SGLT2 and SGLT1 dual-targeting antisense oligonucleotide and use thereof

Abstract

An SGLT2 and SGLT1 dual-targeting antisense oligonucleotide and the use thereof. An SGLT2 and SGLT1 dual-targeting antisense oligonucleotide, which has a length of 10-18 nucleotides. The antisense oligonucleotide is at least partially complementary to a segment of nucleotides in the respective transcribed mRNAs of SGLT2 and SGLT1, and reduces the amount of corresponding SGLT2 and SGLT1 mRNAs or the expression level of corresponding proteins. The antisense oligonucleotide has a good inhibitory effect on both SGLT2 and SGLT1 gene expression.

Description

Antisense oligonucleotides targeting both SGLT2 and SGLT1 and their applications

[0001] Cross-references to related applications

[0002] This application claims priority to Chinese patent application No. 2024117383870, filed on November 29, 2024, the entire contents of which are incorporated herein by reference. Technical Field

[0003] This invention belongs to the field of biomedicine, specifically relating to a dual-targeting antisense oligonucleotide of SGLT2 and SGLT1 and its uses. Background Technology

[0004] According to data released by the International Diabetes Federation, there are 425 million people with diabetes worldwide, and this number is projected to reach 629 million by 2045. The prevention and treatment of diabetes has attracted global attention. Diabetes is mainly divided into four types: type 1 diabetes (beta cell destruction, absolute insulin deficiency), type 2 diabetes (insufficient insulin secretion accompanied by insulin resistance), gestational diabetes, and other special types of diabetes. The majority are type 1 (approximately 5.0%) and type 2 (over 90%) diabetes.

[0005] Glucose cannot freely cross cell membranes in living organisms and must rely on glucose transport proteins on the cell membrane. Studies have shown that there are two main classes of glucose transport proteins in the body: glucose transporters (GLUTs) and sodium-glucose cotransporters (SGLTs). GLUTs transport glucose down their concentration gradient via diffusion without consuming energy and belong to the solute carrier family 2 (SLC2) gene family. SGLTs, on the other hand, transport glucose up their concentration gradient by consuming energy and belong to the solute carrier family 5 (SLC5) gene family. SGLTs play an important role in the active reabsorption of glucose, and there are two main types: SGLT1 and SGLT2.

[0006] SGLT1 is primarily expressed in the brush border of the small intestine and the S3 segment of the proximal convoluted tubule of the kidney, with smaller amounts expressed in the heart, trachea, and brain. Its main function is to transport glucose and galactose in the intestinal lumen and reabsorb the 10% of glucose that has not been reabsorbed by SGLT2 in the proximal convoluted tubule of the kidney. SGLT2 is specifically expressed in the S1 and S2 segments of the proximal convoluted tubule of the kidney and is responsible for the reabsorption of glucose from the primary urine, mediating approximately 90% of renal glucose reabsorption. When the blood glucose concentration in body fluids is too high, exceeding the absorption capacity of SGLT2 and SGLT1, unabsorbed glucose will be excreted in the urine, resulting in glycosuria. Based on these mechanisms, inhibiting SGLT reabsorption can potentially treat diabetes and related diseases.

[0007] Several SGLT2 small molecule inhibitors (empagliflozin, dapagliflozin, canagliflozin, and other small molecule inhibitors) have been approved for marketing, with indications including diabetes, diabetic nephropathy, chronic kidney disease, and heart failure. However, studies have found that when SGLT2 is inhibited, the reabsorption function of SGLT1 increases compensatorily, capable of compensating for 40-50% of glucose absorption in urine. Based on this, the blood glucose-lowering effect of SGLT2 small molecule inhibitors is only moderate, and there is still room for improvement.

[0008] Most small-molecule SGLT2 inhibitors require daily administration, and the vast majority target SGLT2 alone, resulting in only moderate blood glucose-lowering effects. Due to the widespread expression of SGLT1, dual-targeting inhibitors have only a weak affinity for SGLT1 to avoid toxicity, making the development of excellent dual-targeting small-molecule inhibitors difficult. While SGLT2 and SGLT1 belong to the same family and have similar structures, the fact that SGLT1 is also expressed in other tissues such as the small intestine presents challenges for dual-targeting molecule development. Currently, only one dual-targeting small-molecule inhibitor, sotagliflozin, is approved, with an inhibitory concentration (IC50) of 1,500 for both human SGLT1 and SGLT2. 50 The effective doses were 36 nM and 1.8 nM, respectively. Due to their low selectivity for SGLT1, their efficacy was not outstanding, their approved indications were narrow, and their commercialization was not successful.

[0009] In addition to its primary function, SGLT2 inhibitors can also be used to treat chronic kidney disease and cardiovascular disease. Chronic kidney disease is a gradual and progressive loss of the kidneys' ability to excrete waste products, concentrate urine, and retain electrolytes. Unlike acute kidney failure, which has a sudden but reversible decline in kidney function, chronic kidney disease irreversibly worsens to end-stage renal disease (ESRD). Clinically, chronic kidney disease is diagnosed as glomerulonephritis, latent nephritis, pyelonephritis, Henoch-Schönlein purpura nephritis, lupus nephritis, gouty nephropathy, nephrotic syndrome, membranous nephropathy, diabetic nephropathy, hypertensive nephropathy, polycystic kidney disease, etc. When these kidney diseases are prolonged and difficult to cure, lasting more than three months, and the patient shows abnormalities in urine and related blood indicators, abnormalities in renal pathology and imaging, or an effective glomerular filtration rate of less than 60%, they can all be collectively referred to as "chronic kidney disease." Large-scale clinical studies have shown that SGLT2 inhibitors can significantly improve adverse cardiovascular and renal outcomes in patients with type II diabetes. Therefore, these drugs have become the first-line treatment for patients with type II diabetes complicated by cardiovascular disease and chronic kidney disease.

[0010] Therefore, there is an urgent need to develop a new drug that targets both SGLT2 and SGLT1 genes to fill the gap in current drug applications. Summary of the Invention

[0011] In order to address the problems existing in the prior art, the purpose of this disclosure is to provide an antisense oligonucleotide that targets both SGLT2 and SGLT1 and its uses.

[0012] In one aspect, this disclosure provides a dual-targeting antisense oligonucleotide for SGLT2 and SGLT1, the antisense oligonucleotide being 10-18 nucleotides in length, wherein the antisense oligonucleotide is at least partially complementary to a segment of nucleotides in the respective transcribed mRNA of SGLT2 and SