligomeric double chain according to Embodiment A140, having a sugar motif (from 5' to 3') selected from yyfyyyyyyyfyfyyyyee, where 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, each "f" represents a 2'-fluoro sugar moiety, and each "[FHNA]" represents a 3'-fluoro-hexitol sugar moiety.

[0635] Embodiment A142. An oligomeric double chain according to any one of Embodiments A119 to A139, wherein three or fewer of the nucleosides of the first modified oligonucleotide contain a fluorine-containing modified sugar moiety.

[0636] Embodiment A143. The first modified state is efyyydyyyyyyyyyyyyyyyy,efyyydyyyyyyyyyyyyyyyy,e[FHE]yyydyyyyyyyyyyyyyyyy,e[FHE]yyydyyyyyyyyyyyyyyyyy,efyydydyyyyyyyyyyyyyyy,efyydydyyyyyyyyyyyyyyy,efyydydyyyyyyyyyyyyyyyy,e[FHE]yydydyyyyyyyyyyyyyyyy,e[FHE]yydydyyyyyyyyyyyyyyyyyy,efyyyyyyyyyyyyyyyyyyyy,efyyyyyyyyyyyyyyyyy An oligomeric double chain according to Embodiment A142, having a sugar motif (from 5' to 3') selected from yyyyyyyyy, efyyyfyyyyyyyyfydyyyyyy, efyyyfyyyyyyyyfydyyyyyy, efyyyfyyyyyyyyfydyyyyyyee, efyyyfyyyyyyyyfydyyyyyyy, where 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, each "f" represents a 2'-fluoro sugar moiety, and each "[FHNA]" represents a 3'-fluoro-hexitol sugar moiety.

[0637] Embodiment A144. An oligomeric double chain according to any one of Embodiments A119 to A139, wherein two or fewer of the nucleosides of the first modified oligonucleotide contain a fluorine-containing modified sugar moiety.

[0638] Embodiment A145. The oligomer double chain according to Embodiment A144, wherein the first modified oligonucleotide has a sugar motif (from 5' to 3') selected from efyyyyyyyyyyyfyyyyyyyyee, efyyyyyyyyyyyyfyyyyyyyyy, e[FHNA]yyyyyyyyyyy[FHNA]yyyyyyyee, and e[FHNA]yyyyyyyyyyy[FHNA]yyyyyyyyy, where each "y" represents a 2'-OMe sugar moiety, each "e" represents a 2'-MOE sugar moiety, each "f" represents a 2'-fluoro sugar moiety, and each "[FHNA]" represents a 3'-fluoro-hexitol sugar moiety.

[0639] Embodiment A146. An oligomeric double chain according to any one of Embodiments A119 to A139, wherein only one of the nucleosides of the first modified oligonucleotide contains a fluorine-containing modified sugar moiety.

[0640] Embodiment A147. The oligomeric double chain according to Embodiment A146, wherein the first modified oligonucleotide has a sugar motif (from 5' to 3') selected from efyyydyyyyyyyydydyyyyyy, efyyydyyyyyyyydydyyyyyee, e[FHNA]yyydyyyyyyyydydyyyyyyy, and e[FHNA]yyydyyyyyyyydydyyyyyee, where 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 "f" represents a 2'-fluoro sugar moiety.

[0641] Embodiment A148. An oligomeric double helix according to any one of Embodiments A119 to A146, wherein two or fewer of the nucleosides of the first modified oligonucleotide are 2'-deoxynucleosides.

[0642] Embodiment A149. The oligomer double chain according to Embodiment A148, wherein the first modified oligonucleotide has a sugar motif (from 5' to 3') selected from efyydydyyyyyyfyfyyyyyyee, efyydydyyyyyyfyfyyyyyyy, e[FHNA]yydydyyyyyyfyfyyyyyyee, and e[FHNA]yydydyyyyyyfyfyyyyyyy, where 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, each "f" represents a 2'-fluoro sugar moiety, and each "[FHNA]" represents a 3'-fluoro-hexitol sugar moiety.

[0643] Embodiment A150. The oligomeric double helix according to any one of Embodiments A119 to A147, wherein only one of the nucleosides of the first modified oligonucleotide is a 2'-deoxynucleoside.

[0644] Embodiment A151. The first modified state is efyyydyyyyyyyyyyyyyyyyee,efyyydyyyyyyyyyyyyyyyyy,e[FHE]yyydyyyyyyyyyyyyyyee,e[FHE]yyydyyyyyyyyyyyyyyyyyy,eyyyyyyyyyyyyyyyyyyy,eyyyyyyyyyyyyyyyyyyyy,efyyyyyyyyyyyyyyyyyyyyyy,eyyy[FHE]yyyyyyyyyyyyyyy An oligomeric double chain according to Embodiment A150, having sugar motifs (from 5' to 3') selected from yy and e[FHNA]yyyfyyyyyyyfydyyyyyee, where 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, each "f" represents a 2'-fluoro sugar moiety, and each "[FHNA]" represents a 3'-fluoro-hexitol sugar moiety.

[0645] Embodiment A152. An oligomeric double chain according to any one of Embodiments A119 to A151, wherein four or fewer of the nucleosides of the second modified oligonucleotide contain a fluorine-containing modified sugar moiety.

[0646] Embodiment A153. The oligomeric double chain according to Embodiment A152, wherein the second modified oligonucleotide has a sugar motif (from 5' to 3') selected from yyyyyyfyfffyyyyyyyyy, eeyyyyfyfffyyyyyyyyy, yyyyyfyfffyyyyyyyyy, eeyyyyfyfffyyyyyyyyy, yyyyfyfffyyyyyyyyyy, and eeyyfyfffyyyyyyyyyy, where each "y" represents a 2'-OMe sugar moiety, each "e" represents a 2'-MOE sugar moiety, and each "f" represents a 2'-fluoro sugar moiety.

[0647] Embodiment A154. An oligomeric double chain according to any one of Embodiments A119 to A151, wherein three or fewer of the nucleosides of the second modified oligonucleotide contain a fluorine-containing modified sugar moiety.

[0648] Embodiment A155. The oligomeric double chain according to Embodiment A154, wherein the second modified oligonucleotide has a sugar motif (from 5' to 3') selected from eeyyyyfyfyyfyyyyyyyyee and yyyyyyfyfyfyyyyyyyyyy, where each "y" represents a 2'-OMe sugar moiety, each "e" represents a 2'-MOE sugar moiety, and each "f" represents a 2'-fluoro sugar moiety.

[0649] Embodiment A156. An oligomeric double chain according to any one of Embodiments A119 to A152, wherein two or fewer of the nucleosides of the second modified oligonucleotide contain a fluorine-containing modified sugar moiety.

[0650] Embodiment A157. The oligomeric double chain according to Embodiment A156, wherein the second modified oligonucleotide has a sugar motif (from 5' to 3') selected from eeyyyyyyyffyyyyyyyyee, yyyyyyyyffyyyyyyyyyy, eeyyyyyffyyyyyyyyyee, and yyyyyyyffyyyyyyyyyyy, where each "y" represents a 2'-OMe sugar moiety, each "e" represents a 2'-MOE sugar moiety, and each "f" represents a 2'-fluoro sugar moiety.

[0651] Embodiment A158. An oligomeric double chain according to any one of Embodiments A119 to A151, wherein none of the nucleosides of the second modified oligonucleotide contain a fluorine-containing modified sugar moiety.

[0652] Embodiment A159. The oligomeric double chain according to Embodiment A158, wherein the second modified oligonucleotide has a sugar motif (from 5' to 3') selected from yyyyyyyyyyyyyyyyyyyyy, eeyyyyyyyyyyyyyyyyyyyy, yyyyyyyyyyydyyyyyyyyyyy, and eeyyyyyyyyydyyyyyyyyyyy.

[0653] Embodiment A160. An oligomeric double helix according to any one of Embodiments A119 to A159, wherein less than 50%, less than 40%, less than 30%, less than 20%, or less than 10% of the nucleoside bonds of the first modified oligonucleotide are modified nucleoside bonds.

[0654] Embodiment A161. An oligomer double helix according to any one of Embodiments A119 to A160, wherein the internucleoside bonds between the first and second nucleosides counting from the 5' end of the first modified oligonucleotide, and between the second and third nucleosides, and the internucleoside bonds between the first and second nucleosides counting from the 3' end of the first modified oligonucleotide, and between the second and third nucleosides, are phosphorothioate internucleoside bonds.

[0655] Embodiment A162. The oligomeric double helix according to any one of Embodiments A119 to A161, wherein the first modified oligonucleotide has an internucleoside linking motif (5' to 3') selected from ssooooooooooooooooooss, ssooosooooooooooooooss, ssoooooooooooooooooss, and ssooooooooooooooooss, where each "o" represents a phosphodiester internucleoside linkage and each "s" represents a phosphorothioate internucleoside linkage.

[0656] Embodiment A163. An oligomeric double helix according to any one of Embodiments A119 to A162, wherein less than 50%, less than 40%, less than 30%, less than 20%, or less than 10% of the nucleoside bonds of the second modified oligonucleotide are modified nucleoside bonds.

[0657] Embodiment A164. An oligomeric double helix according to any one of Embodiments A119 to A163, wherein the internucleoside bonds between the first and second nucleosides counting from the 5' end of the second modified oligonucleotide, and between the second and third nucleosides, and the internucleoside bonds between the first and second nucleosides counting from the 3' end of the second modified oligonucleotide, and between the second and third nucleosides, are phosphorothioate internucleoside bonds.

[0658] Embodiment A165. An oligomeric double helix according to any one of Embodiments A119 to A164, wherein the second modified oligonucleotide has a nucleoside-linking motif (5' to 3') selected from ssooooooooooooooooss, ssooooooosooooooooss, ssoooooozozoooooooss, and ssooooooooooooooss, where each "o" represents a phosphodiester nucleoside linkage, each "s" represents a phosphorothioate nucleoside linkage, and each "z" represents a mesylphosphoamide nucleoside linkage.

[0659] Embodiment A166. The first modified oligonucleotide is a first sugar motif (1 st ) has the second modified oligonucleotide, and the second sugar motif (2 nd ) has the following combination (5' to 3'): 1 st :efyydydyyyyyyfyfyyyyyee and 2 nd :eeyyyyyyyyyyyyyyyyyy, 1 st :efyydydyyyyyyfyfyyyyyyy and 2 nd :yyyyyyyyyyyyyyyyyyyyy, 1 st :efyydydyyyyyyfyfyyyyyee and 2 nd :yyyyyyyyyyyyyyyyyyyyy, 1 st :efyydydyyyyyyfyfyyyyyyy and 2 nd :eeyyyyyyyyyyyyyyyyyy, 1 st :efyyydyyyyyyyfyfyyyyyee and 2 nd :eeyyyyyyyffyyyyyyyyy, 1 st :efyyydyyyyyyydataydatayyyyyyy and 2 nd :yyyyyyyyyfyyyyyyyyyy, 1 st :efyyydyyyyyyyfyfyyyyyee and 2 nd :yyyyyyyyyfyyyyyyyyyy, 1 st:efyyydyyyyyyydataydatayyyyyyy and 2 nd :eeyyyyyyyffyyyyyyyyy, 1 st :efyydydyyyyyyfyfyyyyyee and 2 nd :eeyyyyyyyffyyyyyyyyy, 1 st :efyydydyyyyyyfyfyyyyyyy and 2 nd :yyyyyyyyyfyyyyyyyyyy, 1 st :efyydydyyyyyyfyfyyyyyee and 2 nd :yyyyyyyyyfyyyyyyyyyy, 1 st :efyydydyyyyyyfyfyyyyyyy and 2 nd :eeyyyyyyyffyyyyyyyyy, 1 st :efyyydyyyyyyyfyfyyyyyee and 2 nd :eeyyyyyyyyyyyyyyyyyy, 1 st :efyyydyyyyyyydataydatayyyyyyy and 2 nd :yyyyyyyyyyyyyyyyyyyyy, 1 st :efyyydyyyyyyyfyfyyyyyee and 2 nd :yyyyyyyyyyyyyyyyyyyyyy, next to 1 st :efyyydyyyyyyydataydatayyyyyyy and 2 nd An oligomer double chain according to any one of Embodiments A1 to A165, selected from :eeyyyyfyfyfyyyyyyyyy, where each "y" represents a 2'-OMe sugar moiety, each "e" represents a 2'-MOE sugar moiety, each "f" represents a 2'-fluoro sugar moiety, and each "d" represents a 2'-β-D-deoxyribosyl sugar moiety.

[0660] Embodiment A167. The first modified oligonucleotide is a first sugar motif (1 st ) has the second modified oligonucleotide, and the second sugar motif (2 nd ) has the following combination (5' to 3'): 1st :efyydydyyyyyyfyfyyyyyee and 2 nd :eeyyyyfyfffyyyyyyyyy, 1 st :efyydydyyyyyyfyfyyyyyyy and 2 nd :yyyyyyyy5vyyyyyyyyyy,1 st :efyydydyyyyyyfyfyyyyyee and 2 nd :yyyyyyyy5vyyyyyyyyyy,1 st :efyydydyyyyyyfyfyyyyyyy and 2 nd :eeyyyyfyfffyyyyyyyyy, 1 st :efyyyyyyyyyyyyyyyyyyee and 2 nd :eeyyyyfyfffyyyyyyyyy, 1 st : emiyyyyyyyyyyyyyyyyyyyyy and 2 nd :yyyyyyyy5vyyyyyyyyyy,1 st :efyyyyyyyyyyyyyyyyyyee and 2 nd :yyyyyyyy5vyyyyyyyyyy,1 st : emiyyyyyyyyyyyyyyyyyyyyy and 2 nd :eeyyyyfyfffyyyyyyyyy, 1 st :efyyyyyyyyyyyyyyyyyyee and 2 nd :eeyyyyyyyffyyyyyyyyy, 1 st : emiyyyyyyyyyyyyyyyyyyyyy and 2 nd :yyyyyyyyyfyyyyyyyyyy, 1 st :efyyyyyyyyyyyyyyyyyyee and 2 nd :yyyyyyyyyfyyyyyyyyyy, 1 st : emiyyyyyyyyyyyyyyyyyyyyy and 2 nd :eeyyyyyyyffyyyyyyyyy, 1 st :efyyyyyyyyyyyyyyyyyyee and 2 nd :eeyyyyyyyyyyyyyyyyyy, 1st : emiyyyyyyyyyyyyyyyyyyyyy and 2 nd :yyyyyyyyyyyyyyyyyyyyy, 1 st :efyyyyyyyyyyyyyyyyyyee and 2 nd :yyyyyyyyyyyyyyyyyyyyy, 1 st : emiyyyyyyyyyyyyyyyyyyyyy and 2 nd :eeyyyyyyyyyyyyyyyyyy, 1 st : emiyyyyyyyyyyyyyyyyyyyyyy and 2 nd :yyyyyyyyyfyyyyyyyyyy, 1 st :efyyyfyyyyyyyyyyyyyyyee and 2 nd :eeyyyyyyyffyyyyyyyyy, 1 st : emiyyyyyyyyyyyyyyyyyyyyyy and 2 nd :eeyyyyyyyffyyyyyyyyy, 1 st :efyyyfyyyyyyyyyyyyyyyee and 2 nd :yyyyyyyyyfyyyyyyyyyy, 1 st : emiyyyyyyyyyyyyyyyyyyyyyy and 2 nd :yyyyyyyyyyyyyyyyyyyyy, 1 st :efyyyfyyyyyyyyyyyyyyyee and 2 nd :eeyyyyyyyyyyyyyyyyyy, 1 st : emiyyyyyyyyyyyyyyyyyyyyyy and 2 nd :eeyyyyyyyyyyyyyyyyyy, 1 st :efyyyfyyyyyyyyyyyyyyyee and 2 nd :yyyyyyyyyyyyyyyyyyyyy, 1 st :efyyyfyyyyyyyyyfyyyyee and 2 nd :eeyyyyfyfffyyyyyyy, 1 st : efyyyfyyyyyyyyyyyyyyy and 2 nd :yyyyyyyy5vyyyyyyyy, 1st :efyyyfyyyyyyyyyfyyyyee and 2 nd :yyyyyyyy5vyyyyyyyy, 1 st : efyyyfyyyyyyyyyyyyyyy and 2 nd :eeyyyyfyfffyyyyyyy, 1 st :efyyyfyyyyyyyyyfyyyyee and 2 nd :eeyyyyffyyyyyyyyy, 1 st : efyyyfyyyyyyyyyyyyyyy and 2 nd :yyyyyyfyyyyyyyyyy, 1 st :efyyyfyyyyyyyyyfyyyyee and 2 nd :yyyyyyfyyyyyyyyyy, 1 st : efyyyfyyyyyyyyyyyyyyy and 2 nd :eeyyyyffyyyyyyyyy, 1 st :e[FHNA]yydydyyyyfyfyfyyyyyee and 2 nd :eeyyyyfyfffyyyyyyyyy, 1 st :efyyyfyyyyyyyyyyyyyyyey and 2 nd :eeyyyyfyfffyyyyyyyyy, 1 st :efyyyfyyyyyyyyyyyyyyyey and 2 nd :yyyyyyyy5vyyyyyyyyyy,1 st :e[FHNA]yydydyyyyfyfyfyyyyyyy and 2 nd :yyyyyyyy5vyyyyyyyyyy,1 st :e[FHNA]yydydyyyyfyfyfyyyyyee and 2 nd :yyyyyyyy5vyyyyyyyyyy,1 st :e[FHNA]yydydyyyyfyfyfyyyyyyy and 2 nd :eeyyyyfyfffyyyyyyyyy, 1 st :e[FHNA]yydydyyyyfyfyfyyyyyee and 2 nd :eeyyyyyyyyyyyyyyyyyy, 1st : e[FHNA]yydydyyyyfyfyfyyyyyyy and 2 nd : yyyyyyfyfyfyyyyyyyyyy, 1 st : e[FHNA]yydydyyyyfyfyfyyyyyee and 2 nd : yyyyyyfyfyfyyyyyyyyyy, and 1 st : e[FHNA]yydydyyyyfyfyfyyyyyyy and 2 nd : selected from eeyyyyfyfyfyyyyyyyyee, wherein each "y" represents a 2'-OMe sugar moiety, each "e" represents a 2'-MOE sugar moiety, each "f" represents a 2'-fluoro sugar moiety, each "[FHNA]" represents a 3'-fluoro-hexitol sugar moiety, and each "d" represents a 2'-β-D-deoxyribosyl sugar moiety, the oligomer duplex according to any one of Embodiments A1 to A165.

[0661] Embodiment A168. The first modified oligonucleotide has a first sugar motif (1 st ), and the second modified oligonucleotide has a second sugar motif (2 nd ), and the first and second sugar motifs are in the following combinations (from 5' to 3'): 1 st : efyyyfyyyyyyyfyfyyyyyyy and 2 nd : yyyyyyfyfffyyyyyyyyyy, 1 st : efyyyfyyyyyyyfyfyyyyyee and 2 nd : eeyyyyfyfffyyyyyyyyee, 1 st : efyyyfyyyyyyyfyfyyyyyee and 2 nd : yyyyyyfyfffyyyyyyyyyy, and 1 st : efyyyfyyyyyyyfyfyyyyyyy and 2 nd : eeyyyyfyfffyyyyyyyyee, selected from, wherein each "y" represents a 2'-OMe sugar moiety, each "e" represents a 2'-MOE sugar moiety, and each "f" represents a 2'-fluoro sugar moiety, the oligomer duplex according to any one of Embodiments A1 to A165.

[0662] Embodiment A169. The first modified oligonucleotide is a first sugar motif (1 st ) has the second modified oligonucleotide, and the second sugar motif (2 nd ) has the following combination (5' to 3'): 1 st : emiyyyyyyyyyyyyyyyyyyyyyy and 2 nd :yyyyyyyyyyyyyyyyyyyyy, 1 st :efyyyfyyyyyyyyyyyyyyyee and 2 nd :eeyyyyyyyyyyyyyyyyyy, 1 st : emiyyyyyyyyyyyyyyyyyyyyyy and 2 nd :eeyyyyyyyyyyyyyyyyyy, 1 st :efyyyfyyyyyyyyyyyyyyyee and 2 nd :yyyyyyyyyyyyyyyyyyyyy, 1 st : emiyyyyyyyyyyyyyyyyyyyyyy and 2 nd :yyyyyyyyyydyyyyyyyyyy, 1 st :efyyyfyyyyyyyyyyyyyyyee and 2 nd :eeyyyyyyyydyyyyyyyyy, 1 st : emiyyyyyyyyyyyyyyyyyyyyyy and 2 nd :eeyyyyyyyydyyyyyyyyy, 1 st :efyyyfyyyyyyyyyyyyyyyee and 2 nd :yyyyyyyyyydyyyyyyyyyy, 1 st :efyyyyyyyyyyydatayyyyyyyee and 2 nd :eeyyyyfyfffyyyyyyyyy, 1 st : eiyyyyyyyyyyydatayyyyyyyyy and 2 nd :yyyyyyyy5vyyyyyyyyyy,1 st :efyyyyyyyyyyydatayyyyyyyee and 2 nd:yyyyyyyy5vyyyyyyyyyy,1 st : eiyyyyyyyyyyydatayyyyyyyyy and 2 nd :eeyyyyfyfffyyyyyyyyy, 1 st :efyyyyyyyyyyydatayyyyyyyee and 2 nd :eeyyyyyyyyyyyyyyyyyy, 1 st : eiyyyyyyyyyyydatayyyyyyyyy and 2 nd :yyyyyyyyyyyyyyyyyyyyy, 1 st :efyyyyyyyyyyydatayyyyyyyee and 2 nd :yyyyyyyyyyyyyyyyyyyyy, 1 st : eiyyyyyyyyyyydatayyyyyyyyy and 2 nd :eeyyyyyyyyyyyyyyyyyy, 1 st :efyyydyyyyyyyfyfyyyyyee and 2 nd :eeyyyyfyfffyyyyyyyyy, 1 st :efyyydyyyyyyydataydatayyyyyyy and 2 nd :yyyyyyyy5vyyyyyyyyyy,1 st :efyyydyyyyyyyfyfyyyyyee and 2 nd :yyyyyyyy5vyyyyyyyyyy,1 st :efyyydyyyyyyydataydatayyyyyyy and 2 nd :eeyyyyfyfffyyyyyyyyy, 1 st :efyyyfyyyyyyyyyfyyyyee and 2 nd :eeyyfyfffyyyyyyyyy, 1 st : efyyyfyyyyyyyyyyyyyyy and 2 nd :yyyyyy5vyyyyyyyyyy, 1 st :efyyyfyyyyyyyyyfyyyyee and 2 nd :yyyyyy5vyyyyyyyyyy, 1 st : efyyyfyyyyyyyyyyyyyyy and 2 nd: eeyyfyfffyyyyyyyyee, 1 st : efyyyfyyyyyyyfydyyyyyee and 2 nd : eeyyyyfyfffyyyyyyyyee, 1 st : efyyyfyyyyyyyfydyyyyyyy and 2 nd : yyyyyyfyfffyyyyyyyyyy, 1 st : efyyyfyyyyyyyfydyyyyyee and 2 nd : yyyyyyfyfffyyyyyyyyyy, 1 st : efyyyfyyyyyyyfydyyyyyyy and 2 nd : eeyyyyfyfffyyyyyyyyee, 1 st : e[FHNA]yyyfyyyyyyyfyfyyyyyee and 2 nd : eeyyyyfyfffyyyyyyyyee, 1 st : e[FHNA]yyyfyyyyyyyfyfyyyyyyy and 2 nd : yyyyyyfyfffyyyyyyyyyy, 1 st : e[FHNA]yyyfyyyyyyyfyfyyyyyee and 2 nd : yyyyyyfyfffyyyyyyyyyy, and 1 st : e[FHNA]yyyfyyyyyyyfyfyyyyyyy and 2 nd : selected from among eeyyyyfyfffyyyyyyyyee, wherein each "y" represents a 2'-OMe sugar moiety, each "e" represents a 2'-MOE sugar moiety, each "f" represents a 2'-fluoro sugar moiety, each "[FHNA]" represents a 3'-fluoro-hexitol sugar moiety, each "d" represents a 2'-β-D-deoxyribosyl sugar moiety, the oligomer duplex according to any one of Embodiments A1 to A165.

[0663] Embodiment A170. The first modified oligonucleotide has a first sugar motif (1 st ), and the second modified oligonucleotide has a second sugar motif (2 nd) has the following combination (5' to 3'): 1 st :efyyyyyyyyyyydatayyyyyyyee and 2 nd :eeyyyyyyyffyyyyyyyyy, 1 st : eiyyyyyyyyyyydatayyyyyyyyy and 2 nd :yyyyyyyyyfyyyyyyyyyy, 1 st :efyyyyyyyyyyydatayyyyyyyee and 2 nd :yyyyyyyyyfyyyyyyyyyy, 1 st : eiyyyyyyyyyyydatayyyyyyyyy and 2 nd :eeyyyyyyyffyyyyyyyyy, 1 st :efyyyyyyyyyyyyyyyyyyee and 2 nd :eeyyyyfyfffyyyyyyyyy, 1 st : emiyyyyyyyyyyyyyyyyyyyyy and 2 nd :yyyyyyyy5vyyyyyyyyyy,1 st :efyyyyyyyyyyyyyyyyyyee and 2 nd :yyyyyyyy5vyyyyyyyyyy,1 st : emiyyyyyyyyyyyyyyyyyyyyy and 2 nd :eeyyyyfyfffyyyyyyyyy, 1 st :efyyyyyyyyyyyyyyyyyyee and 2 nd :eeyyyyyyyffyyyyyyyyy, 1 st : emiyyyyyyyyyyyyyyyyyyyyy and 2 nd :yyyyyyyyyfyyyyyyyyyy, 1 st :efyyyyyyyyyyyyyyyyyyee and 2 nd :yyyyyyfyffyyyyyyyyyy, next to 1 st : emiyyyyyyyyyyyyyyyyyyyyy and 2 ndAn oligomeric double chain according to any one of Embodiments A1 to A165, selected from :eeyyyyfyfffyyyyyyyyyy, where each "y" represents a 2'-OMe sugar moiety, each "e" represents a 2'-MOE sugar moiety, and each "f" represents a 2'-fluoro sugar moiety.

[0664] Embodiment A171. An oligomer double chain according to any one of Embodiments A119 to A170, wherein the internucleoside bonds between the first and second nucleosides counting from the 5' end of the first modified oligonucleotide, and between the second and third nucleosides, and the internucleoside bonds between the first and second nucleosides counting from the 3' end of the first modified oligonucleotide, and between the second and third nucleosides, are phosphorothioate internucleoside bonds, and all other internucleoside bonds of the first modified oligonucleotide are phosphodiester internucleoside bonds.

[0665] Embodiment A172. An oligomer double chain according to any one of Embodiments A119 to A171, wherein the nucleoside bonds between the first and second nucleosides counting from the 5' end of the second modified oligonucleotide, and between the second and third nucleosides, and the nucleoside bonds between the first and second nucleosides counting from the 3' end of the second modified oligonucleotide, and between the second and third nucleosides, are phosphorothioate nucleoside bonds, and all other nucleoside bonds of the second modified oligonucleotide are phosphodiester nucleoside bonds.

[0666] Embodiment A173. An oligomeric double helix according to any one of Embodiments A119 to A172, wherein the nucleic acid base sequence of the first modified oligonucleotide includes or consists of any one of the nucleic acid base sequences of SEQ ID NOs: 967, 968, 971, 972, 974, 975, 1254, 1255, and 1033 to 1038.

[0667] Embodiment A174. The oligomeric double helix according to any one of Embodiments A1 to A171, wherein the cytosine nucleic acid base in the first and / or second modified oligonucleotide is optionally 5-methylcytosine.

[0668] Embodiment A175. An oligomeric double chain according to any one of Embodiments A119 to A174, wherein the double chain comprises a conjugate group including a conjugate moiety and a conjugate linker.

[0669] Embodiment A176. The oligomeric double chain according to Embodiment A175, wherein the conjugate portion comprises an active drug substance, an aliphatic chain, a lipid, a peptide, a protein, a hydrocarbon, a polyamine, a polyamide, a polyether, a thioether, an aptamer, an antibody or antibody fragment, a vitamin, a fatty acid, a carbohydrate, an intercalator, or a reporter molecule.

[0670] Embodiment A177. The oligomer double chain according to Embodiment A175, wherein the conjugate group comprises C22 alkyl, C20 alkyl, C17 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, or C5 alkyl, and the alkyl chain optionally has one or more unsaturated bonds.

[0671] Embodiment A178. The oligomeric double chain according to Embodiment A175, wherein the conjugate group comprises a 6-palmitamide hexyl moiety or a 2-(hydroxymethyl)-6-palmitamide hexyl moiety.

[0672] Embodiment A179. The oligomeric double helix according to Embodiment A175, wherein the double helix includes a conjugate portion that binds to a type 1 transferrin receptor (TfR1).

[0673] Embodiment A180. The oligomeric double chain according to Embodiment A179, wherein the conjugate portion is selected from an antibody or fragment thereof, a protein or peptide, or an aptamer that can bind to TfR1.

[0674] Embodiment A181. The oligomeric double chain according to Embodiment A180, wherein the conjugate portion is a cyclic protein or a cyclic peptide.

[0675] Embodiment A182. The oligomeric double chain according to Embodiment A181, wherein the conjugate group consists of a bicyclic ligand and a conjugate linker.

[0676] Embodiment A183. The oligomeric double chain according to Embodiment A182, wherein the bicyclic ligand comprises a polypeptide and a molecular skeleton consisting of 13 to 22 linked amino acids or amino acid mimes, and each of the first, second, and third amino acids of the polypeptide contains a reactive group, each separately forming a bond with the molecular skeleton, thereby forming two polypeptide loops bonded to the molecular skeleton.

[0677] Embodiment A184. The oligomeric double helix according to Embodiment A183, wherein the bicyclic ligand comprises a sequence selected from any one of sequence numbers 1071 to 1252.

[0678] Embodiment A185. An oligomeric double chain according to any one of Embodiments A182 to A184, wherein the conjugate linker includes a (bicyclo[6.1.0]nonine)-formyl (BCN) moiety.

[0679] Embodiment A186. The oligomeric double chain according to Embodiment A185, wherein the conjugate linker comprises a 6-(BCN-carbamate)-2-(hydroxymethyl)hexylphosphoryl moiety or a 6-(BCN-carbamate)hexylphosphoryl moiety.

[0680] Embodiment A187. An oligomeric double chain according to any one of Embodiments A119 to A174, comprising a conjugate group consisting of a conjugate moiety and a conjugate linker, wherein the linker comprises a 6-(BCN-carbamate)-2-(hydroxymethyl)hexylphosphoryl moiety or a 6-(BCN-carbamate)hexylphosphoryl moiety.

[0681] Embodiment A188. Chemical notation below: A peptide having Ac-CP[HyP]DAYLGC[tBuGly]SYCEPW[K(N3)]-NH2 (SEQ ID NO: 1045), During the ceremony, Ac=acetylester C = cysteine, P = proline, D = aspartic acid, A = Alanine, Y = tyrosine, L = leucine, G = glycine, S = serine, E = glutamic acid, W = tryptophan, [HyP] = trans-4-hydroxy-L-proline, [tBuGly] = t-butyl-glycine, [K(N3)] = 6-azidridine, An oligomeric double chain according to any one of Embodiments A119 to A174, comprising a bicyclic compound containing a peptide, wherein each cysteine ​​forms a covalent bond with the molecular skeleton 1,1',1''-(1,3,5-triazinan-1,3,5-triyl)tris(2-bromoetanone) (TATB).

[0682] Embodiment A189. The following structure:

[0683] [ka] An oligomeric double chain according to any one of Embodiments A119 to A174, comprising a bicyclic compound having a salt thereof (wherein Q is N3 (BCY17901, SEQ ID NO: 1045), NH2 (BCY21757, SEQ ID NO: 1202), SH (BCY21758, SEQ ID NO: 1203), a conjugate linker, or a conjugate linker covalently bonded to an oligonucleotide).

[0684] Embodiment A190. The oligomeric double chain according to Embodiment A188, wherein Q is N3.

[0685] Embodiment A191. An oligomeric double chain according to any one of Embodiments A119 to A174, comprising a conjugate group having the following structure.

[0686] [ka]

[0687] Embodiment A192. An oligomeric double chain according to any one of Embodiments A119 to A174, comprising a conjugate group having the following structure.

[0688] [ka]

[0689] Embodiment A193. An oligomeric double chain according to any one of Embodiments A175 to A191, wherein the bicyclic compound or conjugate group is bonded to the second modified oligonucleotide.

[0690] Embodiment A194. The oligomeric double chain according to any one of Embodiments A175 to A191, wherein the bicyclic compound or conjugate group is bonded to the 5' or 3' end of the second modified oligonucleotide.

[0691] Embodiment A195. An oligomeric double helix according to any one of Embodiments A175 to A191, wherein the bicyclic compound or conjugate group is bonded to the 5' terminal nucleoside of the second modified oligonucleotide.

[0692] Embodiment A196. Chemical notation below: vPT es U fs U yo A yo A yo G do A yo U yo G yo A yo G yo A yo C yo A fo G yo A fo A yo A yo U yo U yo G ys A es A e An oligomeric compound comprising an oligonucleotide modified by (SEQ ID NO: 1033), wherein, A = adenine nucleic acid base, C = cytosine nucleic acid base, G = guanine nucleic acid base, T=thymine nucleobase, U = uracil nucleic acid base, d = 2'-β-D-deoxyribosyl sugar moiety, e=2'-MOE sugar moiety, f = 2'-fluorosugar portion, y=2'-OMe sugar moiety, o = phosphodiester nucleoside interbonding, s = phosphorothioate nucleoside bond, and An oligomeric compound in which the vP=5' vinylphosphonate portion is located.

[0693] Embodiment A197. Chemical notation below: m C es A es A yo U yo Uyo U yo C yo U yo G yo U fo C fo U yo C yo A yo U yo C yo U yo U yo A ys A es A e An oligomeric compound comprising an oligonucleotide modified by (SEQ ID NO: 1027), wherein the formula, A = adenine nucleic acid base, m C=5-methylcytosine nucleic acid base, C = cytosine nucleic acid base, G = guanine nucleic acid base, U = uracil nucleic acid base, e=2'-MOE sugar moiety, f = 2'-fluorosugar portion, y=2'-OMe sugar moiety, o = phosphodiester nucleoside bond, and An oligomeric compound in which s = phosphorothioate nucleoside bond.

[0694] Embodiment A198. Chemical notation below: [Ac-C P[HyP]DAYLGC[tBuGly]SYCEPW[K(N3)]-NH2]-[6-(BCN-carbamate)hexyl] o m C es A es A yo U yo U yo U yo C yo U yo G yo U fo C fo U yo C yo A yo U yo C yo U yo U yo A ysA es A e An oligomeric compound comprising a conjugated modified oligonucleotide according to (SEQ ID NO: 1039), wherein the formula is: Ac=acetyl, C=cysteine, [HyP]=trans-4-hydroxy-L-proline, D=aspartic acid, A=alanine, Y=tyrosine, L=leucine, G=glycine, [tBuGly]=t-butylglycine, S=serine, E=glutamic acid, P=proline, W=tryptophan, [K(N3)]=6-azidridin, NH2=amino, BCN=(bicyclo[6.1.0]nonine)-formyl, m C=5-methylcytosine nucleic acid base, C=cytosine nucleic acid base, A=adenine nucleic acid base, G=guanine nucleic acid base, U=uracil nucleic acid base, e=2'-MOE sugar moiety, f=2'-fluoro sugar moiety, y=2'-OMe sugar moiety, o=phosphodiester nucleoside bond, and s=phosphorothioate nucleoside bond. This oligomeric compound is formed in which each cysteine ​​molecule forms a covalent bond with the molecular skeleton 1,1',1''-(1,3,5-triazinan-1,3,5-triyl)tris(2-bromoetanone) (TATB).

[0695] Embodiment A199. An oligomeric double chain comprising the oligomeric compound described in Embodiment A195 and the oligomeric compound described in Embodiment A196.

[0696] Embodiment A200. An oligomeric double chain comprising the oligomeric compound described in Embodiment A195 and the oligomeric compound described in Embodiment A197.

[0697] Embodiment A201. Chemical notation below: vP-T es U fs U yo A yo A do G yo A do U yo G yo A yo G yo A yo C yo A fo Gyo A fo A yo A yo U yo U yo G ys A es A e An oligomeric compound comprising an oligonucleotide modified by (SEQ ID NO: 1034), wherein, A = adenine nucleic acid base, C = cytosine nucleic acid base, G = guanine nucleic acid base, T=thymine nucleobase, U = uracil nucleic acid base, d = 2'-β-D-deoxyribosyl sugar moiety, e=2'-MOE sugar moiety, f = 2'-fluorosugar portion, y=2'-OMe sugar moiety, o = phosphodiester nucleoside interbonding, s = phosphorothioate nucleoside bond, and An oligomeric compound in which the vP=5' vinylphosphonate portion is located.

[0698] Embodiment A202. Chemical notation below: C es A es A yo U yo U yo U yo C fo U yo G fo U yo C fo U yo C yo A yo U yo C yo U yo U yo A ys A es A e An oligomeric compound comprising an oligonucleotide modified by (SEQ ID NO: 1028), wherein the formula, A = adenine nucleic acid base, C = cytosine nucleic acid base, G = guanine nucleic acid base, U = uracil nucleic acid base, e=2'-MOE sugar moiety, f = 2'-fluorosugar portion, y=2'-OMe sugar moiety, o = phosphodiester nucleoside bond, and An oligomeric compound in which s = phosphorothioate nucleoside bond.

[0699] Embodiment A203. Chemical notation below: [Ac-C P[HyP]DAYLGC[tBuGly]SYCEPW[K(N3)]-NH2]-[6-(BCN-carbamate)hexyl] o C es A es A yo U yo U yo U yo C fo U yo G fo U yo C fo U yo C yo A yo U yo C yo U yo U yo A ys A es A e( An oligomeric compound comprising a conjugated modified oligonucleotide according to SEQ ID NO: 1040, wherein, Ac=acetyl, C=cysteine, [HyP]=trans-4-hydroxy-L-proline, D=aspartic acid, A=alanine, Y=tyrosine, L=leucine, G=glycine, [tBuGly]=t-butylglycine, S=serine, E=glutamic acid, P=proline, W=tryptophan, [K(N3)]=6-azidridin, NH2=amino, BCN=(bicyclo[6.1.0]nonine)-formyl, C=cytosine nucleic acid base, A=adenine nucleic acid base, G=guanine nucleic acid base, U=uracil nucleic acid base, e=2'-MOE sugar moiety, f=2'-fluoro sugar moiety, y=2'-OMe sugar moiety, o=phosphodiester nucleoside bond, and s=phosphorothioate nucleoside bond. This oligomeric compound is formed in which each cysteine ​​molecule of the peptide forms a covalent bond with the molecular skeleton of 1,1',1''-(1,3,5-triazinan-1,3,5-triyl)tris(2-bromoetanone) (TATB).

[0700] Embodiment A204. An oligomeric double chain comprising the oligomeric compound described in Embodiment A200 and the oligomeric compound described in Embodiment A201.

[0701] Embodiment A205. An oligomeric double chain comprising the oligomeric compound described in Embodiment A200 and the oligomeric compound described in Embodiment A202.

[0702] Embodiment A206. Chemical notation below: vPT es A fs U yo A yo A yo A do U yo A yo G yo A yo U yo U yo C yo U fo G yo U fo A yo G yo C yo U yo U ys A es A e An oligomeric compound comprising an oligonucleotide modified by (SEQ ID NO: 1035), wherein, A = adenine nucleic acid base, C = cytosine nucleic acid base, G = guanine nucleic acid base, T=thymine nucleobase, U = uracil nucleic acid base, d = 2'-β-D-deoxyribosyl sugar moiety, e=2'-MOE sugar moiety, f = 2'-fluorosugar portion, y=2'-OMe sugar moiety, o = phosphodiester nucleoside interbonding, s = phosphorothioate nucleoside bond, and An oligomeric compound in which the vP=5' vinylphosphonate portion is located.

[0703] Embodiment A207. Chemical notation below: A es A es G yo C yo U yo A yo C yo A yo G yo A fo A fo U yo C yo U yo A yo U yo U yo U yo A ys T es A e An oligomeric compound comprising an oligonucleotide modified by (SEQ ID NO: 1029), wherein the formula, A = adenine nucleic acid base, C = cytosine nucleic acid base, G = guanine nucleic acid base, T=thymine nucleobase, U = uracil nucleic acid base, e=2'-MOE sugar moiety, f = 2'-fluorosugar portion, y=2'-OMe sugar moiety, o = phosphodiester nucleoside bond, and An oligomeric compound in which s = phosphorothioate nucleoside bond.

[0704] Embodiment A208. Chemical notation below: [Ac-C P[HyP]DAYLGC[tBuGly]SYCEPW[K(N3)]-NH2]-[6-(BCN-carbamate)hexyl] o A es A es G yo C yo U yo A yo C yo A yo Gyo A fo A fo U yo C yo U yo A yo U yo U yo U yo A ys T es A e An oligomeric compound comprising a conjugated modified oligonucleotide according to (SEQ ID NO: 1041), wherein the formula, Ac=acetyl, C=cysteine, [HyP]=trans-4-hydroxy-L-proline, D=aspartic acid, A=alanine, Y=tyrosine, L=leucine, G=glycine, [tBuGly]=t-butylglycine, S=serine, E=glutamic acid, P=proline, W=tryptophan, [K(N3)]=6-azidridin, NH2=amino, BCN=(bicyclo[6.1.0]nonine)-formyl, C=cytosine nucleic acid base, A=adenine nucleic acid base, G=guanine nucleic acid base, T=thymine nucleic acid base, U=uracil nucleic acid base, e=2'-MOE sugar moiety, f=2'-fluoro sugar moiety, y=2'-OMe sugar moiety, o=phosphodiester nucleoside bond, and s=phosphorothioate nucleoside bond. This oligomeric compound is formed in which each cysteine ​​molecule of the peptide forms a covalent bond with the molecular skeleton of 1,1',1''-(1,3,5-triazinan-1,3,5-triyl)tris(2-bromoetanone) (TATB).

[0705] Embodiment A209. An oligomeric double chain comprising the oligomeric compound described in Embodiment A205 and the oligomeric compound described in Embodiment A206.

[0706] Embodiment A210. An oligomer compound comprising the oligomer compound described in Embodiment A205 and the oligomer compound described in Embodiment A207.

[0707] Embodiment A211. Chemical notation below: vPT es A fs U yo A yo Ado A yo T do A yo G yo A yo U yo U yo C yo U fo G yo U fo A yo G yo C yo U yo U ys A es A e An oligomeric compound comprising an oligonucleotide modified by (SEQ ID NO: 1036), wherein, A = adenine nucleic acid base, C = cytosine nucleic acid base, G = guanine nucleic acid base, T=thymine nucleobase, U = uracil nucleic acid base, d = 2'-β-D-deoxyribosyl sugar moiety, e=2'-MOE sugar moiety, f = 2'-fluorosugar portion, y=2'-OMe sugar moiety, o = phosphodiester nucleoside interbonding, s = phosphorothioate nucleoside bond, and An oligomeric compound in which the vP=5' vinylphosphonate portion is located.

[0708] Embodiment A212. Chemical notation below: A es A es G yo C yo U yo A yo C fo A yo G fo A yo A fo U yo C yo U yo A yo U yo U yo U yo A ys U es A eAn oligomeric compound comprising an oligonucleotide modified by (SEQ ID NO: 1030), wherein the formula, A = adenine nucleic acid base, C = cytosine nucleic acid base, G = guanine nucleic acid base, U = uracil nucleic acid base, e=2'-MOE sugar moiety, f = 2'-fluorosugar portion, y=2'-OMe sugar moiety, o = phosphodiester nucleoside bond, and An oligomeric compound in which s = phosphorothioate nucleoside bond.

[0709] Embodiment A213. The following chemical notation: [Ac-C P[HyP]DAYLGC[tBuGly]SYCEPW[K(N3)]-NH2]-[6-(BCN-carbamate)hexyl] o A es A es G yo C yo U yo A yo C fo A yo G fo A yo A fo U yo C yo U yo A yo U yo U yo U yo A ys U es A e An oligomeric compound comprising a conjugated modified oligonucleotide according to (SEQ ID NO: 1042), wherein, Ac=acetyl, C=cysteine, [HyP]=trans-4-hydroxy-L-proline, D=aspartic acid, A=alanine, Y=tyrosine, L=leucine, G=glycine, [tBuGly]=t-butylglycine, S=serine, E=glutamic acid, P=proline, W=tryptophan, [K(N3)]=6-azidridin, NH2=amino, BCN=(bicyclo[6.1.0]nonine)-formyl, C=cytosine nucleic acid base, A=adenine nucleic acid base, G=guanine nucleic acid base, U=uracil nucleic acid base, e=2'-MOE sugar moiety, f=2'-fluoro sugar moiety, y=2'-OMe sugar moiety, o=phosphodiester nucleoside bond, and s=phosphorothioate nucleoside bond. This oligomeric compound is formed in which each cysteine ​​molecule of the peptide forms a covalent bond with the molecular skeleton of 1,1',1''-(1,3,5-triazinan-1,3,5-triyl)tris(2-bromoetanone) (TATB).

[0710] Embodiment A214. An oligomeric double chain comprising the oligomeric compound described in Embodiment A210 and the oligomeric compound described in Embodiment A211.

[0711] Embodiment A215. An oligomeric double chain comprising the oligomeric compound described in Embodiment A210 and the oligomeric compound described in Embodiment A212.

[0712] Embodiment A216. Chemical notation below: vPT es U fs A yo A yo G yo T do U yo U yo U yo A yo G yo U yo C yo U fo U yo A fo A yo U yo C yo U yo U ys A es Ae An oligomeric compound comprising an oligonucleotide modified by (SEQ ID NO: 1037), wherein the formula, A = adenine nucleic acid base, C = cytosine nucleic acid base, G = guanine nucleic acid base, T=thymine nucleobase, U = uracil nucleic acid base, d = 2'-β-D-deoxyribosyl sugar moiety, e=2'-MOE sugar moiety, f = 2'-fluorosugar portion, y=2'-OMe sugar moiety, o = phosphodiester nucleoside interbonding, s = phosphorothioate nucleoside bond, and An oligomeric compound in which the vP=5' vinylphosphonate portion is located.

[0713] Embodiment A217. Chemical notation below: A es A es G yo A yo U yo U yo A yo A yo G yo A fo C fo U yo A yo A yo A yo A yo C yo U yo U ys A es A e An oligomeric compound comprising an oligonucleotide modified by (SEQ ID NO: 1031), wherein the formula, A = adenine nucleic acid base, C = cytosine nucleic acid base, G = guanine nucleic acid base, U = uracil nucleic acid base, e=2'-MOE sugar moiety, f = 2'-fluorosugar portion, y=2'-OMe sugar moiety, o = phosphodiester nucleoside bond, and An oligomeric compound in which s = phosphorothioate nucleoside bond.

[0714] Embodiment A218. The following chemical notation: [Ac-C P[HyP]DAYLGC[tBuGly]SYCEPW[K(N3)]-NH2]-[6-(BCN-carbamate)hexyl] o A es A es G yo A yo U yo U yo A yo A yo G yo A fo C fo U yo A yo A yo A yo A yo C yo U yo U ys A es A e An oligomeric compound comprising a conjugated modified oligonucleotide according to (SEQ ID NO: 1043), wherein, Ac=acetyl, C=cysteine, [HyP]=trans-4-hydroxy-L-proline, D=aspartic acid, A=alanine, Y=tyrosine, L=leucine, G=glycine, [tBuGly]=t-butylglycine, S=serine, E=glutamic acid, P=proline, W=tryptophan, [K(N3)]=6-azidridin, NH2=amino, BCN=(bicyclo[6.1.0]nonine)-formyl, C=cytosine nucleic acid base, A=adenine nucleic acid base, G=guanine nucleic acid base, U=uracil nucleic acid base, e=2'-MOE sugar moiety, f=2'-fluoro sugar moiety, y=2'-OMe sugar moiety, o=phosphodiester nucleoside bond, and s=phosphorothioate nucleoside bond. This oligomeric compound is formed in which each cysteine ​​molecule of the peptide forms a covalent bond with the molecular skeleton of 1,1',1''-(1,3,5-triazinan-1,3,5-triyl)tris(2-bromoetanone) (TATB).

[0715] Embodiment A219. An oligomeric double helix comprising the modified oligonucleotide described in Embodiment A215 and the modified oligonucleotide described in Embodiment A216.

[0716] Embodiment A220. An oligomeric double helix comprising the modified oligonucleotide described in Embodiment A215 and the conjugate described in Embodiment A217.

[0717] Embodiment A221. Chemical notation below: vPT es U fs A yo A yo G do U yo T do U yo U yo A yo G yo U yo C yo U fo U yo A fo A yo U yo C yo U yo U ys A es A e An oligomeric compound comprising an oligonucleotide modified by (SEQ ID NO: 1038), wherein the formula, A = adenine nucleic acid base, C = cytosine nucleic acid base, G = guanine nucleic acid base, T=thymine nucleobase, U = uracil nucleic acid base, d = 2'-β-D-deoxyribosyl sugar moiety, e=2'-MOE sugar moiety, f = 2'-fluorosugar portion, y=2'-OMe sugar moiety, o = phosphodiester nucleoside interbonding, s = phosphorothioate nucleoside bond, and An oligomeric compound in which vP = 5' vinylphosphonate moiety.

[0718] Embodiment A222. Chemical notation below: A es A es G yo A yo U yo U yo A fo A yo G fo A yo C fo U yo A yo A yo A yo A yo C yo U yo U ys A es A e An oligomeric compound comprising an oligonucleotide modified by (SEQ ID NO: 1032), wherein the formula, A = adenine nucleic acid base, C = cytosine nucleic acid base, G = guanine nucleic acid base, U = uracil nucleic acid base, e=2'-MOE sugar moiety, f = 2'-fluorosugar portion, y=2'-OMe sugar moiety, o = phosphodiester nucleoside bond, and An oligomeric compound in which s = phosphorothioate nucleoside bond.

[0719] Embodiment A223. The following chemical notation: [Ac-C P[HyP]DAYLGC[tBuGly]SYCEPW[K(N3)]-NH2]-[6-(BCN-carbamate)hexyl] o A es A es G yo A yo U yo U yo A fo A yo G fo A yo C fo U yo A yo A yo Ayo A yo C yo U yo U ys A es A e An oligomeric compound comprising a conjugated modified oligonucleotide according to (SEQ ID NO: 1044), wherein, Ac=acetyl, C=cysteine, [HyP]=trans-4-hydroxy-L-proline, D=aspartic acid, A=alanine, Y=tyrosine, L=leucine, G=glycine, [tBuGly]=t-butylglycine, S=serine, E=glutamic acid, P=proline, W=tryptophan, [K(N3)]=6-azidridin, NH2=amino, BCN=(bicyclo[6.1.0]nonine)-formyl, C=cytosine nucleic acid base, A=adenine nucleic acid base, G=guanine nucleic acid base, U=uracil nucleic acid base, e=2'-MOE sugar moiety, f=2'-fluoro sugar moiety, y=2'-OMe sugar moiety, o=phosphodiester nucleoside bond, and s=phosphorothioate nucleoside bond. This oligomeric compound is formed in which each cysteine ​​molecule of the peptide forms a covalent bond with the molecular skeleton of 1,1',1''-(1,3,5-triazinan-1,3,5-triyl)tris(2-bromoetanone) (TATB).

[0720] Embodiment A224. An oligomeric double chain comprising the oligomeric compound described in Embodiment A220 and the oligomeric compound described in Embodiment A221.

[0721] Embodiment A225. An oligomeric double chain comprising the oligomeric compound described in Embodiment A220 and the oligomeric compound described in Embodiment A222.

[0722] A268. A group of oligomeric double chains or oligomeric compounds according to any one of Embodiments A1 to A225, which are concentrated with respect to a first and / or second modified oligonucleotide comprising at least one specific phosphorothioate nucleoside bond having a specific stereochemical configuration.

[0723] Embodiment A269. The population according to Embodiment A267, wherein the population is enriched with respect to a first and / or second modified oligonucleotide comprising at least one specific phosphorothioate nucleoside linkage having a (Sp) or (Rp) configuration.

[0724] Embodiment A270. An oligomeric double-chain or oligomeric compound according to any one of Embodiments A1 to A225, wherein the first modified oligonucleotide consists of 23 linked nucleosides, and the second modified oligonucleotide consists of 21 linked nucleosides.

[0725] Embodiment A271. An antisense compound comprising or consisting of an oligomeric double chain or oligomeric compound described in any one of Embodiments A1 to A225.

[0726] Embodiment A272. The antisense compound according to Embodiment A270, wherein the antisense compound is an RNAi agent capable of reducing the amount of PLN nucleic acid through the activation of RISC / Ago2.

[0727] Embodiment A273. A pharmaceutical composition comprising an oligomeric double-chain or oligomeric compound described in any one of Embodiments A1 to A225 or A269, a group described in any one of Embodiments A267 to A268, or an antisense compound described in Embodiment A270 or A271, and a pharmaceutically acceptable diluent or carrier.

[0728] Embodiment A274. The pharmaceutical composition according to Embodiment A272, wherein the pharmaceutically acceptable diluent is water or phosphate-buffered saline.

[0729] Embodiment A275. The pharmaceutical composition according to Embodiment A273, wherein the pharmaceutical composition essentially consists of an oligomeric double chain, an oligomeric compound, or an antisense compound, and water or phosphate-buffered saline.

[0730] Embodiment A276. A method for reducing the amount of PLN RNA or PLN protein in cells, tissues, organs, or subjects, comprising contacting the cells, tissues, organs, or subjects with an oligomeric double-strand or oligomeric compound described in any one of Embodiments A1 to A225 or A269, a population described in any one of Embodiments A267 to A268, an antisense compound described in Embodiment A270 or A271, or a pharmaceutical composition described in any one of Embodiments A272 to A274.

[0731] Embodiment A277. The method according to Embodiment A275, wherein the cells are muscle cells and / or cardiac cells.

[0732] Embodiment A278. A method comprising administering to a subject an oligomeric double-chain or oligomeric compound described in any one of Embodiments A1 to A225 or A269, a population described in any one of Embodiments A267 to A268, an antisense compound described in Embodiment A270 or A271, or a pharmaceutical composition described in any one of Embodiments A272 to A274, wherein the subject has or is at risk of developing a cardiovascular or cardiac injury, disease, condition or disorder, cardiomyopathy, cardiac arrhythmia, and / or heart failure.

[0733] Embodiment A279. A method for preventing or treating a disease, disorder, condition, or injury related to cardiac calcium misregulation, or a method for delaying the symptoms of a disease, disorder, or condition related to an injured, weakened, and / or overworked heart, comprising administering to a subject having or at risk of having a disease, disorder, or condition related to cardiac calcium misregulation a therapeutically effective amount of an oligomeric double-chain or oligomeric compound described in any one of Embodiments A1 to A225 or A269, a population described in any one of Embodiments A267 to A268, an antisense compound described in Embodiment A270 or A271, or a pharmaceutical composition described in any one of Embodiments A272 to A274, wherein the disease, disorder, condition, or injury is selected from a disease, disorder, condition, or injury of the heart or cardiovascular system, cardiomyopathy, cardiac arrhythmia, and / or heart failure.

[0734] Embodiment A280. A method for preventing or treating a cardiac or cardiovascular disease, disorder, condition, or injury related to heart failure, or for delaying the symptoms of heart failure, comprising administering to a subject who has or is at risk of having a cardiac or cardiovascular disease, disorder, condition, or injury, an effective dose of an oligomeric double-chain or oligomeric compound described in any one of Embodiments A1 to A225 or A269, a population described in any one of Embodiments A267 to A268, an antisense compound described in Embodiment A270 or A271, or a pharmaceutical composition described in any one of Embodiments A272 to A274, wherein the disease, disorder, condition, or injury is cardiomyopathy, cardiac arrhythmia, and / or heart failure.

[0735] Embodiment A281. A method for reducing the amount of PLN RNA and / or PLN protein in the heart of a subject having, or at risk of developing, a disease, disorder, or condition related to an injured, weakened, and / or overworked heart, comprising administering to a subject having, or at risk of developing, a therapeutically effective amount of an oligomeric double-strand or oligomeric compound according to any one of Embodiments A1 to A225 or A269, a population according to any one of Embodiments A267 to A268, an antisense compound according to Embodiment A270 or A271, or a pharmaceutical composition according to any one of Embodiments A272 to A274, wherein the disease, disorder, condition, or injury is cardiomyopathy, cardiac arrhythmia, and / or heart failure.

[0736] Embodiment A282. The method according to any one of Embodiments A275 to A280, wherein the amount of PLN RNA and / or PLN protein in the target myocardium is reduced.

[0737] Embodiment A283. The method according to any one of Embodiments A276 to A281, wherein the disease, disorder, or condition is cardiomyopathy or arrhythmia.

[0738] Embodiment A284. The method according to Embodiment A282, wherein the cardiomyopathy is a hereditary cardiomyopathy.

[0739] Embodiment A285. The method according to Embodiment A283, wherein the hereditary cardiomyopathy is associated with a p.Arg14del, Arg9Cys(R9C), or Arg25Cys(R25C) gene mutation.

[0740] Embodiment A286. The method according to Embodiment A282, wherein the cardiomyopathy is dilated cardiomyopathy (DCM).

[0741] Embodiment A287. The method according to Embodiment A285, wherein the DCM is a hereditary DCM.

[0742] Embodiment A288. The method according to Embodiment A286, wherein the hereditary DCM is associated with TTN, LMNA, RBM20, SCN5A, MYH7, TNNT2, and TPM1 mutations.

[0743] Embodiment A289. The method according to Embodiment A285, wherein the DCM is an arrhythmogenic DCM.

[0744] Embodiment A290. The method according to any one of Embodiments A277 to A281, wherein the heart failure is heart failure with preserved ejection fraction (HFpEF), heart failure with reduced ejection fraction (HFrEF), acute heart failure, or exacerbation of chronic heart failure.

[0745] Embodiment A291. The method according to Embodiment A282, wherein the arrhythmia is ventricular tachycardia (vtac) or ventricular fibrillation (vfib).

[0746] Embodiment A292. The method according to Embodiment A278, wherein the symptoms of a disease, disorder, or condition related to an injured, weakened, and / or overworked heart, or heart failure, are reduced myocardial contractility and / or impaired cardiac relaxation.

[0747] Embodiment A293. The method according to any one of Embodiments A277A to A291, wherein the method prevents or delays the effects of an injured, weakened, and / or overworked heart and / or the progression of heart failure.

[0748] Embodiment A294. Administration of an oligomeric double-chain or oligomeric compound described in any one of Embodiments A1 to A225 or A269, a population described in any one of Embodiments A267 to A268, an antisense compound described in Embodiment A270 or A271, or a pharmaceutical composition described in any one of Embodiments A272 to A274 results in improvements in cardiac function, cardiovascular death, cardiomegaly, cardiac 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 flow profile, left ventricle (LV) strain, left ventricle (LV) strain rate, infarct size, hospitalization due to heart failure, and 6-minute walk test results in the subject. The method according to any one of embodiments A277 to A291, which improves the test (6MWT), Kansas City Cardiomyopathy Questionnaire Score (KCCQS), heart rate, or cardiac rhythm.

[0749] Embodiment A295. The method according to any one of Embodiments A275 to A293, wherein the oligomeric double chain or oligomeric compound described in any one of Embodiments A1 to A225 or A269, the group described in any one of Embodiments A267 to A268, the antisense compound described in Embodiment A270 or A271, or the pharmaceutical composition described in any one of Embodiments A272 to A274 comprises a conjugate moiety having affinity for a transferrin receptor.

[0750] Embodiment A296. The method according to any one of Embodiments A275 to A293, wherein the oligomeric double chain or oligomeric compound described in any one of Embodiments A1 to A225 or A269, the group described in any one of Embodiments A267 to A268, the antisense compound described in Embodiment A270 or A271, or the pharmaceutical composition described in any one of Embodiments A272 to A274 comprises a bicyclic compound having affinity for a transferrin receptor.

[0751] Embodiment A297. Use of an oligomeric double-chain or oligomeric compound according to any one of Embodiments A1 to A225 or A269, a group according to any one of Embodiments A267 to A268, an antisense compound according to Embodiment A270 or A271, or a pharmaceutical composition according to any one of Embodiments A272 to A274 for the treatment or prevention of a disease, disorder, or condition associated with an injured, weakened, and / or overworked heart or heart failure.

[0752] Embodiment A298. Use of an oligomeric double-chain or oligomeric compound according to any one of Embodiments A1 to A225 or A269, a group according to any one of Embodiments A267 to A268, an antisense compound according to Embodiment A270 or A271, or a pharmaceutical composition according to any one of Embodiments A272 to A274 in the manufacture of a pharmaceutical for the treatment or prevention of a disease, disorder, or condition associated with an injured, weakened, and / or overworked heart or heart failure.

[0753] Embodiment A299. The use according to Embodiment A296 or A297, wherein the disease, disorder, or condition relating to or relating to a damaged, weakened, and / or overworked heart is cardiomyopathy, cardiac arrhythmia, and / or heart failure.

[0754] Embodiment A300. The use described in Embodiment A298, wherein the cardiomyopathy is a hereditary cardiomyopathy.

[0755] Embodiment A301. The use described in Embodiment A299, wherein the hereditary cardiomyopathy is associated with a p.Arg14del, Arg9Cys(R9C), or Arg25Cys(R25C) gene mutation.

[0756] Embodiment A302. The use described in Embodiment A298, wherein the cardiomyopathy is dilated cardiomyopathy (DCM).

[0757] Embodiment A303. The use described in Embodiment A301, wherein the DCM is a hereditary DCM.

[0758] Embodiment A304. The hereditary DCM is associated with TTN, LMNA, RBM20, SCN5A, MYH7, TNNT2, and TPM1 mutations, as described in Embodiment A302.

[0759] Embodiment A305. The use described in Embodiment A301, wherein the DCM is an arrhythmogenic DCM.

[0760] Embodiment A306. The use described in Embodiment A298, wherein the heart failure is heart failure with maintained ejection fraction (HFpEF), heart failure with reduced ejection fraction (HFrEF), acute heart failure, or exacerbation of chronic heart failure.

[0761] Embodiment A307. The use according to Embodiment A298, wherein the arrhythmia is ventricular tachycardia (vtac) or ventricular fibrillation (vfib).

[0762] Embodiment B1. An oligomeric double chain comprising a first oligomeric compound and a second oligomeric compound, (1) The first oligomer compound comprises a modified oligonucleotide consisting of 8 to 50 linked nucleosides, wherein the nucleic acid base 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 nucleic acid bases of any one nucleic acid base sequence from SEQ ID NOs. 3 to 314, 627 to 782, 939 to 976, 1033 to 1038, or 1254 to 1255, and each of the nucleosides of the first modified oligonucleotide independently comprises a modified sugar moiety or sugar surrogate, and at least one modified nucleoside of the first modified oligonucleotide and less than 40% of the nucleoside contain fluorine. (2) An oligomeric double helix comprising a second oligomeric compound comprising a modified oligonucleotide consisting of 8 to 50 consecutively linked nucleosides, wherein the nucleic acid base 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 nucleic acid bases of any one nucleic acid base sequence among SEQ ID NOs. 315 to 626, 783 to 938, 977 to 1016, or 1027 to 1032, each of the nucleosides of the second modified oligonucleotide independently comprises a modified sugar moiety or sugar surrogate, and less than 40% of the nucleosides of the second modified oligonucleotide contain fluorine.

[0763] Embodiment B2. The oligomeric double helix according to Embodiment B1, wherein the first modified oligonucleotide is at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% complementary to the isolength portion of the PLN nucleic acid, and the PLN nucleic acid has the nucleic acid base sequence of SEQ ID NO: 1 or SEQ ID NO: 2.

[0764] Embodiment B3. An oligomeric double chain according to Embodiment B1 or B2, wherein each of the nucleosides of the first modified oligonucleotide independently comprises a modified sugar moiety or sugar surrogate independently selected from a 2'-F sugar moiety, a 2'-MOE sugar moiety, a 2'-OMe sugar moiety, a 2'-deoxyribosyl sugar moiety, and a 3'-fluorohexitol sugar moiety.

[0765] Embodiment B4. An oligomeric double chain according to any one of Embodiments B1 to B3, wherein less than 35%, less than 30%, less than 25%, less than 20%, less than 15%, less than 14%, less than 13%, less than 12%, less than 10%, less than 5%, or less than 1% of the nucleoside in the first modified oligonucleotide contains fluorine.

[0766] Embodiment B5. An oligomer double chain according to any one of Embodiments B1 to B4, wherein one or fewer nucleosides, two or fewer nucleosides, three or fewer nucleosides, or four or fewer nucleosides in the first modified oligonucleotide contain a fluorine-containing modified sugar moiety or a fluorine-containing sugar surrogate.

[0767] Embodiment B6. An oligomer double chain according to any one of Embodiments B1 to B5, wherein the space between the 3rd and 21st nucleosides from the 5' end of the modified oligonucleotide, and one or fewer nucleosides, two or fewer nucleosides, or three or fewer nucleosides in the sequence of the first modified oligonucleotide containing them, contain a fluorine-containing modified sugar moiety or a fluorine-containing sugar surrogate.

[0768] Embodiment B7. A nucleoside containing a fluorine-containing modified sugar moiety or a fluorine-containing sugar surrogate of the first modified oligonucleotide is independently, i. The second nucleoside from the 5' end, ii. The 14th and 16th nucleosides counting from the 5' end, or iii. Selected from the 2nd, 14th, and 16th nucleosides counting from the 5' end, The oligomer double chain according to any one of Embodiments B1 to 6, wherein each of the fluorine-containing modified sugar moieties or fluorine-containing sugar surrogates is independently a 2'-fluorosugar moiety or a 3'-fluoro-hexitol sugar moiety.

[0769] Embodiment B8. An oligomeric double chain according to any one of Embodiments B1 to B7, wherein one or less of the fluorine-containing modified sugar moieties in the first modified oligonucleotide is a 3'-fluorohexitol sugar moiety.

[0770] Embodiment B9. The oligomeric double helix according to any one of Embodiments B1 to B8, wherein one or more nucleosides of the first modified oligonucleotide are 2'-deoxynucleosides.

[0771] Embodiment B10. The oligomeric double helix according to Embodiment B9, wherein one or more 2'-deoxynucleosides are one or more nucleosides in the region of the sequence of the first modified oligonucleotide between the 5th to the 16th nucleosides counted from the 5' end of the first modified oligonucleotide and including those nucleosides.

[0772] Embodiment B11. The oligomeric double helix according to Embodiment B10, wherein the one or more 2'-deoxynucleosides are located in a region of the sequence of the first modified oligonucleotide that is the 5th, 6th, and / or 7th nucleoside counted from the 5' end of the first modified oligonucleotide, or the 14th, 15th, and / or 16th nucleoside.

[0773] Embodiment B12. The oligomeric double chain according to any one of Embodiments B9 to B11, wherein less than 20% or less than 15% of the nucleoside of the first modified oligonucleotide contains fluorine.

[0774] Embodiment B13. The oligomeric double helix according to any one of Embodiments B9 to B12, wherein the one or more 2'-deoxynucleosides are the 5th, 6th, and / or 7th nucleosides counted from the 5' end of the first modified oligonucleotide.

[0775] Embodiment B14. The oligomeric double helix according to any one of Embodiments B9 to B13, wherein only two nucleosides of the first modified oligonucleotide are 2'-deoxynucleosides.

[0776] Embodiment B15. The oligomeric double helix according to Embodiment B14, wherein the two 2'-deoxynucleosides are the 5th and 7th nucleosides, or the 14th and 16th nucleosides, counting from the 5' end of the first modified oligonucleotide.

[0777] Embodiment B16. The oligomeric double helix according to Embodiment B14, wherein the two 2'-deoxynucleosides are the 5th or 7th nucleosides from the 5' end of the first modified oligonucleotide.

[0778] Embodiment B17. The oligomeric double helix according to any one of Embodiments B9 to B13, wherein only one of the nucleosides of the first modified oligonucleotide is a 2'-deoxynucleoside.

[0779] Embodiment B18. The oligomeric double helix according to Embodiment B17, wherein the 2'-deoxynucleoside is the 6th or 16th nucleoside from the 5' end of the first modified oligonucleotide.

[0780] Embodiment B19. The oligomeric double helix according to Embodiment B17, wherein the 2'-deoxynucleoside is the sixth nucleoside from the 5' end of the first modified oligonucleotide.

[0781] Embodiment B20. An oligomeric double chain according to any one of Embodiments B1 to B19, wherein one or more of the nucleosides of the first modified oligonucleotide independently contain a sugar surrogate or a bicyclic sugar moiety.

[0782] Embodiment B21. The oligomeric double chain according to Embodiment B20, wherein the bicyclic sugar portion includes a 2'-4' crosslink selected from -O-CH2- and -O-CH(CH3)-.

[0783] Embodiment B22. An oligomeric double chain according to any one of Embodiments B1 to B21, wherein one or more of the nucleosides of the first modified oligonucleotide contain a 2'-OMe sugar moiety.

[0784] Embodiment B23. The oligomeric double chain according to Embodiment B22, wherein at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, or at least 60% of the nucleoside of the first modified oligonucleotide comprises a 2'-OMe sugar moiety.

[0785] Embodiment B24. An oligomeric double helix according to Embodiment B22 or B23, wherein one or more nucleosides containing a 2'-OMe sugar moiety are located between the 3rd and 21st nucleosides counting from the 5' end of the first modified oligonucleotide, and in the sequence region of the first modified oligonucleotide containing them.

[0786] Embodiment B25. An oligomeric double helix according to Embodiment B22 or B23, wherein the 3'-terminal nucleoside of the first modified oligonucleotide contains a 2'-OMe sugar moiety, and / or the nucleoside immediately 5' to the 3'-terminal nucleoside of the first modified oligonucleotide contains a 2'-OMe sugar moiety.

[0787] Embodiment B26. An oligomeric double chain according to any one of Embodiments B1 to B25, wherein one or more of the nucleosides of the first modified oligonucleotide contain a 2'-MOE sugar moiety.

[0788] Embodiment B27. The oligomeric double chain according to Embodiment B26, wherein the 5'-terminal nucleoside and / or 3'-terminal nucleoside of the first modified oligonucleotide contains a 2'-MOE sugar moiety.

[0789] Embodiment B28. An oligomeric double helix according to any one of Embodiments B1 to B27, wherein the nucleoside immediately 5' of the 3' terminal nucleoside of the first modified oligonucleotide contains a 2'-MOE sugar moiety.

[0790] Embodiment B29. An oligomeric double helix according to any one of Embodiments B1 to B24 and B26 to B28, wherein the 5'-terminal nucleoside and the 3'-terminal nucleoside of the first modified oligonucleotide contain a 2'-MOE sugar moiety, and the nucleoside immediately 5' of the 3'-terminal nucleoside of the first modified oligonucleotide contains a 2'-MOE sugar moiety.

[0791] Embodiment B30. The oligomeric double helix according to any one of Embodiments B1 to B29, wherein the first modified oligonucleotide comprises a stabilized phosphate group bonded to the 5' terminal nucleoside.

[0792] Embodiment B31. The oligomeric double chain according to Embodiment B30, wherein the stabilized phosphate group comprises cyclopropylphosphonate or vinylphosphonate.

[0793] Embodiment B32. The oligomeric double chain according to any one of Embodiments B1 to B31, wherein the double chain comprises a conjugate group including a conjugate portion and a conjugate linker.

[0794] Embodiment B33. The oligomeric double chain according to Embodiment B32, wherein the conjugate group includes a cell-targeting moiety.

[0795] Embodiment B34. The oligomeric double chain according to Embodiment B32, wherein the conjugate portion comprises an active drug substance, an aliphatic chain, a lipid, a peptide, a protein, a hydrocarbon, a polyamine, a polyamide, a polyether, a thioether, an aptamer, an antibody or antibody fragment, a vitamin, a fatty acid, a carbohydrate, an intercalator, or a reporter molecule.

[0796] Embodiment B35. The oligomer double chain according to Embodiment B32, wherein the conjugate group comprises C22 alkyl, C20 alkyl, C17 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, or C5 alkyl, and the alkyl chain optionally has one or more unsaturated bonds.

[0797] Embodiment B36. The oligomeric double chain according to Embodiment B32, wherein the conjugate group comprises a 6-palmitamide hexyl moiety or a 2-(hydroxymethyl)-6-palmitamide hexyl moiety.

[0798] Embodiment B37. The oligomeric double helix according to Embodiment B32, wherein the double helix includes a conjugate portion that binds to a type 1 transferrin receptor (TfR1).

[0799] Embodiment B38. The oligomeric double chain according to Embodiment B37, wherein the conjugate portion is selected from antibodies or fragments thereof, proteins or peptides, and aptamers that can bind to TfR1.

[0800] Embodiment B39. The oligomeric double chain according to Embodiment B38, wherein the conjugate portion is a cyclic protein or a cyclic peptide.

[0801] Embodiment B40. The oligomeric double chain according to Embodiment B37, wherein the conjugate group consists of a bicyclic ligand and a conjugate linker.

[0802] Embodiment B41. The oligomeric double chain according to Embodiment B40, wherein the bicyclic ligand comprises a peptide and molecular skeleton consisting of 13 to 22 linked amino acids or amino acid mimes, and each of the first, second, and third amino acids of the peptide contains a reactive group, each of which separately forms a bond with the molecular skeleton, thereby forming two peptide loops bonded to the molecular skeleton.

[0803] Embodiment B42. The oligomeric double chain according to Embodiment B41, wherein the peptide has an amino acid sequence selected from any one of SEQ ID NOs: 1071 to 1253, and each cysteine ​​forms a covalent bond with the molecular skeleton 1,1',1''-(1,3,5-triazinane-1,3,5-triyl)tris(2-bromoetanone) (TATB) or the molecular skeleton 1,1',1''-(1,3,5-triazinane-1,3,5-triyl)tripprop-2-en-1-one (TATA).

[0804] Embodiment B43. The conjugate group has the following structure:

[0805] [ka] The oligomeric double helix according to Embodiment B41, having a salt thereof, wherein Q is N3 (BCY17901, SEQ ID NO: 1045), NH2 (BCY21757, SEQ ID NO: 1202), SH (BCY21758, SEQ ID NO: 1203), a conjugate linker, or a conjugate linker covalently bonded to an oligonucleotide.

[0806] Embodiment B44. An oligomeric double helix according to any one of Embodiments B32 to B43, wherein the conjugate group is conjugated to the second modified oligonucleotide.

[0807] Embodiment B45. An oligomeric double helix according to any one of Embodiments B32 to B43, wherein the conjugate group is conjugated to the 5' or 3' end of the second modified oligonucleotide.

[0808] Embodiment B46. An oligomeric double helix according to any one of Embodiments B32 to B43, wherein the conjugate group is bonded to the 5'-terminal nucleoside or the 3'-terminal nucleoside of the second modified oligonucleotide.

[0809] Embodiment B47. An oligomeric double helix according to any one of Embodiments B32 to B43, wherein the conjugate group is bonded to the 5' terminal nucleoside of the second modified oligonucleotide.

[0810] Embodiment B48. The oligomeric double helix according to any one of Embodiments B32 to B43, wherein the conjugate group is bonded to the 3' terminal nucleoside of the second modified oligonucleotide.

[0811] Embodiment B49. An oligomeric double chain according to any one of Embodiments B32 to B48, wherein the conjugate linker of the conjugate group consists of a single bond.

[0812] Embodiment B50. An oligomeric double chain according to any one of Embodiments B32 to B48, wherein the conjugate linker of the conjugate group is cleavable.

[0813] Embodiment B51. An oligomeric double helix according to any one of Embodiments B32 to B50, wherein the conjugate linker comprises 1 to 3 linker-nucleosides.

[0814] Embodiment B52. An oligomeric double chain according to any one of Embodiments B32 to B48, wherein the conjugate linker includes a (bicyclo[6.1.0]nonine)-formyl (BCN) moiety.

[0815] Embodiment B53. The oligomeric double chain according to Embodiment B52, wherein the conjugate linker comprises a 6-(BCN-carbamate)-2-(hydroxymethyl)hexylphosphoryl moiety or a 6-(BCN-carbamate)hexylphosphoryl moiety.

[0816] Embodiment B54. The oligomeric double chain according to Embodiment B41, wherein the conjugate group has the following structure.

[0817] [ka]

[0818] Embodiment B55. The oligomeric double chain according to Embodiment B41, wherein the conjugate group has the following structure.

[0819] [ka]

[0820] Embodiment B56. The nucleic acid base sequence of the first modified oligonucleotide is the nucleic acid bases 295-316, 296-317, 297-318, 298-320, 299-320, 300-321, 301-322, 302-324, 303-324, 304-325, 304-326, 305-327, 306-325, 306-328, 307-328, 308-329, 309-330, 310-331, 311-332, 312-333, 313-334, 314-335, 315-336, 316-337, 317-339, 318-339, 3 19-340, 320-341, 321-342, 322-344, 323-345, 324-345, 324-346, 325-345, 325-347, 326-347, 327-348, 328-349, 329-350, 330-351, 331-352, 332-3 53, 333~354, 334~355, 505~526, 506~528, 507~529, 508~530, 509~531, 510~531, 511~532, 512~533, 513~535, 514~535, 514~536, 515~536, 516~535, 5 16-537, 517-538, 518-539, 519-541, 520-541, 521-542, 522-544, 523-544, 524-546, 535-556, 536-557, 537-558, 538-559, 539-560, 540-561, 541- 563, 542~563, 543~564, 544~565, 545~566, 546~567, 547~568, 548~570, 549~571, 550~572, 551~572, 552~574, 553~574, 554~575, 555~577, 556~578, 557~579, 558~580, 559~580, 560~581, 561~582, 562~583, 563~584, 595~616, 596~618, 597~618, 598~620, 599~621, 600~622, 601~623, 602~623, 603~ 624, 604~625, 605~627, 606~628, 607~628, 608~629, 609~630, 610~631, 611~632, 612~633, 613~635, 665~687, 666~687, 667~689, 668~689, 669~690,670~691, 671~692, 672~694, 673~694, 674~695, 675~696, 676~697, 677~698, 678~700, 679~701, 680~702, 681~703, 682~703, 683~704, 684~705, 68 5-706, 686-708, 687-708, 688-709, 689-710, 690-711, 691-712, 692-714, 693-715, 1675-1696, 1676-1698, 1677-1698, 1678-1699, 1679-1700, 168 An oligomeric double helix according to any one of Embodiments B1 to B55, wherein the isolength portions within the nucleic acid bases selected from any one of 0-1702, 1681-1702, 1682-1703, 1683-1705, 1684-1705, 1685-1706, 1686-1707, 1687-1709, 1688-1709, 1689-1710, 1690-1712, 1691-1713, 1692-1714, or 1693-1714 are at least 80%, at least 85%, at least 90%, at least 95%, or 100% complementary to the isolength portions within the nucleic acid bases.

[0821] Embodiment B57. An oligomeric double helix according to any one of Embodiments B1 to B55, wherein the nucleic acid base sequence of the first modified oligonucleotide is at least 80%, at least 85%, at least 90%, at least 95%, or 100% complementary to the isochromatic portions within nucleic acid bases 304-326, 306-325, 324-346, 325-345, 514-536, and 516-535 of SEQ ID NO: 1.

[0822] Embodiment B58. The oligomeric double helix according to any one of Embodiments B1 to B55, wherein the nucleic acid base sequence of the first modified oligonucleotide contains 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 nucleic acid bases from any one of the nucleic acid base sequences of SEQ ID NOs. 3 to 314, 627 to 782, 939 to 976, 1033 to 1038, or 1254 to 1255.

[0823] Embodiment B59. The oligomeric double helix according to any one of Embodiments B1 to B55, wherein the nucleic acid base sequence of the first modified oligonucleotide includes one of the nucleic acid base sequences of SEQ ID NOs: 3-314, 627-782, 939-976, 1033-1038, or 1254-1255.

[0824] Embodiment B60. The oligomeric double helix according to any one of Embodiments B1 to B55, wherein the nucleic acid base sequence of the first modified oligonucleotide consists of one of the nucleic acid base sequences of SEQ ID NOs: 3-314, 627-782, 939-976, 1033-1038, or 1254-1255.

[0825] Embodiment B61. The oligomeric double helix according to any one of Embodiments B1 to B55, wherein the nucleic acid base sequence of the first modified oligonucleotide contains 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 nucleic acid bases from any one of the nucleic acid base sequences of SEQ ID NOs. 29, 171, 176, 967, 968, 971, 972, 974, 975, 1254, 1255, or 1033 to 1038.

[0826] Embodiment B62. The oligomeric double helix according to any one of Embodiments B1 to B55, wherein the nucleic acid base sequence of the first modified oligonucleotide includes one of the nucleic acid base sequences of SEQ ID NOs: 29, 171, 176, 967, 968, 971, 972, 974, 975, 1254, 1255, or 1033 to 1038.

[0827] Embodiment B63. The oligomer double helix according to any one of Embodiments B1 to B55, wherein the nucleic acid base sequence of the first modified oligonucleotide consists of one of the nucleic acid base sequences of SEQ ID NOs: 29, 171, 176, 967, 968, 971, 972, 974, 975, 1254, 1255, or 1033 to 1038.

[0828] Embodiment B64. An oligomeric double helix according to any one of Embodiments B1 to B55, wherein the first modified oligonucleotide and the second modified oligonucleotide each independently consist of 18-30, 18-25, 18-24, 18-23, 18-22, 18-21, 18-19, 19-30, 19-25, 19-24, 19-23, 19-21, 19-20, 20-30, 20-25, 20-24, 20-23, 20-22, or 20-21 linked nucleosides.

[0829] Embodiment B65. The oligomeric double helix according to any one of Embodiments B1 to B55, wherein the first modified oligonucleotide consists of 23 nucleosides.

[0830] Embodiment B66. The first modified state is efyyydyyyyyyyyyyyyyyyyee,efyyydyyyyyyyyyyyyyyyyy,e[FHE]yyydyyyyyyyyyyyyyyyee,e[FHE]yyydyyyyyyyyyyyyyyyyy,efyydydyyyyyyyyyyyyyyyee,efyydydyyyyyyyyyyyyyyyyy,e[FHE]yydydyyyyyyyyyyyyyyee,e[FHE]yydyyyyyyyyyyyyy yyyyyyy, efyyyfyyyyyyyfyfyyyyyyy, efyyyfyyyyyyyfyfyyyyyy, efyyyyyyyyyyyfyfyyyyyyy, efyyyfyyyyyyyfyfyyyyyyee, efyyyyyyy yyyyfyyyyyyyy, efyyyyyyyyyyyfyyyyyyyyy, e[FHNA]yyyfyyyyyyyfyfyyyyyyee, e[FHNA]yyyfyyyyyyyfyfyyyyyyy, efyyydyyyyyyydyd yyyyyee, efyyydyyyyyyydydyyyyyyy, efyydydyyyyyyfyfyyyyyyy, efyyyfyyyyyyyfyyyyyyyy, efyyyfyyyyyyyfyyyyyyyyy, efyyyyyyy yyyyfyfyyyyyyy, efyyyyyyyyyyyfyfyyyyyyy, e[FHNA]yydydyyyyfyfyfyyyyyyy, efyyyfyyyyyyyfydyyyyyyy, efyyyfyyyyyyyfydyyyyy An oligomer double chain according to any one of Embodiments B1 to B65, having a sugar motif (from 5' to 3') selected from ee, efyyyfyyyyyyyfyfyyyee, and efyyyfyyyyyyyyfyfyyyyy, 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, each "f" represents a 2'-fluoro sugar moiety, and each "[FHNA]" represents a 3'-fluoro-hexitol sugar moiety.

[0831] Embodiment B67. An oligomeric double chain according to any one of Embodiments B1 to B65, wherein the first modified oligonucleotide has a sugar motif (from 5' to 3') selected from among efyydydyyyyyyfyfyyyyyee, efyyydyyyyyyyfyfyyyyyyee, efyydydyyyyyyfyfyyyyyyy, e[FHNA]yydydyyyyfyfyfyyyyyyy, efyyyyyyyyyyyyfyfyyyyyyee, and efyyydyyyyyyyfyfyyyyyyyy.

[0832] Embodiment B68. The oligomeric double helix according to any one of Embodiments B1 to B67, wherein the first modified oligonucleotide comprises at least one modified internucleoside bond.

[0833] Embodiment B69. The oligomeric double helix according to Embodiment B68, wherein at least one modified in...

Claims

1. An oligomeric double chain comprising a first oligomeric compound and a second oligomeric compound, (1) The first oligomer compound comprises a modified oligonucleotide consisting of 8 to 50 linked nucleosides, wherein the nucleic acid base 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 nucleic acid bases of any one nucleic acid base sequence from SEQ ID NOs. 3 to 314, 627 to 782, 939 to 976, 1033 to 1038, 1254 to 1255, or 1258 to 1287, each of the nucleosides of the first modified oligonucleotide independently comprises a modified sugar moiety or sugar surrogate, and at least one modified nucleoside of the first modified oligonucleotide and less than 40% of the nucleosides contain fluorine. (2) The second oligomer compound comprises a second modified oligonucleotide consisting of 8 to 50 consecutively linked nucleosides, wherein the second modified oligonucleotide comprises a region having a nucleic acid base sequence complementary to the region of the first modified oligonucleotide, and the nucleic acid base sequence of the second modified oligonucleotide is at least 8 of any one of the nucleic acid base sequences of SEQ ID NOs: 315-626, 783-938, 977-1016, 1027-1032, 1256-1257, or 1288-1290. An oligomeric double helix comprising 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 nucleic acid bases, wherein each of the nucleosides of the second modified oligonucleotide independently comprises a modified sugar moiety or sugar surrogate, and less than 40% of the nucleosides of the second modified oligonucleotide contain fluorine.

2. The oligomeric double helix according to claim 1, wherein the first modified oligonucleotide is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% complementary to the isolength portion of the PLN nucleic acid, and the PLN nucleic acid has the nucleic acid base sequence of SEQ ID NO: 1 or SEQ ID NO:

2.

3. Each of the nucleosides of the first modified oligonucleotide independently comprises (i) a modified sugar moiety or sugar surrogate, or (ii) independently a sugar moiety selected from a 2'-F sugar moiety, a 2'-MOE sugar moiety, a 2'-OMe sugar moiety, a 2'-deoxy sugar moiety, and a 3'-fluorohexitol sugar moiety, or (iii) a modified sugar moiety, and each of the nucleosides of the second modified oligonucleotide independently comprises (i) a modified sugar moiety or sugar surrogate, or (ii) independently a sugar moiety selected from a 2'-F sugar moiety, a 2'-MOE sugar moiety, a 2'-OMe sugar moiety, a 2'-deoxy sugar moiety, and a 3'-fluorohexitol sugar moiety, or (iii) a modified sugar moiety, the oligomer double chain according to claim 1 or 2.

4. The oligomeric double chain according to any one of claims 1 to 3, wherein less than 35%, less than 30%, less than 25%, less than 20%, less than 15%, less than 14%, less than 13%, less than 12%, less than 10%, less than 5%, or less than 1% of the nucleoside in the first modified oligonucleotide contains fluorine.

5. The oligomer double chain according to any one of claims 1 to 4, wherein one or fewer nucleosides, two or fewer nucleosides, three or fewer nucleosides, or four or fewer nucleosides in the first modified oligonucleotide include a fluorine-containing modified sugar moiety or a fluorine-containing sugar surrogate.

6. The oligomer double chain according to any one of claims 1 to 5, wherein the space between the 3rd and 21st nucleosides counted from the 5' end of the modified oligonucleotide, and one or fewer nucleosides, two or fewer nucleosides, or three or fewer nucleosides in the sequence of the first modified oligonucleotide containing them, comprises a fluorine-containing modified sugar moiety or a fluorine-containing sugar surrogate.

7. i) one or more nucleosides of the first modified oligonucleotide containing a fluorine-containing modified sugar moiety or ii) a fluorine-containing sugar surrogate, independently i. The second nucleoside from the 5' end, ii. The 14th and 16th nucleosides counting from the 5' end, or iii. Selected from the 2nd, 14th, and 16th nucleosides counting from the 5' end, The oligomer double chain according to any one of claims 1 to 6, wherein each i) fluorine-containing modified sugar moiety or ii) fluorine-containing sugar surrogate is independently a 2'-fluorosugar moiety or a 3'-fluorohexitol sugar moiety.

8. The oligomer double chain according to any one of claims 1 to 7, wherein one or less of the fluorine-containing sugar moieties in the first modified oligonucleotide is a 3'-fluorohexitol sugar moiety.

9. The oligomeric double helix according to any one of claims 1 to 8, wherein one or more nucleosides of the first modified oligonucleotide are 2'-deoxynucleosides.

10. The oligomeric double helix according to claim 9, wherein one or more 2'-deoxynucleosides are one or more nucleosides in the region of the sequence of the first modified oligonucleotide between the 5th to the 16th nucleosides counted from the 5' end of the first modified oligonucleotide and including those nucleosides.

11. The oligomeric double helix according to claim 10, wherein the one or more 2'-deoxynucleosides are located in a region of the sequence of the first modified oligonucleotide that is either the 5th and / or 6th and / or 7th nucleosides counting from the 5' end of the first modified oligonucleotide, or the 14th and / or 15th and / or 16th nucleosides.

12. The oligomeric double-chain according to any one of claims 9 to 11, wherein less than 20% or less than 15% of the nucleoside of the first modified oligonucleotide contains fluorine.

13. The oligomeric double helix according to any one of claims 9 to 12, wherein the one or more 2'-deoxynucleosides are the fifth and / or sixth and / or seventh nucleosides counting from the 5' end of the first modified oligonucleotide.

14. The oligomeric double helix according to any one of claims 9 to 13, wherein one or two nucleosides of the first modified oligonucleotide are 2'-deoxynucleosides.

15. The oligomeric double helix according to claim 14, wherein the two 2'-deoxynucleosides are the 5th and 7th nucleosides, or the 14th and 16th nucleosides, counting from the 5' end of the first modified oligonucleotide.

16. The oligomeric double helix according to claim 14, wherein the sole 2'-deoxynucleoside is the 6th or 16th nucleoside from the 5' end of the first modified oligonucleotide.

17. The oligomeric double helix according to any one of claims 1 to 8, wherein none of the nucleosides of the first modified oligonucleotide are 2'-deoxynucleosides.

18. The oligomeric double helix according to any one of claims 1 to 17, wherein the first oligomeric compound comprises a two-nucleoside overhang including the 3'-terminal nucleoside of the first modified oligonucleotide and the nucleoside immediately to the 5' side of the 3'-terminal nucleoside.

19. The oligomeric double helix according to claim 18, wherein the overhang nucleoside is two modified adenosine (AA) nucleosides, two modified uridine (UU) nucleosides, two modified inosine (II) nucleosides, or two modified nucleosides (AI or IA) one of which is inosine and the other is adenosine.

20. The oligomeric double chain according to any one of claims 1 to 19, wherein one or more of the nucleosides of the first modified oligonucleotide independently comprises a sugar surrogate or a bicyclic sugar moiety.

21. The aforementioned bicyclic sugar portion is -O-CH ２ - and -O-CH(CH ３ The oligomeric double chain according to claim 20, comprising a 2'-4' crosslink selected from )-.

22. The oligomeric double chain according to any one of claims 1 to 21, wherein one or more of the nucleosides of the first modified oligonucleotide comprises a 2'-OMe sugar moiety.

23. The oligomeric double chain according to claim 22, wherein at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, or at least 60% of the nucleoside of the first modified oligonucleotide comprises a 2'-OMe sugar moiety.

24. The oligomeric double helix according to claim 22 or 23, wherein one or more nucleosides containing a 2'-OMe sugar moiety are located between the 3rd and 21st nucleosides counting from the 5' end of the first modified oligonucleotide and in the sequence region of the first modified oligonucleotide containing them, and / or the first two nucleosides counting from the 5' end of the first modified oligonucleotide and / or the first two nucleosides counting from the 3' end of the first modified oligonucleotide are independently modified nucleosides containing a sugar surrogate or a modified sugar moiety other than a 2'-OMe sugar moiety.

25. The oligomeric double helix according to claim 22 or 23, wherein the 3'-terminal nucleoside of the first modified oligonucleotide comprises a 2'-OMe sugar moiety, and / or the nucleoside immediately 5' to the 3'-terminal nucleoside of the first modified oligonucleotide comprises a 2'-OMe sugar moiety.

26. The oligomeric double chain according to any one of claims 1 to 25, wherein one or more of the nucleosides of the first modified oligonucleotide comprises a 2'-MOE sugar moiety.

27. The oligomeric double chain according to claim 26, wherein the 5'-terminal nucleoside and / or 3'-terminal nucleoside of the first modified oligonucleotide comprises a 2'-MOE sugar moiety.

28. The oligomeric double helix according to any one of claims 1 to 27, wherein the nucleoside immediately to the 5' end of the 3' terminal nucleoside of the first modified oligonucleotide comprises a 2'-MOE sugar moiety.

29. The oligomeric double helix according to any one of claims 1 to 24 and 26 to 28, wherein the 5'-terminal nucleoside and the 3'-terminal nucleoside of the first modified oligonucleotide contain a 2'-MOE sugar moiety, and the nucleoside immediately 5' to the 3'-terminal nucleoside of the first modified oligonucleotide contains a 2'-MOE sugar moiety.

30. The oligomeric double helix according to any one of claims 1 to 29, wherein the first oligomeric compound comprises a stabilized phosphate group bonded to the 5'-terminal nucleoside of the first modified oligonucleotide.

31. The oligomeric double chain according to claim 30, wherein the stabilized phosphate group comprises cyclopropylphosphonate or vinylphosphonate.

32. The oligomeric double chain according to any one of claims 1 to 31, wherein the double chain comprises a conjugate group including a conjugate moiety and a conjugate linker.

33. The oligomeric double helix according to claim 32, wherein the conjugate group comprises a cell-targeting moiety.

34. The oligomeric double chain according to claim 32, wherein the conjugate portion comprises an active drug substance, an aliphatic chain, a lipid, a peptide, a protein, a hydrocarbon, a polyamine, a polyamide, a polyether, a thioether, an aptamer, an antibody, an antibody fragment, a vitamin, a fatty acid, a carbohydrate, an intercalator, or a reporter molecule.

35. The oligomer double chain according to claim 32, wherein the conjugate group comprises C22 alkyl, C20 alkyl, C17 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, or C5 alkyl, and the alkyl chain optionally has one or more unsaturated bonds.

36. The oligomeric double chain according to claim 32, wherein the conjugate group comprises a 6-palmitamide hexyl moiety or a 2-(hydroxymethyl)-6-palmitamide hexyl moiety.

37. The oligomeric double chain according to claim 32, wherein the conjugate group includes a conjugate portion that binds to a type 1 transferrin receptor (TfR1).

38. The oligomeric double chain according to claim 37, wherein the conjugate portion is selected from an antibody or fragment thereof, a protein or peptide, and an aptamer that can bind to TfR1.

39. The oligomeric double chain according to claim 38, wherein the conjugate portion is a cyclic protein or a cyclic peptide.

40. The oligomeric double chain according to claim 37, wherein the conjugate group comprises a bicyclic ligand and a conjugate linker.

41. The oligomeric double chain according to claim 40, wherein the bicyclic ligand comprises a peptide and a molecular skeleton consisting of 13 to 22 linked amino acids or amino acid mimes, and each of the first, second, and third amino acids of the peptide comprises a reactive group, each of which separately forms a bond with the molecular skeleton, thereby forming two peptide loops bonded to the molecular skeleton.

42. The oligomeric double chain according to claim 41, wherein the peptide has an amino acid sequence selected from any one of SEQ ID NOs: 1062 to 1253, and each cysteine ​​forms a covalent bond with the molecular skeleton 1,1',1''-(1,3,5-triazinane-1,3,5-triyl)tris(2-bromoetanone) (TATB) or the molecular skeleton 1,1',1''-(1,3,5-triazinane-1,3,5-triyl)tripprop-2-en-1-one (TATA).

43. The aforementioned bicyclic ligand or conjugate group has the following structure: 【Chemistry 1】 or having a salt thereof, where Q is N ３ (BCY17901, Sequence ID 1045), NH ２ The oligomeric double helix according to claim 41, wherein SH (BCY21757, SEQ ID NO: 1202), SH (BCY21758, SEQ ID NO: 1203), a conjugate linker, or a conjugate linker covalently bonded to an oligonucleotide.

44. The oligomeric double helix according to any one of claims 32 to 43, wherein the conjugate group is conjugated to the second modified oligonucleotide.

45. The oligomeric double helix according to any one of claims 32 to 43, wherein the conjugate group is bonded to the 5' or 3' end of the second modified oligonucleotide.

46. The oligomeric double helix according to any one of claims 32 to 43, wherein the conjugate group is bonded to the 5'-terminal nucleoside or the 3'-terminal nucleoside of the second modified oligonucleotide.

47. The oligomeric double helix according to any one of claims 32 to 43, wherein the conjugate group is bonded to the 5' terminal nucleoside of the second modified oligonucleotide.

48. The oligomeric double helix according to any one of claims 32 to 43, wherein the conjugate group is bonded to the 3' terminal nucleoside of the second modified oligonucleotide.

49. The oligomeric double chain according to any one of claims 32 to 48, wherein the conjugate linker of the conjugate group consists of a single bond.

50. The oligomeric double chain according to any one of claims 32 to 48, wherein the conjugate linker of the conjugate group is cleavable.

51. The oligomeric double helix according to any one of claims 32 to 50, wherein the conjugate linker comprises 1 to 3 linker-nucleosides.

52. The oligomeric double chain according to any one of claims 32 to 48, wherein the conjugate linker comprises a (bicyclo[6.1.0]nonine)-formyl (BCN) moiety.

53. The oligomeric double chain according to any one of claims 32 to 48, wherein the conjugate linker comprises a 6-(BCN-carbamate)-2-(hydroxymethyl)hexylphosphoryl moiety or a 6-(BCN-carbamate)hexylphosphoryl moiety.

54. The oligomeric double chain according to claim 41, wherein the conjugate group has the following structure. 【Chemistry 2】

55. The oligomeric double chain according to claim 41, wherein the conjugate group has the following structure. 【Transformation 3】

56. The nucleic acid base sequence of the first modified oligonucleotide described above is 295-316, 296-317, 297-318, 298-320, 299-320, 300-321, 301-322, 302-324, 303-324, 304-325, 304-326, 305-327, 306-325, 306-328, 307-328, 308-329, 309-330, 310-331, 311-332, 312-333, 313-334, 314-335, 315-336, 316-337, 317-339, 318-339, 319-3 40, 320-341, 321-342, 322-344, 323-345, 324-345, 324-346, 325-345, 325-347, 326-347, 327-348, 328-349, 329-350, 330-351, 331-352, 332-353, 3 33-354, 334-355, 505-526, 506-528, 507-529, 508-530, 509-531, 510-531, 511-532, 512-533, 513-535, 514-535, 514-536, 515-536, 516-535, 516-53 7, 517-538, 518-539, 519-541, 520-541, 521-542, 522-544, 523-544, 524-546, 535-556, 536-557, 537-558, 538-559, 539-560, 540-561, 541-563, 54 2-563, 543-564, 544-565, 545-566, 546-567, 547-568, 548-570, 549-571, 550-572, 551-572, 552-574, 553-574, 554-575, 555-577, 556-578, 557-579 , 558-580, 559-580, 560-581, 561-582, 562-583, 563-584, 595-616, 596-618, 597-618, 598-620, 599-621, 600-622, 601-623, 602-623, 603-624, 604 ~625, 605~627, 606~628, 607~628, 608~629, 609~630, 610~631, 611~632, 612~633, 613~635, 665~687, 666~687, 667~689, 668~689, 669~690, 670~691,671-692, 672-694, 673-694, 674-695, 675-696, 676-697, 677-698, 678-700, 679-701, 680-702, 681-703, 682-703, 683-704, 684-705, 685-706, 686 ~708, 687~708, 688~709, 689~710, 690~711, 691~712, 692~714, 693~715, 1675~1696, 1676~1698, 1677~1698, 1678~1699, 1679~1700, 1680~1702, 16 An oligomeric double helix according to any one of claims 1 to 55, wherein at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%, or 100%, is complementary to the isolength portions within nucleic acid bases selected from any one of 81-1702, 1682-1703, 1683-1705, 1684-1705, 1685-1706, 1686-1707, 1687-1709, 1688-1709, 1689-1710, 1690-1712, 1691-1713, 1692-1714, or 1693-1714.

57. The oligomeric double helix according to any one of claims 1 to 55, wherein the nucleic acid base sequence of the first modified oligonucleotide is at least 80%, at least 85%, at least 90%, at least 95%, or 100% complementary to the isolength portions in the sequence of nucleic acid bases 304-326, 306-325, 324-346, 325-345, 514-536, or 516-535 of SEQ ID NO:

1.

58. The oligomer double helix according to any one of claims 1 to 55, wherein the nucleic acid base sequence of the first modified oligonucleotide includes 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 nucleic acid bases from any one of the nucleic acid base sequences of SEQ ID NOs: 3-314, 627-782, 939-976, 1033-1038, 1254-1255, or 1258-1287.

59. The oligomer double helix according to any one of claims 1 to 55, wherein the nucleic acid base sequence of the first modified oligonucleotide comprises one nucleic acid base sequence from SEQ ID NOs: 3-314, 627-782, 939-976, 1033-1038, 1254-1255, or 1258-1287.

60. The oligomer double helix according to any one of claims 1 to 55, wherein the nucleic acid base sequence of the first modified oligonucleotide consists of one nucleic acid base sequence from SEQ ID NOs: 3-314, 627-782, 939-976, 1033-1038, 1254-1255, or 1258-1287.

61. The oligomeric double helix according to any one of claims 1 to 55, wherein the nucleic acid base sequence of the first modified oligonucleotide includes at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 consecutive nucleic acid bases from any one of the nucleic acid base sequences of SEQ ID NOs: 29, 171, 176, 967, 968, 971, 972, 974, 975, 1254, 1255, 1033-1038, 1254-1255, or 1258-1287.

62. The oligomer double helix according to any one of claims 1 to 55, wherein the nucleic acid base sequence of the first modified oligonucleotide comprises one nucleic acid base sequence from SEQ ID NOs: 29, 171, 176, 967, 968, 971, 972, 974, 975, 1254, 1255, or 1033-1038, 1254-1255, or 1258-1287.

63. The oligomer double helix according to any one of claims 1 to 55, wherein the nucleic acid base sequence of the first modified oligonucleotide consists of one nucleic acid base sequence from among SEQ ID NOs: 29, 171, 176, 967, 968, 971, 972, 974, 975, 1254, 1255, 1033-1038, 1254-1255, or 1258-1287.

64. The oligomeric double helix according to any one of claims 1 to 63, wherein the first modified oligonucleotide and the second modified oligonucleotide each independently consist of 18-30, 18-25, 18-24, 18-23, 18-22, 18-21, 18-19, 19-30, 19-25, 19-24, 19-23, 19-21, 19-20, 20-30, 20-25, 20-24, 20-23, 20-22, 20-21, 21 and 19, 21 and 20, 23 and 21, 23 and 22, or 22 and 21 linked nucleosides.

65. The oligomeric double helix according to any one of claims 1 to 64, wherein the first modified oligonucleotide comprises 23, 22, or 21 nucleosides.

66. The oligomeric double helix according to any one of claims 1 to 65, wherein the second modified oligonucleotide comprises 21 nucleosides.

67. The oligomeric double helix according to any one of claims 1 to 65, wherein the first modified oligonucleotide consists of 23 nucleosides and the second modified oligonucleotide consists of 21 nucleosides.

68. The oligomeric double helix according to any one of claims 1 to 65, wherein the first modified oligonucleotide consists of 22 nucleosides and the second modified oligonucleotide consists of 21 nucleosides.

69. The oligomeric double helix according to any one of claims 1 to 65, wherein the first modified oligonucleotide consists of 21 nucleosides, and the second modified oligonucleotide consists of 21 nucleosides.

70. The first obtained nucleotide is efyyydyy yyyyyyy, efyyyfyyyyyyyfyfyyyyyey, efyyyyyyyyyyyfyfyyyyyee, efyyyf yyyyyyyfyfyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyy yy, e[FHNA]yyyfyyyyyyfyfyyyyyee, e[FHNA]yyyfyyyyyyyfyfyyyyyyy, e fyyydyyyyyyydydyyyyyee, efyyydyyyyyyydyyyyyyy, efyydydyyyyyyfyf yyyyyyy, efyyyfyyyyyyyfyyyyyyyee, efyyyfyyyyyyyfyyyyyyyyy, efyyyy yyyyyyyfyfyyyyyee, efyyyyyyyyyyyfyfyyyyyyy, e[FHNA]yydydyyyyfyfy fyyyyyyy, efyyyfyyyyyyyfydyyyyyyy, efyyyfyyyyyyyfyyyyyyee, efyyd ydyyyyyyfyfyyyyye, efyydydyyyyyyfyfyyyyyy, efyyydyyyyyyyfyfyyyyye , having a sugar motif (from 5' to 3') selected from among efyyydyyyyyyyyyfyyyyyyy,efyyyyyyyyyyyyyyyyyy,efyyydyyThe oligomer double chain according to any one of claims 1 to 69, wherein each "e" represents a 2'-MOE sugar moiety, each "f" represents a 2'-fluoro sugar moiety, and each "[FHNA]" represents a 3'-fluorohexitol sugar moiety.

71. The first hit fate two, efyydydyy An oligomer diplex according to any one of claims 1 to 69, having a sugar motif (5' to 3') selected from among efyyydyy

72. The oligomeric double helix according to any one of claims 1 to 71, wherein the first modified oligonucleotide comprises at least one modified internucleoside bond.

73. The oligomer double helix according to claim 72, wherein the at least one modified internucleoside bond is a phosphorothioate or mesylphosphoamidate internucleoside bond.

74. The oligomer double helix according to claim 72, wherein less than 50%, less than 40%, less than 30%, less than 20%, or less than 10% of the nucleoside bonds of the first modified oligonucleotide are modified nucleoside bonds.

75. The oligomeric double helix according to any one of claims 1 to 74, wherein each nucleoside bond of the first modified oligonucleotide is independently selected from phosphodiester nucleoside bonds and phosphorothioate nucleoside bonds.

76. The oligomer double helix according to claim 75, wherein the nucleoside bonds between the first and second nucleosides and between the second and third nucleosides, counting from the 5' end of the first modified oligonucleotide, are modified nucleoside bonds.

77. The oligomer double helix according to claim 75, wherein the nucleoside bonds between the first and second nucleosides and between the second and third nucleosides, counting from the 3' end of the first modified oligonucleotide, are modified nucleoside bonds.

78. The oligomer double helix according to claim 75, wherein the nucleoside bonds between the first and second nucleosides and between the second and third nucleosides counting from the 5' end of the first modified oligonucleotide, and the nucleoside bonds between the first and second nucleosides and between the second and third nucleosides counting from the 3' end of the first modified oligonucleotide are modified nucleoside bonds.

79. The oligomer double helix according to any one of claims 72 to 78, wherein the modified nucleoside bond is a phosphorothioate nucleoside bond.

80. The oligomeric double helix according to claim 78 or 79, wherein all other nucleoside bonds in the first modified oligonucleotide are phosphodiester nucleoside bonds.

81. The first set substituent is a nucleoside interbonding motif of ssoooooooooooooooooooooooooooo, and efyydydyy The oligomer double chain according to claim 80, having a sugar motif (from 5' to 3') selected from among, wherein each "d" represents a 2'-deoxy sugar moiety, each "y" represents a 2'-OMe sugar moiety, each "e" represents a 2'-MOE sugar moiety, each "f" represents a 2'-fluoro sugar moiety, each "[FHNA]" represents a 3'-fluorohexitol sugar moiety, each "o" represents a phosphodiester nucleoside bond, and each "s" represents a phosphorothioate nucleoside bond.

82. 1) The first set oxide is a nucleoside interbonding motif of ssoooooooooooooooooooooooooo, as well as efyydydyy 1) The first modified oligo has a sugar motif (from 5' to 3') selected from among yfyyyyyy, or 2) the first modified oligo has a nucleoside-to- The oligomer double chain according to claim 72, wherein each "d" represents a 2'-deoxy sugar moiety, each "y" represents a 2'-OMe sugar moiety, each "e" represents a 2'-MOE sugar moiety, each "f" represents a 2'-fluoro sugar moiety, each "o" represents a phosphodiester nucleoside bond, and each "s" represents a phosphorothioate nucleoside bond.

83. The oligomeric double chain according to any one of claims 1 to 82, wherein less than 30%, less than 25%, less than 20%, less than 15%, less than 14%, less than 13%, less than 12%, less than 10%, or less than 5% of the nucleoside in the second modified oligonucleotide contains fluorine.

84. The oligomer double chain according to any one of claims 1 to 82, wherein four or fewer nucleosides, three or fewer nucleosides, two or fewer nucleosides, or one or fewer nucleosides in the second modified oligonucleotide include a fluorine-containing modified sugar moiety or a fluorine-containing sugar surrogate, and optionally, neither the nucleosides before the seventh nucleoside or after the eleventh nucleoside, counting from the 5' end of the second modified oligonucleotide, include a fluorine-containing modified sugar moiety or a fluorine-containing sugar surrogate.

85. The oligomer double chain according to any one of claims 1 to 84, wherein one or more of the 7th, 9th, and 11th nucleosides counted from the 5' end of the second modified oligonucleotide comprises a fluorine-containing modified sugar moiety.

86. The oligomer double chain according to claim 85, wherein two or more of the 7th, 9th, and 11th nucleosides counted from the 5' end of the second modified oligonucleotide contain a fluorine-containing modified sugar moiety.

87. The oligomeric double chain according to claim 85, wherein the 7th, 9th, and 11th nucleosides counting from the 5' end of the second modified oligonucleotide contain a fluorine-containing modified sugar moiety.

88. The oligomeric double chain according to any one of claims 1 to 84, wherein one or both of the 10th and 11th nucleosides from the 5' end of the second modified oligonucleotide contain a fluorine-containing modified sugar moiety.

89. The oligomer double chain according to any one of claims 84 to 88, wherein the fluorine-containing modified sugar portion is a 2'-fluorosugar portion.

90. The oligomeric double chain according to any one of claims 1 to 89, wherein less than 30%, less than 25%, less than 20%, less than 15%, less than 14%, less than 13%, less than 12%, less than 10%, less than 5%, or less than 1% of the total nucleosides in the oligomeric double chain contains fluorine.

91. The oligomeric double helix according to any one of claims 1 to 90, wherein one or more of the nucleosides of the second modified oligonucleotide independently comprises a sugar surrogate or a bicyclic sugar moiety.

92. The aforementioned bicyclic sugar portion is -O-CH ２ - and -O-CH(CH ３ The oligomeric double chain according to claim 91, comprising a 2'-4' crosslink selected from )-.

93. The oligomeric double chain according to any one of claims 1 to 92, wherein one or more of the nucleosides of the second modified oligonucleotide comprises a 2'-OMe sugar moiety.

94. The oligomeric double chain according to claim 93, wherein at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 65%, at least 70%, at least 80%, at least 85%, or at least 90% of the nucleoside of the second modified oligonucleotide comprises a 2'-OMe sugar moiety.

95. The oligomeric double helix according to claim 93 or 94, wherein one or more nucleosides containing a 2'-OMe sugar moiety are located between the 3rd and 19th nucleosides counting from the 5' end of the second modified oligonucleotide and in the sequence region of the second modified oligonucleotide containing them.

96. The oligomeric double helix according to claim 93 or 94, wherein the 3'-terminal nucleoside of the second modified oligonucleotide comprises a 2'-OMe sugar moiety, and / or the nucleoside immediately 5' to the 3'-terminal nucleoside of the second modified oligonucleotide comprises a 2'-OMe sugar moiety.

97. The oligomeric double-chain according to any one of claims 93, 94, and 96, wherein the 5'-terminal nucleoside of the second modified oligonucleotide comprises a 2'-OMe sugar moiety, and / or the nucleoside immediately 3' to the 5'-terminal nucleoside of the second modified oligonucleotide comprises a 2'-OMe sugar moiety.

98. The oligomeric double chain according to claim 93 or 94, wherein the 5'-terminal nucleoside of the second modified oligonucleotide, the nucleoside immediately 3' to the 5'-terminal nucleoside, the 3'-terminal nucleoside, and the nucleoside immediately 5' to the 3'-terminal nucleoside contain a 2'-OMe sugar moiety.

99. The oligomeric double chain according to any one of claims 1 to 98, wherein one or more of the nucleosides of the second modified oligonucleotide comprises a 2'-MOE sugar moiety.

100. The oligomeric double helix according to any one of claims 1 to 95, wherein the 3'-terminal nucleoside of the second modified oligonucleotide comprises a 2'-MOE sugar moiety, and / or the nucleoside immediately 5' to the 3'-terminal nucleoside of the second modified oligonucleotide comprises a 2'-MOE sugar moiety.

101. The oligomeric double helix according to any one of claims 1 to 96, 99, and 100, wherein the 5'-terminal nucleoside of the second modified oligonucleotide comprises a 2'-MOE sugar moiety, and / or the nucleoside immediately 3' to the 5'-terminal nucleoside of the second modified oligonucleotide comprises a 2'-MOE sugar moiety.

102. The oligomeric double chain according to any one of claims 1 to 95, wherein the 5'-terminal nucleoside of the second modified oligonucleotide, the nucleoside immediately 3' to the 5'-terminal nucleoside, the 3'-terminal nucleoside, and the nucleoside immediately 5' to the 3'-terminal nucleoside contain a 2'-MOE sugar moiety.

103. The given occupants of the 2nd generation are, eeey yyyyyyyee、eeyyyyyyyffyyyyyyyyyy、yyyyyyyyyffyyyyyyyyee、yyyyyyyyyffyyyyyyyyyy、eeyyyyyffyyyyyyyyee、eeyyyyyff yyyyyyyyy, yyyyyyyffyyyyyyyyee, yyyyyyyffyyyyyyyyy, yyyyyyfyffyyyyyyyy, eeyyyyfyfffyyyyyyee, eeyyyyfyffyyy yyyyy, yyyyyyfyffffyyyyyyee, eeyyfyffyyyyyyyyyyyyyyyyyyy, yyyyfyffyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyy y, eeyyyyyyydyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyy An oligomer double chain according to any one of claims 1 to 102, having a sugar motif (from 5' to 3') selected from yyyyee, eey

104. The oligomer double chain according to any one of claims 1 to 102, wherein the second modified oligonucleotide has a sugar motif (from 5' to 3') selected from eeyyyyyyyffyyyyyyyyyyee, eeyyyyyf

105. (1) The nucleic acid base of the 3' terminal nucleoside and / or the nucleoside immediately 5' to the 3' terminal nucleoside of the first modified oligonucleotide and / or the second modified oligonucleotide is adenine or thymine, and / or (2) The nucleic acid base of the 5' terminal nucleoside of the first modified oligonucleotide is thymine, according to any one of claims 1 to 104.

106. The oligomer double helix according to any one of claims 1 to 104, wherein the nucleic acid base of the 3'-terminal nucleoside and the nucleoside immediately 5' to the 3'-terminal nucleoside of the first modified oligonucleotide is adenine, the nucleic acid base of the 5'-terminal nucleoside of the first modified oligonucleotide is thymine, the nucleic acid base of the 3'-terminal nucleoside of the second modified oligonucleotide is adenine, and the nucleic acid base of the nucleoside immediately 5' to the 3'-terminal nucleoside of the second modified oligonucleotide is thymine or uracil.

107. The oligomeric double helix according to any one of claims 1 to 106, wherein the second modified oligonucleotide comprises at least one modified internucleoside bond.

108. The oligomeric double helix according to claim 107, wherein the at least one modified internucleoside bond is a phosphorothioate or mesylphosphoamidate internucleoside bond.

109. The oligomeric double helix according to claim 107, wherein less than 50%, less than 40%, less than 30%, less than 20%, or less than 10% of the nucleoside bonds of the second modified oligonucleotide are modified nucleoside bonds.

110. The oligomeric double helix according to any one of claims 107 to 109, wherein each nucleoside bond of the second modified oligonucleotide is independently selected from phosphodiester nucleoside bonds and phosphorothioate nucleoside bonds.

111. The oligomeric double helix according to any one of claims 107 to 109, wherein the nucleoside bonds between the first and second nucleosides and between the second and third nucleosides, counting from the 5' end of the second modified oligonucleotide, are modified nucleoside bonds.

112. The oligomeric double helix according to any one of claims 107 to 109 and 111, wherein the nucleoside bonds between the first and second nucleosides and between the second and third nucleosides, counting from the 3' end of the second modified oligonucleotide, are modified nucleoside bonds.

113. The oligomer double helix according to any one of claims 107 to 109, wherein the nucleoside bonds between the first and second nucleosides and between the second and third nucleosides counting from the 5' end of the second modified oligonucleotide, and the nucleoside bonds between the first and second nucleosides and between the second and third nucleosides counting from the 3' end of the second modified oligonucleotide are modified nucleoside bonds.

114. The oligomeric double helix according to any one of claims 107 to 113, wherein the modified nucleoside bond is a phosphorothioate nucleoside bond.

115. The oligomeric double helix according to claim 114, wherein all other nucleoside bonds in the second modified oligonucleotide are phosphodiester nucleoside bonds.

116. The oligomer double helix according to claim 115, wherein the second modified oligonucleotide has a nucleoside-to-nucleoside linkage motif of ssooooooooooooooooooooooooooo, and a sugar motif (from 5' to 3') selected from eeyyyyyyyffyyyyyyyyyyyee, eeyyyyyf

117. The oligomeric double helix according to any one of claims 1 to 116, wherein the nucleic acid base sequence of the second modified oligonucleotide includes 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 nucleic acid bases from any one of the nucleic acid base sequences of SEQ ID NOs: 315-626, 783-938, 977-1016, 1027-1032, 1256-1257, or 1288-1290.

118. The oligomer double helix according to any one of claims 1 to 116, wherein the nucleic acid base sequence of the second modified oligonucleotide comprises one nucleic acid base sequence from SEQ ID NOs: 315-626, 783-938, 977-1016, 1027-1032, 1256-1257, or 1288-1290.

119. The oligomer double helix according to any one of claims 1 to 116, wherein the nucleic acid base sequence of the second modified oligonucleotide consists of one nucleic acid base sequence from SEQ ID NOs: 315-626, 783-938, 977-1016, 1027-1032, 1256-1257, or 1288-1290.

120. The oligomer double helix according to any one of claims 1 to 116, wherein the nucleic acid base sequence of the second modified oligonucleotide comprises at least 16 consecutive nucleic acid bases from any one of the nucleic acid base sequences of SEQ ID NOs: 341, 483, 488, 1011-1016, 1027-1032, 1256-1257, or 1288-1290.

121. The oligomer double helix according to any one of claims 1 to 116, wherein the nucleic acid base sequence of the second modified oligonucleotide comprises one nucleic acid base sequence from SEQ ID NOs: 341, 483, 488, 1011-1016, 1027-1032, 1256-1257, or 1288-1290.

122. The oligomer double helix according to any one of claims 1 to 116, wherein the nucleic acid base sequence of the second modified oligonucleotide consists of one nucleic acid base sequence from SEQ ID NOs: 341, 483, 488, 1011-1016, 1027-1032, 1256-1257, or 1288-1290.

123. It is an oligomeric double helix, (1) Sequence IDs 1: 295-316, 296-317, 297-318, 298-320, 299-320, 300-321, 301-322, 302-324, 303-324, 304-325, 304-326, 305-327, 306-325, 306-328, 307- 328, 308-329, 309-330, 310-331, 311-332, 312-333, 313-334, 314-335, 315-336, 316-337, 317-339, 318-339, 319-340, 320-341, 321-342, 322-344, 3 23-345, 324-345, 324-346, 325-345, 325-347, 326-347, 327-348, 328-345, 328-349, 329-350, 330-351, 331-352, 332-353, 333-354, 334-355, 505-52 6, 506-528, 507-529, 508-530, 509-531, 510-531, 511-532, 512-533, 513-535, 514-535, 514-536, 515-536, 516-535, 516-537, 517-538, 518-539, 519 ~541, 520~541, 521~542, 522~544, 523~544, 524~546, 535~556, 536~557, 537~558, 538~559, 539~560, 540~561, 541~563, 542~563, 543~564, 544~565, 545-566, 546-567, 547-568, 548-570, 549-571, 550-572, 551-572, 552-574, 553-574, 554-575, 555-577, 556-578, 557-579, 558-580, 559-580, 560-5 81, 561-582, 562-583, 563-584, 595-616, 596-618, 597-618, 598-620, 599-621, 600-622, 601-623, 602-623, 603-624, 604-625, 605-627, 606-628, 60 7-628, 608-629, 609-630, 610-631, 611-632, 612-633, 613-635, 665-687, 666-687, 667-689, 668-689, 669-690, 670-691, 671-692, 672-694, 673-694,674-695, 675-696, 676-697, 677-698, 678-700, 679-701, 680-702, 681-703, 682-703, 683-704, 684-705, 685-706, 686-708, 687-708, 688-709, 689-7 10, 690-711, 691-712, 692-714, 693-715, 1675-1696, 1676-1698, 1677-1698, 1678-1699, 1679-1700, 1680-1702, 1681-1702, 1682-1703, 1683-1705, 1 A first oligomer compound comprising a first modified oligonucleotide comprising 18 to 30 consecutively linked nucleosides that are at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% complementary, or 100% complementary, to an isolength portion of a nucleic acid base selected from any one of 684-1705, 1685-1706, 1686-1707, 1687-1709, 1688-1709, 1689-1710, 1690-1712, 1691-1713, 1692-1714, or 1693-1714, (2) A second oligomer compound comprising a second modified oligonucleotide consisting of 16 to 28 consecutively linked nucleosides that are at least 90% complementary to the equilength portion of the first modified oligonucleotide, (a) Each of the nucleosides of the first modified oligonucleotide and each of the nucleosides of the second modified oligonucleotide comprises a modified sugar moiety or sugar surrogate, (b) At least one of the modified sugar moieties or sugar surrogates of the first modified oligonucleotide contains fluorine, (c) an oligomeric double chain in which less than 40% of the nucleosides of the first modified oligonucleotide contain fluorine.

124. An oligomeric double helix, comprising (1) a first modified oligonucleotide consisting of 18 to 30 consecutively linked nucleosides, wherein the nucleic acid base sequence of the first modified oligonucleotide is 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 nucleic acid bases from any one of the nucleic acid base sequences of SEQ ID NOs: 3 to 314, 627 to 782, 939 to 976, 1033 to 1038, 1254 to 1255, or 1258 to 1287 An oligomeric double helix comprising: (1) a first oligomeric compound comprising: (2) a second oligomeric compound comprising a second modified oligonucleotide consisting of 16 to 28 consecutively linked nucleosides that are at least 90% complementary to the equilength portion of the first modified oligonucleotide, wherein (a) each of the nucleosides of the first modified oligonucleotide and each of the nucleosides of the second modified oligonucleotide comprises a modified sugar moiety or sugar surrogate; (b) at least one of the modified sugar moieties or sugar surrogates of the first modified oligonucleotide comprises fluorine; and (c) less than 40% of the nucleosides of the first modified oligonucleotide comprises fluorine.

125. The oligomer double chain according to claim 124, wherein each nucleoside of the oligomer double chain comprises (i) a modified sugar moiety, or (ii) independently a sugar moiety selected from a 2'-F sugar moiety, a 2'-MOE sugar moiety, a 2'-OMe sugar moiety, a 2'-deoxy sugar moiety, and a 3'-fluorohexitol sugar moiety.

126. The oligomer double helix according to claim 124, wherein the nucleic acid base sequence of the first modified oligonucleotide includes or consists of any one of the nucleic acid base sequences of SEQ ID NOs: 3-314, 627-782, 939-976, 1033-1038, 1254-1255, or 1258-1287.

127. The oligomer double helix according to claim 124, wherein the nucleic acid base sequence of the first modified oligonucleotide contains 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 nucleic acid bases from any one of the nucleic acid base sequences of SEQ ID NOs: 29, 171, 176, 967, 968, 971, 972, 974, 975, 1033-1038, 1254-1255, or 1258-1287.

128. The oligomer double helix according to claim 124, wherein the nucleic acid base sequence of the first modified oligonucleotide comprises one of the nucleic acid base sequences of SEQ ID NOs: 29, 171, 176, 967, 968, 971, 972, 974, 975, 1033-1038, 1254-1255, or 1258-1287.

129. The oligomer double helix according to claim 124, wherein the nucleic acid base sequence of the first modified oligonucleotide consists of any one of the nucleic acid base sequences of SEQ ID NOs: 29, 171, 176, 967, 968, 971, 972, 974, 975, 1033-1038, 1254-1255, or 1258-1287.

130. The oligomer double helix according to claim 124, wherein the nucleic acid base sequence of the second modified oligonucleotide contains 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 nucleic acid bases from any one of the nucleic acid base sequences of SEQ ID NOs. 315-626, 783-938, 977-1016, 1027-1032, 1256-1257, or 1288-1290.

131. The oligomer double helix according to claim 126, wherein the nucleic acid base sequence of the second modified oligonucleotide includes one of the nucleic acid base sequences of SEQ ID NOs: 315-626, 783-938, 977-1016, 1027-1032, 1256-1257, or 1288-1290.

132. The oligomer double helix according to claim 126, wherein the nucleic acid base sequence of the second modified oligonucleotide consists of one nucleic acid base sequence from SEQ ID NOs: 315-626, 783-938, 977-1016, 1027-1032, 1256-1257, or 1288-1290.

133. The oligomer double helix according to claim 127, wherein the nucleic acid base sequence of the second modified oligonucleotide contains 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 nucleic acid bases from any one of the nucleic acid base sequences of SEQ ID NOs. 341, 483, 488, 1011-1016, 1027-1032, 1256-1257, or 1288-1290.

134. The oligomer double helix according to claim 128, wherein the nucleic acid base sequence of the second modified oligonucleotide includes one of the nucleic acid base sequences of SEQ ID NOs: 341, 483, 488, 1011-1016, 1027-1032, 1256-1257, or 1288-1290.

135. The oligomer double helix according to claim 129, wherein the nucleic acid base sequence of the second modified oligonucleotide consists of one nucleic acid base sequence from SEQ ID NOs: 341, 483, 488, 1011-1016, 1027-1032, 1256-1257, or 1288-1290.

136. (1) The nucleic acid base of the 3' terminal nucleoside and / or the nucleoside immediately 5' to the 3' terminal nucleoside of the first modified oligonucleotide and / or the second modified oligonucleotide is adenine or thymine, and / or (2) The nucleic acid base of the 5' terminal nucleoside of the first modified oligonucleotide is thymine, according to any one of claims 123 to 135.

137. The oligomer double helix according to any one of claims 123 to 135, wherein the nucleic acid base of the 3' terminal nucleoside of the first modified oligonucleotide and the nucleoside immediately 5' to the 3' terminal nucleoside is adenine, the nucleic acid base of the 5' terminal nucleoside of the first modified oligonucleotide is thymine, the nucleic acid base of the 3' terminal nucleoside of the second modified oligonucleotide is adenine, and the nucleic acid base of the nucleoside immediately 5' to the 3' terminal nucleoside of the second modified oligonucleotide is thymine or uracil.

138. The oligomeric double helix according to any one of claims 123 to 135, wherein the first oligomeric compound comprises a two-nucleoside overhang including the 3'-terminal nucleoside of the first modified oligonucleotide and the nucleoside immediately to the 5' side of the 3'-terminal nucleoside.

139. The oligomeric double helix according to claim 138, wherein the overhang nucleoside is two modified adenosine (AA) nucleosides, two modified uridine (UU) nucleosides, two modified inosine (II) nucleosides, or two modified nucleosides (AI or IA) one of which is inosine and the other is adenosine.

140. The oligomer double chain according to any one of claims 123 to 139, wherein neither the modified sugar portion nor the sugar surrogate of the nucleoside of the second modified oligonucleotide is fluorine-free.

141. At least one of the modified sugar moieties or sugar surrogates of the second modified oligonucleotide contains fluorine, and less than 40%, less than 30%, less than 25%, less than 20%, less than 15%, less than 14%, less than 13%, less than 12%, less than 10%, or less than 5% of the nucleoside of the second modified oligonucleotide contains fluorine, and / or The oligomeric double chain according to any one of claims 123 to 139, wherein less than 30%, less than 25%, less than 20%, less than 15%, less than 14%, less than 13%, less than 12%, less than 10%, or less than 5% of the total nucleosides in the oligomeric double chain contains fluorine.

142. The oligomer double-chain according to any one of claims 123 to 139, wherein two, three, or four of the nucleosides of the second modified oligonucleotide independently contain a fluorine-containing modified sugar moiety or a fluorine-containing sugar surrogate, or four or fewer nucleosides, three or fewer nucleosides, two or fewer nucleosides, or one or fewer nucleosides of the second modified oligonucleotide contain a fluorine-containing modified sugar moiety or a fluorine-containing sugar surrogate.

143. The oligomer double chain according to any one of claims 123 to 142, wherein two, three, or four of the nucleosides of the first modified oligonucleotide independently contain a fluorine-containing modified sugar moiety or a fluorine-containing sugar surrogate, or four or fewer nucleosides, three or fewer nucleosides, two or fewer nucleosides, or one or fewer nucleosides of the first modified oligonucleotide contain a fluorine-containing modified sugar moiety or a fluorine-containing sugar surrogate.

144. The oligomeric double chain according to any one of claims 123 to 143, wherein the space between the 3rd and 21st nucleosides counted from the 5' end of the modified oligonucleotide, and one or fewer nucleosides, two or fewer nucleosides, or three or fewer nucleosides in the sequence of the first modified oligonucleotide containing them, comprises a fluorine-containing modified sugar moiety or a fluorine-containing sugar surrogate.

145. One or more nucleosides comprising a fluorine-containing modified sugar moiety or a fluorine-containing sugar surrogate of the first modified oligonucleotide are independently, i. The second nucleoside from the 5' end, ii. The 14th and 16th nucleosides counting from the 5' end, or iii. Selected from the 2nd, 14th, and 16th nucleosides counting from the 5' end, The oligomer double chain according to any one of claims 123 to 144, wherein each of the fluorine-containing modified sugar moieties or fluorine-containing sugar surrogates is independently a 2'-fluorosugar moiety or a 3'-fluorohexitol sugar moiety.

146. The oligomeric double helix according to any one of claims 123 to 145, wherein none of the nucleosides of the second modified oligonucleotide are 2'-deoxynucleosides, and / or none of the nucleosides of the first modified oligonucleotide are 2'-deoxynucleosides.

147. The oligomeric double chain according to any one of claims 123 to 146, wherein all of the nucleosides of the second modified oligonucleotide contain a modified ribosyl sugar moiety.

148. The oligomeric double helix according to any one of claims 123 to 145 and 147, wherein one, two, or three of the nucleosides of the first modified oligonucleotide are 2'-deoxynucleosides, or three or fewer, two or fewer, or one or fewer nucleosides of the first modified oligonucleotide are 2'-deoxynucleosides, or only three, two or only one nucleosides of the first modified oligonucleotide are 2'-deoxynucleosides.

149. The oligomeric double helix according to claim 148, wherein the fifth and seventh nucleosides counted from the 5' end of the first modified oligonucleotide are 2'-deoxynucleosides, or the sixth nucleoside counted from the 5' end of the first modified oligonucleotide is a 2'-deoxynucleoside.

150. (a) The 5'-terminal nucleoside and the 3'-terminal nucleoside of the second modified oligonucleotide, the nucleoside immediately 3' to the 5'-terminal nucleoside, and the nucleoside immediately 5' to the 3'-terminal nucleoside contain a 2'-MOE sugar moiety and / or (b) The 5'-terminal nucleoside and the 3'-terminal nucleoside of the first modified oligonucleotide, and the nucleoside immediately 5' to the 3'-terminal nucleoside, contain a 2'-MOE sugar moiety and / or (c) The oligomeric double chain according to any one of claims 123 to 149, wherein any nucleoside in the first and second modified oligonucleotides that do not contain fluorine or a 2'-MOE sugar moiety contains a 2'-OMe sugar moiety.

151. The oligomeric double helix according to any one of claims 123 to 149, wherein the 3'-terminal nucleoside of the first modified oligonucleotide comprises a 2'-OMe sugar moiety, and / or the nucleoside immediately 5' to the 3'-terminal nucleoside of the first modified oligonucleotide comprises a 2'-OMe sugar moiety, and optionally, the 5'-terminal nucleoside of the first modified oligonucleotide comprises a 2'-MOE sugar moiety.

152. The oligomeric double helix according to any one of claims 123 to 151, wherein the first oligomeric compound comprises a stabilized phosphate group bonded to the 5'-terminal nucleoside of the first modified oligonucleotide.

153. The oligomeric double chain according to claim 152, wherein the stabilized phosphate group comprises cyclopropylphosphonate or vinylphosphonate.

154. The oligomer double chain according to any one of claims 123 to 153, wherein four or fewer of the nucleosides of the first modified oligonucleotide include a fluorine-containing modified sugar moiety or a fluorine-containing sugar surrogate.

155. The first obtained origin is efy The oligomer double chain according to claim 154, having a sugar motif (from 5' to 3') selected from b, fyyyyfyyyyyyyyyyyyyyyyyyyyy, where each "d" represents a 2'-deoxy sugar moiety, each "y" represents a 2'-OMe sugar moiety, each "e" represents a 2'-MOE sugar moiety, each "f" represents a 2'-fluoro sugar moiety, and each "[FHNA]" represents a 3'-fluoro-hexitol sugar moiety.

156. The oligomer double chain according to any one of claims 123 to 153, wherein three or fewer of the nucleosides of the first modified oligonucleotide include a fluorine-containing modified sugar moiety or a fluorine-containing sugar surrogate.

157. The first obtained endpoint is efyyydyy ydyyyyyyfyfyyyyyee, e[FHNA]yydydyyyyyfyfyyyyyyy, efyyyyyyyyyyyfyfyyyyyee, efyyyfyyyyyyyyyyyyy yyy、efyyyfyyyyyyyfydyyyyyee、efyyyfyyyyyyyfydyyyyyyy、efyyyfyyyyyyyfydyyyyyee、efyyyfyyyyyyyfydy yyyyyy, efyydydyyyyyyfyfyyyyye, efyydydyyyyyyfyfyyyyyy, efyyydyyyyyyyfyfyyyyye, efyyydyyyyyyyfyf yyyyyy, efyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyy, efyydydyyyyyyfyfyyyyy, efyyydyyyyyyyyfyfyy The oligomer double chain according to claim 156, having a sugar motif (from 5' to 3') selected from yyy and efyyyyyyyyyyyyyyyyyy, where each "d" represents a 2'-deoxy sugar moiety, each "y" represents a 2'-OMe sugar moiety, each "e" represents a 2'-MOE sugar moiety, each "f" represents a 2'-fluoro sugar moiety, and each "[FHNA]" represents a 3'-fluoro-hexitol sugar moiety.

158. The oligomer double chain according to any one of claims 123 to 153, wherein two or fewer of the nucleosides of the first modified oligonucleotide include a fluorine-containing modified sugar moiety or a fluorine-containing sugar surrogate.

159. The oligomer double chain according to claim 158, wherein the first modified polypeptide has a sugar motif (from 5' to 3') selected from efy

160. The oligomer double chain according to any one of claims 123 to 153, wherein only one of the nucleosides of the first modified oligonucleotide contains a fluorine-containing modified sugar moiety or a fluorine-containing sugar surrogate.

161. The oligomer double chain according to claim 160, wherein the first modified oligonucleotide has a sugar motif (from 5' to 3') selected from efyyydyy

162. The oligomeric double helix according to any one of claims 123 to 158 and 160, wherein two or fewer of the nucleosides of the first modified oligonucleotide are 2'-deoxynucleosides.

163. The first set nucleotide is efyydydyy The oligomer double chain according to claim 162, having a sugar motif (from 5' to 3') selected from yydydyyyyyyfyfyyyyy, where each "d" represents a 2'-deoxy sugar moiety, each "y" represents a 2'-OMe sugar moiety, each "e" represents a 2'-MOE sugar moiety, each "f" represents a 2'-fluoro sugar moiety, and each "[FHNA]" represents a 3'-fluoro-hexitol sugar moiety.

164. The oligomeric double helix according to any one of claims 123 to 154, 156, 158, and 160, wherein only one of the nucleosides of the first modified oligonucleotide is a 2'-deoxynucleoside.

165. The first obtained endpoint is efyyydyy The oligomer double chain according to claim 164, having a sugar motif (from 5' to 3') selected from e, efyyydyyyyyyyyfyyyyyye, efyyydyyyyyyyfyyyyyyy, and efyyydyyyyyyyfyyyyyy, wherein each "d" represents a 2'-deoxy sugar moiety, each "y" represents a 2'-OMe sugar moiety, each "e" represents a 2'-MOE sugar moiety, each "f" represents a 2'-fluoro sugar moiety, and each "[FHNA]" represents a 3'-fluoro-hexitol sugar moiety.

166. The oligomeric double chain according to any one of claims 123 to 154, wherein none of the nucleosides of the first modified oligonucleotide contain a 2'-deoxy sugar moiety.

167. The oligomer double chain according to claim 166, wherein the first modified oligonucleotide has a sugar motif (from 5' to 3') selected from efy

168. The oligomer double chain according to any one of claims 123 to 139 and 141 to 167, wherein four or fewer of the nucleosides of the second modified oligonucleotide include a fluorine-containing modified sugar moiety or a fluorine-containing sugar surrogate.

169. The oligomer double chain according to claim 168, wherein the second modified oligonucleotide has a sugar motif (from 5' to 3') selected from yyyyyyfyffffy

170. The oligomer double chain according to any one of claims 123 to 139 and 141 to 167, wherein three or fewer of the nucleosides of the second modified oligonucleotide include a fluorine-containing modified sugar moiety or a fluorine-containing sugar surrogate.

171. The oligomer double chain according to claim 170, wherein the second modified oligonucleotide has a sugar motif (from 5' to 3') selected from eeyyyyf

172. The oligomer double chain according to any one of claims 123 to 139 and 141 to 167, wherein two or fewer of the nucleosides of the second modified oligonucleotide include a fluorine-containing modified sugar moiety or a fluorine-containing sugar surrogate.

173. The oligomer double chain according to claim 172, wherein the second modified polypeptide has a sugar motif (from 5' to 3') selected from eeyyyyyyyffy

174. None of the nucleosides of the second modified substituent contain a fluorine-containing modified sugar moiety or a fluorine-containing sugar surrogate, and the second modified substituent has a sugar motif (from 5' to 3') selected from y

175. The oligomeric double helix according to any one of claims 123 to 174, wherein one or more of the nucleoside bonds of the first modified oligonucleotide are modified nucleoside bonds, and / or less than 50%, less than 40%, less than 30%, less than 20%, or less than 10% of the nucleoside bonds of the first modified oligonucleotide are modified nucleoside bonds.

176. The oligomer double helix according to any one of claims 123 to 175, wherein the internucleoside bonds between the first and second nucleosides counting from the 5' end of the first modified oligonucleotide, and between the second and third nucleosides, and the internucleoside bonds between the first and second nucleosides counting from the 3' end of the first modified oligonucleotide, and between the second and third nucleosides, are phosphorothioate internucleoside bonds.

177. The oligomer double helix according to any one of claims 123 to 175, wherein the first modified oligonucleotide has a nucleoside linkage motif (from 5' to 3') selected from among ssoooooooooooooooooooooooooooooooooooooooo, ssooososoo

178. The oligomeric double helix according to any one of claims 123 to 177, wherein one or more of the nucleoside bonds of the second modified oligonucleotide are modified nucleoside bonds.

179. The oligomeric double helix according to any one of claims 123 to 178, wherein less than 50%, less than 40%, less than 30%, less than 20%, or less than 10% of the nucleoside bonds of the second modified oligonucleotide are modified nucleoside bonds.

180. The oligomer double helix according to any one of claims 123 to 179, wherein the internucleoside bonds between the first and second nucleosides counting from the 5' end of the second modified oligonucleotide, and between the second and third nucleosides, and the internucleoside bonds between the first and second nucleosides counting from the 3' end of the second modified oligonucleotide, and between the second and third nucleosides, are phosphorothioate internucleoside bonds.

181. The oligomeric double helix according to any one of claims 123 to 180, wherein the second modified oligonucleotide has a nucleoside linkage motif (from 5' to 3') selected from ssoooooooooooooooooooss, ssoooooooooooooooooooss, ssoooooooooozozooooooooooss, and ssoooooooooooooooooooooss, where each "o" represents a phosphodiester nucleoside linkage, each "s" represents a phosphorothioate nucleoside linkage, and each "z" represents a mesylphosphoamide nucleoside linkage.

182. The first modified oligonucleotide has a first sugar motif (1 ｓｔ ), the second modified oligonucleotide has a second sugar motif (2 ｎｄ ), and the first and second sugar motifs are in the following combinations (from 5' to 3'): 1 ｓｔ : efyyddyyyyyyyyfyfyyyyyee and 2 ｎｄ : ee yyyyyyfyfyfyyyyyyyyyee, 1 ｓｔ : efyyddyyyyyyyyfyfyyyyyyy and 2 ｎｄ : yyyyyyfyfyfyyyyyyyyyyy, 1 ｓｔ : efyyddyyyyyyyyfyfyyyyyee and 2 ｎｄ : yyyyyyfyfyfyyyyyyyyyyy, 1 ｓｔ : efyyddyyyyyyyyfyfyyyyyyy and 2 ｎｄ : ee yyyyyyfyfyfyyyyyyyyyee, 1 ｓｔ : efyyyyyyyyyyyyfyfyyyyyee and 2 ｎｄ : ee yyyyyyffyyyyyyyyee, 1 ｓｔ : efyyyyyyyyyyyyfyfyyyyyyy and 2 ｎｄ : yyyyyyyyffyyyyyyyyyy, 1 ｓｔ : efyyyyyyyyyyyyfyfyyyyyee and 2 ｎｄ : yyyyyyyyffyyyyyyyyyy, 1 ｓｔ : efyyyyyyyyyyyyfyfyyyyyyy and 2 ｎｄ : ee yyyyyyffyyyyyyyyee, 1 ｓｔ : efyyyddyyyyyyyyfyfyyyyyee and 2 ｎｄ : ee yyyyyyffyyyyyyyyee, 1 ｓｔ : efyyyddyyyyyyyyfyfyyyyyyy and 2 ｎｄ : yyyyyyyyffyyyyyyyyyy, 1 ｓｔ : efyyyddyyyyyyyyfyfyyyyyee and 2 ｎｄ : yyyyyyyyffyyyyyyyyyy, 1 ｓｔ : eyyyydyy ｎｄ :eeyyyyyyffyyyyyyyyee, 1 ｓｔ : efyydydyy ｎｄ :eeyyyyyyffyyyyyyyyee, 1 ｓｔ : eyeydydyy ｎｄ :yyyyyyyyyffyyyyyyyyyy, 1 ｓｔ : efyydydyy ｎｄ :yyyyyyyyyffyyyyyyyyyy, 1 ｓｔ : eyeydydyy ｎｄ :eeyyyyyyffyyyyyyyyee, 1 ｓｔ : efyyydyy ｎｄ :eeyyyfyfyfyyyyyyyyee, 1 ｓｔ : eyyyydyy ｎｄ :yyyyyyfyfyfyyyyyyyyyy, 1 ｓｔ : efyyydyy ｎｄ :yyyyyyfyfyfyyyyyyyyyy, 1 ｓｔ : eyyyydyy ｎｄ :eeyyyfyfyfyyyyyyyyee, 1 ｓｔ : efy ｎｄ :eeyyyfyfyfyyyyyyyyee, 1 ｓｔ : ey ｎｄ :yyyyyyfyfyfyyyyyyyyyy, 1 ｓｔ : efy ｎｄ :yyyyyyfyfyfyyyyyyyyyy, 1 ｓｔ : ey ｎｄ :eeyyyfyfyfyyyyyyyyee, 1 ｓｔ : efy ｎｄ :eeyyyyyyffyyyyyyyyee, 1 ｓｔ : efy ｎｄ :yyyyyyyyyffyyyyyyyyyy, 1 ｓｔ : efy ｎｄ :yyyyyyyyyffyyyyyyyyyy, 1 ｓｔ : efy ｎｄ :eeyyyyyyffyyyyyyyyee, 1 ｓｔ : efy ｎｄ :eeyyyfyfyfyyyyyyyyee, 1 ｓｔ : efy ｎｄ :yyyyyyfyfyfyyyyyyyyyy, 1 ｓｔ : efy ｎｄ :yyyyyyfyfyfyyyyyyyyyy, 1 ｓｔ : efy ｎｄ :eeyyyfyfyfyyyyyyyyee, 1 ｓｔ : efyydydyy ｎｄ :eeyyyfyfyfyyyyyyyyee, 1 ｓｔ : eyeydydyy ｎｄ :yyyyyyfyfyfyyyyyyyyyy, 1 ｓｔ : efyydydyy ｎｄ :yyyyyyfyfyfyyyyyyyyyy, 1 ｓｔ : eyeydydyy ｎｄ :eeyyyfyfyfyyyyyyyyee, 1 ｓｔ : efyydydyy ｎｄ :eeyyyyyyffyyyyyyyyee, 1 ｓｔ : efyyddyyyyyyyyfyfyyyyyyy and 2 ｎｄ : yyyyyyyyyyffyyyyyyyyyy, 1 ｓｔ : efyyddyyyyyyyyfyfyyyyyye and 2 ｎｄ : yyyyyyyyyyffyyyyyyyyyy, 1 ｓｔ : efyyddyyyyyyyyfyfyyyyyyy and 2 ｎｄ : eeyyyyyyyyyffyyyyyyyyye, 1 ｓｔ : efyyyddyyyyyyyyfyfyyyyyye and 2 ｎｄ : eeyyyyyyyyyffyyyyyyyyye, 1 ｓｔ : efyyyddyyyyyyyyfyfyyyyyyy and 2 ｎｄ : yyyyyyyyyyffyyyyyyyyyy, 1 ｓｔ : efyyyddyyyyyyyyfyfyyyyyye and 2 ｎｄ : yyyyyyyyyyffyyyyyyyyyy, 1 ｓｔ : efyyyddyyyyyyyyfyfyyyyyyy and 2 ｎｄ : eeyyyyyyyyyffyyyyyyyyye, 1 ｓｔ : efyyyddyyyyyyyyfyfyyyyyye and 2 ｎｄ : eeyyyyyyfyfyfyyyyyyyyyye, 1 ｓｔ : efyyyddyyyyyyyyfyfyyyyyyy and 2 ｎｄ : yyyyyyyyfyfyfyyyyyyyyyyy, 1 ｓｔ : efyyyddyyyyyyyyfyfyyyyyye and 2 ｎｄ : yyyyyyyyfyfyfyyyyyyyyyyy, 1 ｓｔ : efyyyddyyyyyyyyfyfyyyyyyy and 2 ｎｄ : eeyyyyyyfyfyfyyyyyyyyyye, 1 ｓｔ : efyyyyyyyyyyyyyfyfyyyyyy and 2 ｎｄ : eeyyyyyyyyyffyyyyyyyyye, 1 ｓｔ : efyyyyyyyyyyyyyfyfyyyyyy and 2 ｎｄ : yyyyyyyyyyffyyyyyyyyyy, 1 ｓｔ : efy ｎｄ :eeyyyfyfyfyyyyyyyyee, 1 ｓｔ : efy ｎｄ :yyyyyyfyfyfyyyyyyyyyy, 1 ｓｔ : eyeydydyy ｎｄ :eeyyyfyfyfyyyyyyyyee, 1 ｓｔ : eyeydydyy ｎｄ :yyyyyyfyfyfyyyyyyyyyy, 1 ｓｔ : eyeydydyy ｎｄ :eeyyyyyyffyyyyyyyyee, 1 ｓｔ : eyeydydyy ｎｄ :yyyyyyyyyffyyyyyyyyyy, 1 ｓｔ : eyyyydyy ｎｄ :eeyyyyyyffyyyyyyyyee, 1 ｓｔ : eyyyydyy ｎｄ :yyyyyyyyyffyyyyyyyyyy, 1 ｓｔ : eyyyydyy ｎｄ :eeyyyfyfyfyyyyyyyyee, 1 ｓｔ : eyyyydyy ｎｄ An oligomeric double chain according to any one of claims 1 to 4, 12, 18, 19, 30 to 69, 72, 80, 105 to 115, 117 to 139, 152, 153, and 175 to 181, wherein the formula is selected from yyyyyyfyfyfyyyyyyyyy, where each "y" represents a 2'-OMe sugar moiety, each "e" represents a 2'-MOE sugar moiety, each "f" represents a 2'-fluoro sugar moiety, and each "d" represents a 2'-deoxy sugar moiety.

183. The first modified oligonucleotide is a first sugar motif (1 ｓｔ The second modified oligonucleotide has a second sugar motif (2 ｎｄ ) and the first and second sugar motifs are in the following combination (from 5' to 3'): 1 ｓｔ : efyydydyy ｎｄ :eeyyyfyffffyyyyyyyyee, 1 ｓｔ : eyeydydyy ｎｄ :yyyyyyfyffffyyyyyyyyyy, 1 ｓｔ : efyydydyy ｎｄ :yyyyyyfyffffyyyyyyyyyy, 1 ｓｔ : eyeydydyy ｎｄ :eeyyyfyffffyyyyyyyyee, 1 ｓｔ : efy ｎｄ :eeyyyfyffffyyyyyyyyee, 1 ｓｔ : ey ｎｄ :yyyyyyfyffffyyyyyyyyyy, 1 ｓｔ : efy ｎｄ :yyyyyyfyffffyyyyyyyyyy, 1 ｓｔ : ey ｎｄ :eeyyyfyffffyyyyyyyyee, 1 ｓｔ : efy ｎｄ :eeyyyyyyffyyyyyyyyee, 1 ｓｔ : ey ｎｄ :yyyyyyyyyffyyyyyyyyyy, 1 ｓｔ : efy ｎｄ :yyyyyyyyyffyyyyyyyyyy, 1 ｓｔ : ey ｎｄ :eeyyyyyyffyyyyyyyyee, 1 ｓｔ : efy ｎｄ :eeyyyfyfyfyyyyyyyyee, 1 ｓｔ : ey ｎｄ :yyyyyyfyfyfyyyyyyyyyy, 1 ｓｔ : efy ｎｄ :yyyyyyfyfyfyyyyyyyyyy, 1 ｓｔ : ey ｎｄ :eeyyyfyfyfyyyyyyyyee, 1 ｓｔ : efy ｎｄ :yyyyyyyyyffyyyyyyyyyy, 1 ｓｔ : efy ｎｄ :eeyyyyyyffyyyyyyyyee, 1 ｓｔ : efy ｎｄ :eeyyyyyyffyyyyyyyyee, 1 ｓｔ : efy ｎｄ :yyyyyyyyyffyyyyyyyyyy, 1 ｓｔ : efy ｎｄ :yyyyyyfyfyfyyyyyyyyyy, 1 ｓｔ : efy ｎｄ :eeyyyfyfyfyyyyyyyyee, 1 ｓｔ : efy ｎｄ :eeyyyfyfyfyyyyyyyyee, 1 ｓｔ : efy ｎｄ :yyyyyyfyfyfyyyyyyyyyy, 1 ｓｔ : efy ｎｄ :eeyyyfyffffyyyyyyee, 1 ｓｔ : efy ｎｄ :yyyyyyfyffffyyyyyyyy, 1 ｓｔ : efy ｎｄ :yyyyyyfyffffyyyyyyyy, 1 ｓｔ : efy ｎｄ :eeyyyfyffffyyyyyyee, 1 ｓｔ : efy ｎｄ :eeyyyffyyyyyyyyee, 1 ｓｔ : efy ｎｄ :yyyyyyffyyyyyyyyyy, 1 ｓｔ : efy ｎｄ :yyyyyyffyyyyyyyyyy, 1 ｓｔ : efy ｎｄ :eeyyyffyyyyyyyyee, 1 ｓｔ : e[FHNA]yydydyyyyfyfyfyyyyyyee and 2 ｎｄ :eeyyyfyffffyyyyyyyyee, 1 ｓｔ : efy ｎｄ :eeyyyfyffffyyyyyyyyee, 1 ｓｔ : efy ｎｄ :yyyyyyfyffffyyyyyyyyyy, 1 ｓｔ : e[FHNA]yydydyyyyfyfyfyyyyyyyy and 2 ｎｄ :yyyyyyfyffffyyyyyyyyyy, 1 ｓｔ : e[FHNA]yydydyyyyfyfyfyyyyyyee and 2 ｎｄ :yyyyyyfyffffyyyyyyyyyy, 1 ｓｔ : e[FHNA]yydydyyyyfyfyfyyyyyyyy and 2 ｎｄ :eeyyyfyffffyyyyyyyyee, 1 ｓｔ : e[FHNA]yydydyyyyfyfyfyyyyyyee and 2 ｎｄ :eeyyyfyfyfyyyyyyyyee, 1 ｓｔ : e[FHNA]yydydyyyyfyfyfyyyyyyyy and 2 ｎｄ :yyyyyyfyfyfyyyyyyyyyy, 1 ｓｔ : e[FHNA]yydydyyyyfyfyfyyyyyyee and 2 ｎｄ : y ｓｔ : e[FHNA]yydydyyyyfyfyfyyyyyyyy and 2 ｎｄ An oligomeric double chain according to any one of claims 1 to 4, 12, 18, 19, 30 to 69, 72, 80, 105 to 115, 117 to 139, 152, 153, and 175 to 181, wherein the formula is selected from eeyyyyfyfyyyyyyyyyyy, where each "y" represents a 2'-OMe sugar moiety, each "e" represents a 2'-MOE sugar moiety, each "f" represents a 2'-fluoro sugar moiety, each "[FHNA]" represents a 3'-fluorohexitol sugar moiety, and each "d" represents a 2'-deoxy sugar moiety.

184. The first modified oligonucleotide has a first sugar motif (1st), the second modified oligonucleotide has a second sugar motif (2nd), and the first and second sugar motifs are in the following combination (5' to 3'): 1 ｓｔ : efy ｎｄ :yyyyyyyyyyyyyyyyyyyy, 1 ｓｔ : efy ｎｄ :eeyyyfyffffyyyyyyyyee, 1 ｓｔ : efy ｎｄ : yyyyyyfyfffy ｓｔ : efy ｎｄ An oligomeric double chain according to any one of claims 1 to 4, 12, 18, 19, 30 to 69, 72, 80, 105 to 115, 117 to 139, 152, 153, and 175 to 181, wherein the formula is selected from eeyyyyfyfffyyyyyyyyyy, where each "y" represents a 2'-OMe sugar moiety, each "e" represents a 2'-MOE sugar moiety, and each "f" represents a 2'-fluoro sugar moiety.

185. The first modified oligonucleotide is a first sugar motif (1 ｓｔ The second modified oligonucleotide has a second sugar motif (2 ｎｄ ) and the first and second sugar motifs are in the following combination (from 5' to 3'): 1 ｓｔ : efy ｎｄ :yyyyyyyyyyyyyyyyyyyy, 1 ｓｔ : efy ｎｄ :eeyyyyyyyyyyyyyyyyy, 1 ｓｔ : efy ｎｄ :eeyyyyyyyyyyyyyyyyy, 1 ｓｔ : efy ｎｄ :yyyyyyyyyyyyyyyyyyyy, 1 ｓｔ : efy ｎｄ :yyyyyyyyyydyyyyyyyyyy, 1 ｓｔ : efy ｎｄ :eeyyyyyyydyyyyyyyyee, 1 ｓｔ : efy ｎｄ :eeyyyyyyydyyyyyyyyee, 1 ｓｔ : efy ｎｄ :yyyyyyyyyydyyyyyyyyyy, 1 ｓｔ : ey ｎｄ :eeyyyfyffffyyyyyyyyee, 1 ｓｔ : ey ｎｄ :yyyyyyfyffffyyyyyyyyyy, 1 ｓｔ : ey ｎｄ :yyyyyyfyffffyyyyyyyyyy, 1 ｓｔ : ey ｎｄ :eeyyyfyffffyyyyyyyyee, 1 ｓｔ : ey ｎｄ :eeyyyfyfyfyyyyyyyyee, 1 ｓｔ : ey ｎｄ :yyyyyyfyfyfyyyyyyyyyy, 1 ｓｔ : ey ｎｄ :yyyyyyfyfyfyyyyyyyyyy, 1 ｓｔ : ey ｎｄ :eeyyyfyfyfyyyyyyyyee, 1 ｓｔ : efyyydyy ｎｄ :eeyyyfyffffyyyyyyyyee, 1 ｓｔ : eyyyydyy ｎｄ :yyyyyyfyffffyyyyyyyyyy, 1 ｓｔ : efyyydyy ｎｄ :yyyyyyfyffffyyyyyyyyyy, 1 ｓｔ : eyyyydyy ｎｄ :eeyyyfyffffyyyyyyyyee, 1 ｓｔ : efy ｎｄ :eeyfyffffyyyyyyyyee, 1 ｓｔ : efy ｎｄ :yyyyfyffffyyyyyyyyyy, 1 ｓｔ : efy ｎｄ :yyyyfyffffyyyyyyyyyy, 1 ｓｔ : efy ｎｄ :eeyfyffffyyyyyyyyee, 1 ｓｔ : efy ｎｄ :eeyyyfyffffyyyyyyyyee, 1 ｓｔ : ey ｎｄ :yyyyyyfyffffyyyyyyyyyy, 1 ｓｔ : efy ｎｄ :yyyyyyfyffffyyyyyyyyyy, 1 ｓｔ : ey ｎｄ :eeyyyfyffffyyyyyyyyee, 1 ｓｔ : e[FHNA]yyyfy ｎｄ :eeyyyfyffffyyyyyyyyee, 1 ｓｔ : e[FHNA]yyyfyyyyyyyfyfyyyyyyyy and 2 ｎｄ :yyyyyyfyffffyyyyyyyyyy, 1 ｓｔ : e[FHNA]yyyfy ｎｄ : yyyyyyfyfffy ｓｔ : e[FHNA]yyyfyyyyyyyfyfyyyyyyyy and 2 ｎｄ An oligomeric double chain according to any one of claims 1 to 4, 12, 18, 19, 30 to 69, 72, 80, 105 to 115, 117 to 139, 152, 153, and 175 to 181, wherein the formula is selected from eeyyyyfyfffyyyyyyyyyy, where each "y" represents a 2'-OMe sugar moiety, each "e" represents a 2'-MOE sugar moiety, each "f" represents a 2'-fluoro sugar moiety, each "[FHNA]" represents a 3'-fluorohexitol sugar moiety, and each "d" represents a 2'-deoxy sugar moiety.

186. The first modified oligonucleotide is a first sugar motif (1 ｓｔ The second modified oligonucleotide has a second sugar motif (2 ｎｄ ) and the first and second sugar motifs are in the following combination (from 5' to 3'): 1 ｓｔ : ey ｎｄ :eeyyyyyyffyyyyyyyyee, 1 ｓｔ : ey ｎｄ :yyyyyyyyyffyyyyyyyyyy, 1 ｓｔ : ey ｎｄ :yyyyyyyyyffyyyyyyyyyy, 1 ｓｔ : ey ｎｄ :eeyyyyyyffyyyyyyyyee, 1 ｓｔ : efy ｎｄ :eeyyyfyffffyyyyyyyyee, 1 ｓｔ : ey ｎｄ :yyyyyyfyffffyyyyyyyyyy, 1 ｓｔ : efy ｎｄ :yyyyyyfyffffyyyyyyyyyy, 1 ｓｔ : ey ｎｄ :eeyyyfyffffyyyyyyyyee, 1 ｓｔ : efy ｎｄ :eeyyyyyyffyyyyyyyyee, 1 ｓｔ : ey ｎｄ :yyyyyyyyyffyyyyyyyyyy, 1 ｓｔ : efy ｎｄ : yyyyyyfyfffy ｓｔ : ey ｎｄ An oligomeric double chain according to any one of claims 1 to 4, 12, 18, 19, 30 to 69, 72, 80, 105 to 115, 117 to 139, 152, 153, and 175 to 181, wherein the formula is selected from eeyyyyfyfffyyyyyyyyyy, where each "y" represents a 2'-OMe sugar moiety, each "e" represents a 2'-MOE sugar moiety, and each "f" represents a 2'-fluoro sugar moiety.

187. The oligomer double helix according to any one of claims 123 to 186, wherein the nucleoside bonds between the first and second nucleosides counting from the 5' end of the first modified oligonucleotide, and between the second and third nucleosides, and the nucleoside bonds between the first and second nucleosides counting from the 3' end of the first modified oligonucleotide, and between the second and third nucleosides, are phosphorothioate nucleoside bonds, and all other nucleoside bonds of the first modified oligonucleotide are phosphodiester nucleoside bonds.

188. The oligomer double helix according to any one of claims 123 to 187, wherein the nucleoside bonds between the first and second nucleosides counting from the 5' end of the second modified oligonucleotide, and between the second and third nucleosides, and the nucleoside bonds between the first and second nucleosides counting from the 3' end of the second modified oligonucleotide, and between the second and third nucleosides, are phosphorothioate nucleoside bonds, and all other nucleoside bonds of the second modified oligonucleotide are phosphodiester nucleoside bonds.

189. The oligomeric double helix according to any one of claims 123 to 188, wherein the nucleic acid base sequence of the first modified oligonucleotide includes or consists of any one of the nucleic acid base sequences of SEQ ID NOs: 967, 968, 971, 972, 974, 975, 1033-1038, 1254-1255, or 1258-1287.

190. The oligomeric double helix according to any one of claims 1 to 189, wherein the cytosine nucleic acid base in the first and / or second modified oligonucleotide is optionally 5-methylcytosine.

191. The oligomeric double chain according to any one of claims 123 to 190, wherein the oligomeric double chain comprises a conjugate group including a conjugate moiety and a conjugate linker.

192. The oligomeric double chain according to claim 191, wherein the conjugate portion comprises an active drug substance, an aliphatic chain, a lipid, a peptide, a protein, a hydrocarbon, a polyamine, a polyamide, a polyether, a thioether, an aptamer, an antibody, an antibody fragment, a vitamin, a fatty acid, a carbohydrate, an intercalator, or a reporter molecule.

193. The oligomer double chain according to claim 191, wherein the conjugate group comprises C22 alkyl, C20 alkyl, C17 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, or C5 alkyl, and the alkyl chain optionally has one or more unsaturated bonds.

194. The oligomeric double chain according to claim 191, wherein the conjugate group comprises a 6-palmitamide hexyl moiety or a 2-(hydroxymethyl)-6-palmitamide hexyl moiety.

195. The oligomeric double chain according to claim 191, wherein the oligomeric double chain includes a conjugate portion that binds to a type 1 transferrin receptor (TfR1).

196. The oligomeric double chain according to claim 195, wherein the conjugate portion is selected from an antibody or fragment thereof, a protein or peptide, and an aptamer that can bind to TfR1.

197. The oligomeric double chain according to claim 196, wherein the conjugate portion is a cyclic protein or a cyclic peptide.

198. The oligomeric double chain according to claim 195, wherein the conjugate group comprises a bicyclic ligand and a conjugate linker.

199. The oligomeric double chain according to claim 198, wherein the bicyclic ligand comprises a peptide and a molecular skeleton consisting of 13 to 22 linked amino acids or amino acid mimes, and each of the first, second, and third amino acids of the peptide comprises a reactive group, each of which separately forms a bond with the molecular skeleton, thereby forming two peptide loops bonded to the molecular skeleton.

200. The oligomeric double chain according to claim 199, wherein the bicyclic ligand comprises an amino acid sequence selected from any one of sequence numbers 1062 to 1253.

201. The oligomeric double chain according to any one of claims 198 to 200, wherein the conjugate linker comprises a (bicyclo[6.1.0]nonine)-formyl (BCN) moiety.

202. The oligomeric double chain according to any one of claims 198 to 200, wherein the conjugate linker comprises a 6-(BCN-carbamate)-2-(hydroxymethyl)hexylphosphoryl moiety or a 6-(BCN-carbamate)hexylphosphoryl moiety.

203. An oligomeric double chain according to any one of claims 123 to 190, comprising a conjugate group consisting of a conjugate moiety and a conjugate linker, wherein the conjugate linker comprises a 6-(BCN-carbamate)-2-(hydroxymethyl)hexylphosphoryl moiety or a 6-(BCN-carbamate)hexylphosphoryl moiety.

204. An oligomeric double chain according to any one of claims 123 to 190, comprising a bicyclic ligand containing a peptide having an amino acid sequence selected from any one of SEQ ID NOs: 1062 to 1253, wherein each cysteine ​​forms a covalent bond with the molecular skeleton 1,1',1''-(1,3,5-triazinan-1,3,5-triyl)tris(2-bromoetanone) (TATB), or the molecular skeleton is 1,1',1''-(1,3,5-triazinan-1,3,5-triyl)triplop-2-en-1-one (TATA).

205. The following chemical notation: vPT ｅｓ U ｆｓ U ｙｏ A ｙｏ A ｙｏ G ｄｏ A ｙｏ U ｙｏ G ｙｏ A ｙｏ G ｙｏ A ｙｏ C ｙｏ A ｆｏ G ｙｏ A ｆｏ A ｙｏ A ｙｏ U ｙｏ U ｙｏ G ｙｓ A ｅｓ A ｅ An oligomeric compound comprising an oligonucleotide modified by (SEQ ID NO: 1033), wherein, A = adenine nucleic acid base, C = cytosine nucleic acid base, G = guanine nucleic acid base, T = thymine nucleobase, U = uracil nucleic acid base, d = 2'-deoxy sugar portion, e=2'-MOE sugar moiety, f = 2'-fluorosugar portion, y=2'-OMe sugar moiety, o = phosphodiester nucleoside interbonding, s = phosphorothioate nucleoside bond, and An oligomeric compound in which vP = 5' vinylphosphonate group.

206. The following chemical notation: ｍ C ｅｓ A ｅｓ A ｙｏ U ｙｏ U ｙｏ U ｙｏ C ｙｏ U ｙｏ G ｙｏ U ｆｏ C ｆｏ U ｙｏ C ｙｏ A ｙｏ U ｙｏ C ｙｏ U ｙｏ U ｙｏ A ｙｓ A ｅｓ A ｅ An oligomeric compound comprising an oligonucleotide modified by (SEQ ID NO: 1027), wherein, A = adenine nucleic acid base, ｍ C=5-methylcytosine nucleic acid base, C = cytosine nucleic acid base, G = guanine nucleic acid base, U = uracil nucleic acid base, e=2'-MOE sugar moiety, f = 2'-fluorosugar portion, y=2'-OMe sugar moiety, o = phosphodiester nucleoside interbonding, and An oligomeric compound in which s = phosphorothioate nucleoside bond.

207. The following chemical notation: [X] ｎ - ｍ C ｅｓ A ｅｓ A ｙｏ U ｙｏ U ｙｏ U ｙｏ C ｙｏ U ｙｏ G ｙｏ U ｆｏ C ｆｏ U ｙｏ C ｙｏ A ｙｏ U ｙｏ C ｙｏ U ｙｏ U ｙｏ A ｙｓ A ｅｓ A ｅ - [X] ｋ An oligomeric compound comprising a conjugated modified oligonucleotide according to (SEQ ID NO: 1039), wherein, ｍ C=5-methylcytosine nucleic acid base, C = cytosine nucleic acid base, A = adenine nucleic acid base, G = guanine nucleic acid base, U = uracil nucleic acid base, e=2'-MOE sugar moiety, f = 2'-fluorosugar portion, y=2'-OMe sugar moiety, o = phosphodiester nucleoside interbonding, s = phosphorothioate nucleoside interbonding, [X] = a conjugate group containing a bicyclic ligand, and An oligomeric compound in which n and k are either 0 or 1, where k=0 when n=1, and k=1 when n=0.

208. An oligomeric double chain comprising the oligomeric compound described in claim 205 and the oligomeric compound described in claim 206.

209. An oligomeric double chain comprising the oligomeric compound described in claim 205 and the oligomeric compound described in claim 207.

210. The following chemical notation: vPT-T ｅｓ U ｆｓ U ｙｏ A ｙｏ A ｄｏ G ｙｏ A ｄｏ U ｙｏ G ｙｏ A ｙｏ G ｙｏ A ｙｏ C ｙｏ A ｆｏ G ｙｏ A ｆｏ A ｙｏ A ｙｏ U ｙｏ U ｙｏ G ｙｓ A ｅｓ A ｅ An oligomeric compound comprising an oligonucleotide modified by (SEQ ID NO: 1034), wherein, A = adenine nucleic acid base, C = cytosine nucleic acid base, G = guanine nucleic acid base, T = thymine nucleobase, U = uracil nucleic acid base, d = 2'-deoxy sugar portion, e=2'-MOE sugar moiety, f = 2'-fluorosugar portion, y=2'-OMe sugar moiety, o = phosphodiester nucleoside interbonding, s = phosphorothioate nucleoside bond, and An oligomeric compound in which vP = 5' vinylphosphonate group.

211. The following chemical notation: C ｅｓ A ｅｓ A ｙｏ U ｙｏ U ｙｏ U ｙｏ C ｆｏ U ｙｏ G ｆｏ U ｙｏ C ｆｏ U ｙｏ C ｙｏ A ｙｏ U ｙｏ C ｙｏ U ｙｏ U ｙｏ A ｙｓ A ｅｓ A ｅ An oligomeric compound comprising an oligonucleotide modified by (SEQ ID NO: 1028), wherein the formula, A = adenine nucleic acid base, C = cytosine nucleic acid base, G = guanine nucleic acid base, U = uracil nucleic acid base, e=2'-MOE sugar moiety, f = 2'-fluorosugar portion, y=2'-Ome sugar moiety, o = phosphodiester nucleoside interbonding, and An oligomeric compound in which s = phosphorothioate nucleoside bond.

212. The following chemical notation: [X] ｎ -C ｅｓ A ｅｓ A ｙｏ U ｙｏ U ｙｏ U ｙｏ C ｆｏ U ｙｏ G ｆｏ U ｙｏ C ｆｏ U ｙｏ C ｙｏ A ｙｏ U ｙｏ C ｙｏ U ｙｏ U ｙｏ A ｙｓ A ｅｓ A ｅ - [X] ｋ An oligomeric compound comprising a conjugated modified oligonucleotide according to (SEQ ID NO: 1040), wherein, C = cytosine nucleic acid base, A = adenine nucleic acid base, G = guanine nucleic acid base, U = uracil nucleic acid base, e=2'-MOE sugar moiety, f = 2'-fluorosugar portion, y=2'-Ome sugar moiety, o = phosphodiester nucleoside interbonding, s = phosphorothioate nucleoside interbonding, [X] = a conjugate group containing a bicyclic ligand, and An oligomeric compound in which n and k are either 0 or 1, where k=0 when n=1, and k=1 when n=0.

213. An oligomeric double chain comprising the oligomeric compound described in claim 210 and the oligomeric compound described in claim 211.

214. An oligomeric double chain comprising the oligomeric compound described in claim 210 and the oligomeric compound described in claim 212.

215. The following chemical notation: vPT ｅｓ A ｆｓ U ｙｏ A ｙｏ A ｙｏ A ｄｏ U ｙｏ A ｙｏ G ｙｏ A ｙｏ U ｙｏ U ｙｏ C ｙｏ U ｆｏ G ｙｏ U ｆｏ A ｙｏ G ｙｏ C ｙｏ U ｙｏ U ｙｓ A ｅｓ A ｅ An oligomeric compound comprising an oligonucleotide modified by (SEQ ID NO: 1035), wherein, A = adenine nucleic acid base, C = cytosine nucleic acid base, G = guanine nucleic acid base, T = thymine nucleobase, U = uracil nucleic acid base, d = 2'-deoxy sugar portion, e=2'-MOE sugar moiety, f = 2'-fluorosugar portion, y=2'-OMe sugar moiety, o = phosphodiester nucleoside interbonding, s = phosphorothioate nucleoside bond, and An oligomeric compound in which vP = 5' vinylphosphonate group.

216. The following chemical notation: A ｅｓ A ｅｓ G ｙｏ C ｙｏ U ｙｏ A ｙｏ C ｙｏ A ｙｏ G ｙｏ A ｆｏ A ｆｏ U ｙｏ C ｙｏ U ｙｏ A ｙｏ U ｙｏ U ｙｏ U ｙｏ A ｙｓ T ｅｓ A ｅ An oligomeric compound comprising an oligonucleotide modified by (SEQ ID NO: 1029), wherein, A = adenine nucleic acid base, C = cytosine nucleic acid base, G = guanine nucleic acid base, T = thymine nucleobase, U = uracil nucleic acid base, e=2'-MOE sugar moiety, f = 2'-fluorosugar portion, y=2'-OMe sugar moiety, o = phosphodiester nucleoside interbonding, and An oligomeric compound in which s = phosphorothioate nucleoside bond.

217. The following chemical notation: [X] ｎ -A ｅｓ A ｅｓ G ｙｏ C ｙｏ U ｙｏ A ｙｏ C ｙｏ A ｙｏ G ｙｏ A ｆｏ A ｆｏ U ｙｏ C ｙｏ U ｙｏ A ｙｏ U ｙｏ U ｙｏ U ｙｏ A ｙｓ T ｅｓ A ｅ - [X] ｋ An oligomeric compound comprising a conjugated modified oligonucleotide according to (SEQ ID NO: 1041), wherein, C = cytosine nucleic acid base, A = adenine nucleic acid base, G = guanine nucleic acid base, T = thymine nucleobase, U = uracil nucleic acid base, e=2'-MOE sugar moiety, f = 2'-fluorosugar portion, y=2'-OMe sugar moiety, o = phosphodiester nucleoside interbonding, s = phosphorothioate nucleoside interbonding, [X] = a conjugate group containing a bicyclic ligand, and An oligomeric compound in which n and k are either 0 or 1, where k=0 when n=1, and k=1 when n=0.

218. An oligomeric double chain comprising the oligomeric compound described in claim 215 and the oligomeric compound described in claim 216.

219. An oligomer compound comprising the oligomer compound described in claim 215 and the oligomer compound described in claim 217.

220. The following chemical notation: vPT ｅｓ A ｆｓ U ｙｏ A ｙｏ A ｄｏ A ｙｏ T ｄｏ A ｙｏ G ｙｏ A ｙｏ U ｙｏ U ｙｏ C ｙｏ U ｆｏ G ｙｏ U ｆｏ A ｙｏ G ｙｏ C ｙｏ U ｙｏ U ｙｓ A ｅｓ A ｅ An oligomeric compound comprising an oligonucleotide modified by (SEQ ID NO: 1036), wherein, A = adenine nucleic acid base, C = cytosine nucleic acid base, G = guanine nucleic acid base, T = thymine nucleobase, U = uracil nucleic acid base, d = 2'-deoxy sugar portion, e=2'-MOE sugar moiety, f = 2'-fluorosugar portion, y=2'-OMe sugar moiety, o = phosphodiester nucleoside interbonding, s = phosphorothioate nucleoside bond, and An oligomeric compound in which vP = 5' vinylphosphonate group.

221. The following chemical notation: A ｅｓ A ｅｓ G ｙｏ C ｙｏ U ｙｏ A ｙｏ C ｆｏ A ｙｏ G ｆｏ A ｙｏ A ｆｏ U ｙｏ C ｙｏ U ｙｏ A ｙｏ U ｙｏ U ｙｏ U ｙｏ A ｙｓ U ｅｓ A ｅ An oligomeric compound comprising an oligonucleotide modified by (SEQ ID NO: 1030), wherein, A = adenine nucleic acid base, C = cytosine nucleic acid base, G = guanine nucleic acid base, U = uracil nucleic acid base, e=2'-MOE sugar moiety, f = 2'-fluorosugar portion, y=2'-OMe sugar moiety, o = phosphodiester nucleoside interbonding, and An oligomeric compound in which s = phosphorothioate nucleoside bond.

222. The following chemical notation: [X] ｎ -A ｅｓ A ｅｓ G ｙｏ C ｙｏ U ｙｏ A ｙｏ C ｆｏ A ｙｏ G ｆｏ A ｙｏ A ｆｏ U ｙｏ C ｙｏ U ｙｏ A ｙｏ U ｙｏ U ｙｏ U ｙｏ A ｙｓ U ｅｓ A ｅ - [X] ｋ An oligomeric compound comprising a conjugated modified oligonucleotide according to (SEQ ID NO: 1042), wherein, C = cytosine nucleic acid base, A = adenine nucleic acid base, G = guanine nucleic acid base, U = uracil nucleic acid base, e=2'-MOE sugar moiety, f = 2'-fluorosugar portion, y=2'-OMe sugar moiety, o = phosphodiester nucleoside interbonding, s = phosphorothioate nucleoside interbonding, [X] = a conjugate group containing a bicyclic ligand, and An oligomeric compound in which n and k are either 0 or 1, where k=0 when n=1, and k=1 when n=0.

223. An oligomeric double chain comprising the oligomeric compound described in claim 220 and the oligomeric compound described in claim 221.

224. An oligomeric double chain comprising the oligomeric compound described in claim 220 and the oligomeric compound described in claim 222.

225. The following chemical notation: vPT ｅｓ U ｆｓ A ｙｏ A ｙｏ G ｙｏ T ｄｏ U ｙｏ U ｙｏ U ｙｏ A ｙｏ G ｙｏ U ｙｏ C ｙｏ U ｆｏ U ｙｏ A ｆｏ A ｙｏ U ｙｏ C ｙｏ U ｙｏ U ｙｓ A ｅｓ A ｅ An oligomeric compound comprising an oligonucleotide modified by (SEQ ID NO: 1037), wherein, A = adenine nucleic acid base, C = cytosine nucleic acid base, G = guanine nucleic acid base, T = thymine nucleobase, U = uracil nucleic acid base, d = 2'-deoxy sugar portion, e=2'-MOE sugar moiety, f = 2'-fluorosugar portion, y=2'-OMe sugar moiety, o = phosphodiester nucleoside interbonding, s = phosphorothioate nucleoside bond, and An oligomeric compound in which vP = 5' vinylphosphonate group.

226. The following chemical notation: A ｅｓ A ｅｓ G ｙｏ A ｙｏ U ｙｏ U ｙｏ A ｙｏ A ｙｏ G ｙｏ A ｆｏ C ｆｏ U ｙｏ A ｙｏ A ｙｏ A ｙｏ A ｙｏ C ｙｏ U ｙｏ U ｙｓ A ｅｓ A ｅ An oligomeric compound comprising an oligonucleotide modified by (SEQ ID NO: 1031), wherein, A = adenine nucleic acid base, C = cytosine nucleic acid base, G = guanine nucleic acid base, U = uracil nucleic acid base, e=2'-MOE sugar moiety, f = 2'-fluorosugar portion, y=2'-OMe sugar moiety, o = phosphodiester nucleoside interbonding, and An oligomeric compound in which s = phosphorothioate nucleoside bond.

227. The following chemical notation: [X] ｎ -A ｅｓ A ｅｓ G ｙｏ A ｙｏ U ｙｏ U ｙｏ A ｙｏ A ｙｏ G ｙｏ A ｆｏ C ｆｏ U ｙｏ A ｙｏ A ｙｏ A ｙｏ A ｙｏ C ｙｏ U ｙｏ U ｙｓ A ｅｓ A ｅ - [X] ｋ An oligomeric compound comprising a conjugated modified oligonucleotide according to (SEQ ID NO: 1043), wherein, C = cytosine nucleic acid base, A = adenine nucleic acid base, G = guanine nucleic acid base, U = uracil nucleic acid base, e=2'-MOE sugar moiety, f = 2'-fluorosugar portion, y=2'-OMe sugar moiety, o = phosphodiester nucleoside interbonding, s = phosphorothioate nucleoside interbonding, [X] = a conjugate group containing a bicyclic ligand, and An oligomeric compound in which n and k are either 0 or 1, where k=0 when n=1, and k=1 when n=0.

228. An oligomeric double chain comprising the modified oligonucleotide described in claim 225 and the modified oligonucleotide described in claim 226.

229. An oligomeric double helix comprising the modified oligonucleotide described in claim 225 and the conjugate described in claim 227.

230. The following chemical notation: vPT ｅｓ U ｆｓ A ｙｏ A ｙｏ G ｄｏ U ｙｏ T ｄｏ U ｙｏ U ｙｏ A ｙｏ G ｙｏ U ｙｏ C ｙｏ U ｆｏ U ｙｏ A ｆｏ A ｙｏ U ｙｏ C ｙｏ U ｙｏ U ｙｓ A ｅｓ A ｅ An oligomeric compound comprising an oligonucleotide modified by (SEQ ID NO: 1038), wherein, A = adenine nucleic acid base, C = cytosine nucleic acid base, G = guanine nucleic acid base, T = thymine nucleobase, U = uracil nucleic acid base, d = 2'-deoxy sugar portion, e=2'-MOE sugar moiety, f = 2'-fluorosugar portion, y=2'-OMe sugar moiety, o = phosphodiester nucleoside interbonding, s = phosphorothioate nucleoside bond, and An oligomeric compound in which vP = 5' vinylphosphonate group.

231. The following chemical notation: A ｅｓ A ｅｓ G ｙｏ A ｙｏ U ｙｏ U ｙｏ A ｆｏ A ｙｏ G ｆｏ A ｙｏ C ｆｏ U ｙｏ A ｙｏ A ｙｏ A ｙｏ A ｙｏ C ｙｏ U ｙｏ U ｙｓ A ｅｓ A ｅ An oligomeric compound comprising an oligonucleotide modified by (SEQ ID NO: 1032), wherein, A = adenine nucleic acid base, C = cytosine nucleic acid base, G = guanine nucleic acid base, U = uracil nucleic acid base, e=2'-MOE sugar moiety, f = 2'-fluorosugar portion, y=2'-OMe sugar moiety, o = phosphodiester nucleoside interbonding, and An oligomeric compound in which s = phosphorothioate nucleoside bond.

232. The following chemical notation: [X] ｎ -A ｅｓ A ｅｓ G ｙｏ A ｙｏ U ｙｏ U ｙｏ A ｆｏ A ｙｏ G ｆｏ A ｙｏ C ｆｏ U ｙｏ A ｙｏ A ｙｏ A ｙｏ A ｙｏ C ｙｏ U ｙｏ U ｙｓ A ｅｓ A ｅ - [X] ｋ An oligomeric compound comprising a conjugated modified oligonucleotide according to (SEQ ID NO: 1044), wherein, C = cytosine nucleic acid base, A = adenine nucleic acid base, G = guanine nucleic acid base, U = uracil nucleic acid base, e=2'-MOE sugar moiety, f = 2'-fluorosugar portion, y=2'-OMe sugar moiety, o = phosphodiester nucleoside interbonding, s = phosphorothioate nucleoside interbonding, [X] = a conjugate group containing a bicyclic ligand, and An oligomeric compound in which n and k are either 0 or 1, where k=0 when n=1, and k=1 when n=0.

233. An oligomeric double chain comprising the oligomeric compound described in claim 230 and the oligomeric compound described in claim 231.

234. An oligomeric double chain comprising the oligomeric compound described in claim 230 and the oligomeric compound described in claim 232.

235. The following chemical notation: vPT ｅｓ A ｆｓ U ｙｏ A ｙｏ A ｙｏ A ｙｏ U ｙｏ A ｙｏ G ｙｏ A ｙｏ U ｙｏ U ｙｏ C ｙｏ U ｆｏ G ｙｏ U ｆｏ A ｙｏ G ｙｏ C ｙｏ U ｙｏ U ｙｓ A ｅｓ A ｅ An oligomeric compound comprising an oligonucleotide modified by (SEQ ID NO: 1255), wherein in the formula, A = adenine nucleic acid base, C = cytosine nucleic acid base, G = guanine nucleic acid base, T = thymine nucleobase, U = uracil nucleic acid base, e=2'-MOE sugar moiety, f = 2'-fluorosugar portion, y=2'-OMe sugar moiety, o = phosphodiester nucleoside interbonding, s = phosphorothioate nucleoside bond, and An oligomeric compound in which vP = 5' vinylphosphonate group.

236. The following chemical notation: A ｅｓ A ｅｓ G ｙｏ C ｙｏ U ｙｏ A ｙｏ C ｙｏ A ｙｏ G ｙｏ A ｆｏ A ｆｏ U ｙｏ C ｙｏ U ｙｏ A ｙｏ U ｙｏ U ｙｏ U ｙｏ A ｙｓ T ｅｓ A ｅ An oligomeric compound comprising an oligonucleotide modified by (SEQ ID NO: 1029), wherein, A = adenine nucleic acid base, C = cytosine nucleic acid base, G = guanine nucleic acid base, U = uracil nucleic acid base, T = thymine nucleobase, e=2'-MOE sugar moiety, f = 2'-fluorosugar portion, y=2'-OMe sugar moiety, o = phosphodiester nucleoside interbonding, and An oligomeric compound in which s = phosphorothioate nucleoside bond.

237. The following chemical notation: [X] ｎ -A ｅｓ A ｅｓ G ｙｏ C ｙｏ U ｙｏ A ｙｏ C ｙｏ A ｙｏ G ｙｏ A ｆｏ A ｆｏ U ｙｏ C ｙｏ U ｙｏ A ｙｏ U ｙｏ U ｙｏ U ｙｏ A ｙｓ T ｅｓ A ｅ - [X] ｋ An oligomeric compound comprising a conjugated modified oligonucleotide according to (SEQ ID NO: 1041), wherein, C = cytosine nucleic acid base, A = adenine nucleic acid base, G = guanine nucleic acid base, U = uracil nucleic acid base, T = thymine nucleobase, e=2'-MOE sugar moiety, f = 2'-fluorosugar portion, y=2'-OMe sugar moiety, o = phosphodiester nucleoside interbonding, s = phosphorothioate nucleoside interbonding, [X] = a conjugate group containing a bicyclic ligand, and An oligomeric compound in which n and k are either 0 or 1, where k=0 when n=1, and k=1 when n=0.

238. An oligomeric double chain comprising the oligomeric compound described in claim 235 and the oligomeric compound described in claim 236.

239. An oligomeric double chain comprising the oligomeric compound described in claim 235 and the oligomeric compound described in claim 237.

240. The following structure: 【Chemistry 4】 or its salt (wherein Q is N) ３ (BCY17901, Sequence ID 1045), NH ２ An oligomeric double helix according to any one of claims 123 to 190, 209, 214, 219, 224, 229, 234, 239, comprising a bicyclic ligand or conjugate group having (BCY21757, SEQ ID NO: 1202), SH (BCY21758, SEQ ID NO: 1203), or a conjugate linker, or a conjugate linker covalently bonded to an oligonucleotide, or an oligomeric compound according to any one of claims 207, 212, 217, 222, 227, 232, or 237.

241. Q is N ３ The oligomeric double chain or oligomeric compound according to claim 240, or a conjugate linker.

242. An oligomeric double chain according to any one of claims 123 to 190, 209, 214, 219, 224, 229, 234, or 239, comprising a conjugate group having the following structure, or an oligomeric compound according to any one of claims 207, 212, 217, 222, 227, 232, or 237. 【Transformation 5】

243. An oligomeric double chain according to any one of claims 123 to 190, 209, 214, 219, 224, 229, 234, or 239, comprising a conjugate group having the following structure, or an oligomeric compound according to any one of claims 207, 212, 217, 222, 227, 232, or 237. 【Transformation 6】

244. The oligomeric double chain or oligomeric compound according to any one of claims 191 to 243, wherein the conjugate group is bonded to the second modified oligonucleotide.

245. The oligomeric double chain or compound according to any one of claims 191 to 243, wherein the conjugate group is bonded to the 5' or 3' end of the second modified oligonucleotide.

246. The oligomeric double hemisphere or oligomeric compound according to any one of claims 191 to 243, wherein the conjugate group is bonded to the 5' terminal nucleoside of the second modified oligonucleotide.

247. The following chemical structure: 【Transformation 7】 【Transformation 8】 【Chemistry 9】 Oligomer double chains, such as those of (SEQ ID NO: 1033 and SEQ ID NO: 1027) or their salts.

248. The oligomeric double chain according to claim 247, wherein it is a sodium salt or a potassium salt.

249. The following chemical structure: 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】 Oligomer double helix (according to Sequence ID No. 1033 and Sequence ID No. 1027).

250. The following chemical structure: 【Chemistry 13】 【Chemistry 14】 【Chemistry 15】 Oligomer double chains, such as those of (SEQ ID NO: 1033 and SEQ ID NO: 1039) or their salts.

251. The oligomeric double chain according to claim 250, wherein it is a sodium salt or a potassium salt.

252. The following chemical structure: 【Chemistry 16】 【Chemistry 17】 [Chemistry 18] Oligomer double helix (according to Sequence ID No. 1033 and Sequence ID No. 1039).

253. The following chemical structure: 【Chemistry 19】 【Chemistry 20】 【Chemistry 21】 Oligomer double chains, such as those of (SEQ ID NO: 1034 and SEQ ID NO: 1028) or their salts.

254. The oligomeric double chain according to claim 253, wherein it is a sodium salt or a potassium salt.

255. The following chemical structure: 【Chemistry 22】 【Chemistry 23】 【Chemistry 24】 Oligomer double helix (according to Sequence ID No. 1034 and Sequence ID No. 1028).

256. The following chemical structure: 【Chemistry 25】 【Chemistry 26】 【Chemistry 27】 Oligomer double chains, such as those of (SEQ ID NO: 1034 and SEQ ID NO: 1040) or their salts.

257. The oligomeric double chain according to claim 256, wherein it is a sodium salt or a potassium salt.

258. The following chemical structure: 【Chemistry 28】 【Chemistry 29】 【Transformation 30】 Oligomer double helix (according to Sequence ID No. 1034 and Sequence ID No. 1040).

259. The following chemical structure: 【Chemistry 31】 【Chemistry 32】 【Transformation 33】 Oligomer double chains, such as those of (SEQ ID NO: 1035 and SEQ ID NO: 1029) or their salts.

260. The oligomeric double chain according to claim 259, wherein it is a sodium salt or a potassium salt.

261. The following chemical structure: 【Transformation 34】 【Chemistry 35】 【Transformation 36】 Oligomer double helix (according to Sequence ID No. 1035 and Sequence ID No. 1029).

262. The following chemical structure: 【Chemistry 37】 【Transformation 38】 【Chemistry 39】 Oligomer double chains, such as those of (SEQ ID NO: 1035 and SEQ ID NO: 1041) or their salts.

263. The oligomeric double chain according to claim 262, wherein it is a sodium salt or a potassium salt.

264. The following chemical structure: 【Chemistry 40】 【Chemistry 41】 【Chemistry 42】 Oligomer double helix (according to Sequence ID No. 1035 and Sequence ID No. 1041).

265. The following chemical structure: 【Chemistry 43】 【Chemistry 44】 【Chemistry 45】 Oligomer double chains, such as those of (SEQ ID NO: 1036 and SEQ ID NO: 1030) or their salts.

266. The oligomeric double chain according to claim 265, wherein it is a sodium salt or a potassium salt.

267. The following chemical structure: 【Chemistry 46】 【Chemistry 47】 【Chemistry 48】 Oligomer double helix (according to Sequence ID No. 1036 and Sequence ID No. 1030).

268. The following chemical structure: 【Chemistry 49】 [Transformation 50] 【Chemistry 51】 Oligomer double chains, such as those of (SEQ ID NO: 1036 and SEQ ID NO: 1042) or their salts.

269. The oligomeric double chain according to claim 268, wherein it is a sodium salt or a potassium salt.

270. The following chemical structure: 【Chemistry 52】 【Chemistry 53】 【Chemistry 54】 Oligomer double helix (according to Sequence ID No. 1036 and Sequence ID No. 1042).

271. The following chemical structure: 【Transformation 55】 【Transformation 56】 【Chemistry 57】 Oligomer double chains, such as those of (SEQ ID NO: 1037 and SEQ ID NO: 1031) or their salts.

272. The oligomeric double chain according to claim 271, wherein it is a sodium salt or a potassium salt.

273. The following chemical structure: 【Transformation 58】 【Chemistry 59】 【Transformation 60】 Oligomer double helix (according to Sequence ID No. 1037 and Sequence ID No. 1031).

274. The following chemical structure: 【Chemistry 61】 【Transformation 62】 【Transformation 63】 Oligomer double chains, such as those of (SEQ ID NO: 1037 and SEQ ID NO: 1043) or their salts.

275. The oligomeric double chain according to claim 274, wherein it is a sodium salt or a potassium salt.

276. The following chemical structure: 【Chemistry 64】 【Transformation 65】 【Chemical Formula 66】 Oligomer double helix (according to Sequence ID No. 1037 and Sequence ID No. 1043).

277. The following chemical structure: 【Transformation 67】 【Transformation 68】 【Transformation 69】 Oligomer double chains, such as those of (SEQ ID NO: 1038 and SEQ ID NO: 1032) or their salts.

278. The oligomeric double chain according to claim 277, wherein it is a sodium salt or a potassium salt.

279. The following chemical structure: 【Transformation 70】 【Chemistry 71】 【Chemistry 72】 Oligomer double helix (according to Sequence ID No. 1038 and Sequence ID No. 1032).

280. The following chemical structure: 【Transformation 73】 【Chemistry 74】 【Chemistry 75】 Oligomer double chains, such as those of (SEQ ID NO: 1038 and SEQ ID NO: 1044) or their salts.

281. The oligomeric double chain according to claim 280, wherein it is a sodium salt or a potassium salt.

282. The following chemical structure: 【Transformation 76】 【Chemical 77】 【Transformation 78】 Oligomer double helix (according to Sequence ID No. 1038 and Sequence ID No. 1044).

283. The following chemical structure: 【Transformation 79】 【Chemistry 80】 【Chemistry 81】 Oligomer double chains, such as those of (SEQ ID NO: 1255 and SEQ ID NO: 1029) or their salts.

284. The oligomeric double chain according to claim 283, wherein it is a sodium salt or a potassium salt.

285. The following chemical structure: 【Chemistry 82】 【Chemistry 83】 【Chemical 84】 Oligomer double helix (according to Sequence ID No. 1255 and Sequence ID No. 1029).

286. The following chemical structure: 【Chemical 85】 【Chemical 86】 【Chemistry 87】 Oligomer double chains, such as those of (SEQ ID NO: 1255 and SEQ ID NO: 1041) or their salts.

287. The oligomeric double chain according to claim 286, wherein it is a sodium salt or a potassium salt.

288. The following chemical structure: 【Chemical 88】 【Chemistry 89】 【Chemistry 90】 Oligomer double helix (according to Sequence ID No. 1255 and Sequence ID No. 1041).

289. A collection of oligomeric double chains or oligomeric compounds according to any one of claims 1 to 288, wherein the collection is concentrated with respect to a first and / or second modified oligonucleotide having at least one specific phosphorothioate nucleoside bond having a specific stereochemical configuration.

290. The population according to claim 289, wherein the population is enriched with respect to a first and / or second modified oligonucleotide comprising at least one specific phosphorothioate nucleoside bond having a (Sp) or (Rp) configuration.

291. The oligomeric double helix or oligomeric compound according to any one of claims 1 to 288, wherein the first modified oligonucleotide consists of 23 linked nucleosides, and the second modified oligonucleotide consists of 21 linked nucleosides.

292. An antisense compound comprising or consisting of an oligomeric double chain or oligomeric compound as described in any one of claims 1 to 288.

293. The antisense compound according to claim 292, wherein the antisense compound is an RNAi agent capable of reducing the amount of PLN nucleic acid through the activation of RISC / Ago2.

294. A pharmaceutical composition comprising an oligomeric double chain or oligomeric compound according to any one of claims 1 to 288 or 291, a group according to any one of claims 289 to 290, or an antisense compound according to claim 292 or 293, and a pharmaceutically acceptable diluent or carrier.

295. The pharmaceutical composition according to claim 294, wherein the pharmaceutically acceptable diluent is water or phosphate-buffered saline.

296. The pharmaceutical composition according to claim 295, wherein the pharmaceutical composition essentially comprises an oligomeric double chain, an oligomeric compound, or an antisense compound, and water or phosphate-buffered saline.

297. A method for reducing the amount of PLN RNA and / or PLN protein in cells, tissues, organs, or subjects, comprising contacting the cells, tissues, organs, or subjects with an oligomeric double helix or oligomeric compound according to any one of claims 1 to 288 or 291, a population according to any one of claims 289 to 290, an antisense compound according to claim 292 or 293, or a pharmaceutical composition according to any one of claims 294 to 296.

298. The method according to claim 297, wherein the cells are muscle cells and / or cardiac cells.

299. A method comprising administering to a subject an oligomeric double-chain or oligomeric compound according to any one of claims 1 to 288 or 291, a population according to any one of claims 289 to 290, an antisense compound according to claim 292 or 293, or a pharmaceutical composition according to any one of claims 294 to 296, wherein the subject has or is at risk of developing cardiovascular or cardiac injury, disease, condition or disorder, cardiomyopathy, cardiac arrhythmia, and / or heart failure.

300. A method for preventing or treating a disease, disorder, condition, or injury related to cardiac calcium misregulation, or a method for delaying the symptoms of a disease, disorder, or condition related to an injured, weakened, and / or overworked heart, comprising administering to a subject having or at risk of having a disease, disorder, or condition related to cardiac calcium misregulation a therapeutically effective amount of an oligomeric double-chain or oligomeric compound according to any one of claims 1 to 288 or 291, a population according to any one of claims 289 to 290, an antisense compound according to claim 292 or 293, or a pharmaceutical composition according to any one of claims 294 to 296, wherein the disease, disorder, condition, or injury is selected from cardiac or cardiovascular diseases, disorders, conditions, or injuries, cardiomyopathy, cardiac arrhythmias, and / or heart failure.

301. A method for preventing or treating a cardiac or cardiovascular disease, disorder, condition, or injury related to heart failure, or a method for delaying the symptoms of heart failure, comprising administering to a subject who has or is at risk of having a cardiac or cardiovascular disease, disorder, condition, or injury, a therapeutically effective amount of an oligomeric double-chain or oligomeric compound according to any one of claims 1 to 288 or 291, a population according to any one of claims 289 to 290, an antisense compound according to claim 292 or 293, or a pharmaceutical composition according to any one of claims 294 to 296, wherein the disease, disorder, condition, or injury is cardiomyopathy, cardiac arrhythmia, and / or heart failure.

302. A method for reducing the amount of PLN RNA and / or PLN protein in the heart of a subject having or at risk of developing a disease, disorder, or condition related to an injured, weakened, and / or overworked heart, comprising administering to a subject having or at risk of developing a disease, disorder, or condition related to an injured, weakened, and / or overworked heart, a therapeutically effective amount of an oligomeric double-strand or oligomeric compound according to any one of claims 1 to 288 or 291, a population according to any one of claims 289 to 290, an antisense compound according to claim 292 or 293, or a pharmaceutical composition according to any one of claims 294 to 296, wherein the disease, disorder, condition, or injury is cardiomyopathy, cardiac arrhythmia, and / or heart failure.

303. The method according to any one of claims 297 to 302, wherein the amount of PLN RNA and / or PLN protein in the target myocardium is reduced.

304. The method according to any one of claims 297 to 302, wherein the disease, disorder, or condition is cardiomyopathy or arrhythmia.

305. The method according to claim 304, wherein the cardiomyopathy is hereditary cardiomyopathy.

306. The method according to claim 305, wherein the hereditary cardiomyopathy is associated with a PLN p. Arg14del, Arg9Cys (R9C), or Arg25Cys (R25C) gene mutation.

307. The method according to claim 304, wherein the cardiomyopathy is dilated cardiomyopathy (DCM).

308. The method according to claim 307, wherein the DCM is a hereditary DCM.

309. The method according to claim 308, wherein the heritable DCM is associated with a TTN, LMNA, RBM20, SCN5A, MYH7, TNNT2, or TPM1 mutation.

310. The method according to claim 307, wherein the DCM is an arrhythmogenic DCM.

311. The method according to any one of claims 299 to 303, wherein the heart failure is heart failure with maintained ejection fraction (HFpEF), heart failure with reduced ejection fraction (HFrEF), acute heart failure, or exacerbation of chronic heart failure.

312. The method according to claim 304, wherein the arrhythmia is ventricular tachycardia (VTAC) or ventricular fibrillation (VFIB).

313. The method according to claim 300 or 301, wherein the symptoms of a disease, disorder, or condition related to an injured, weakened, and / or overworked heart, or heart failure, are a decrease in myocardial contractility and / or impaired cardiac relaxation.

314. The method according to any one of claims 299 to 313, wherein the method prevents or delays the effects of an injured, weakened, and / or overworked heart and / or the progression of heart failure.

315. The method according to any one of claims 299 to 313, wherein administration of an oligomeric double-chain or oligomeric compound according to any one of claims 1 to 288 or 291, a population according to any one of claims 289 to 290, an antisense compound according to claim 292 or 293, or a pharmaceutical composition according to any one of claims 294 to 296 improves cardiac function, cardiovascular death, cardiodilator, cardiac 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 flow profile, left ventricular (LV) strain, left ventricular (LV) strain rate, infarct size, hospitalization due to heart failure, 6-minute walk test (6MWT), Kansas City Cardiomyopathy Scale (KCCQS), heart rate, or rhythm in the subject.

316. The method according to any one of claims 297 to 315, wherein the oligomeric double chain or oligomeric compound according to any one of claims 1 to 288 or 291, the group according to any one of claims 289 to 290, the antisense compound according to claim 292 or 293, or the pharmaceutical composition according to any one of claims 294 to 296 comprises a conjugate moiety having affinity for a transferrin receptor.

317. The method according to any one of claims 297 to 315, wherein the oligomeric double chain or oligomeric compound according to any one of claims 1 to 288 or 291, the group according to any one of claims 289 to 290, the antisense compound according to claim 292 or 293, or the pharmaceutical composition according to any one of claims 294 to 296 comprises a bicyclic ligand having affinity for a transferrin receptor.

318. An oligomeric double-chain or oligomeric compound according to any one of claims 1 to 288 or 291, a group according to any one of claims 289 to 290, an antisense compound according to claim 292 or 293, or a pharmaceutical composition according to any one of claims 294 to 296, for use in treating or preventing diseases, disorders, or conditions associated with an injured, weakened, and / or overworked heart or heart failure.

319. Use of an oligomeric double-chain or oligomeric compound according to any one of claims 1 to 288 or 291, a group according to any one of claims 289 to 290, an antisense compound according to claim 292 or 293, or a pharmaceutical composition according to any one of claims 294 to 296 for the treatment or prevention of diseases, disorders, or conditions associated with an injured, weakened, and / or overworked heart or heart failure.

320. Use of an oligomeric double-chain or oligomeric compound according to any one of claims 1 to 288 or 291, a group according to any one of claims 289 to 290, an antisense compound according to claim 292 or 293, or a pharmaceutical composition according to any one of claims 294 to 296 in the manufacture of a pharmaceutical for treating or preventing a disease, disorder, or condition associated with an injured, weakened, and / or overworked heart or heart failure.

321. The use according to any one of claims 318 to 320, wherein the disease, disorder, or condition relating to an injured, weakened, and / or overworked heart, or relating to heart failure, is cardiomyopathy, cardiac arrhythmia, and / or heart failure.

322. The use according to claim 321, wherein the cardiomyopathy is hereditary cardiomyopathy.

323. The use according to claim 322, wherein the hereditary cardiomyopathy is associated with a PLN p. Arg14del, Arg9Cys (R9C), or Arg25Cys (R25C) gene mutation.

324. The use according to claim 321, wherein the cardiomyopathy is dilated cardiomyopathy (DCM).

325. The use according to claim 324, wherein the DCM is a hereditary DCM.

326. The use according to claim 325, wherein the heritable DCM is associated with a TTN, LMNA, RBM20, SCN5A, MYH7, TNNT2, or TPM1 mutation.

327. The use according to claim 324, wherein the DCM is an arrhythmogenic DCM.

328. The use according to claim 321, wherein the heart failure is heart failure with maintained ejection fraction (HFpEF), heart failure with reduced ejection fraction (HFrEF), acute heart failure, or exacerbation of chronic heart failure.

329. The use according to claim 321, wherein the arrhythmia is ventricular tachycardia (VTAC) or ventricular fibrillation (VFIB).

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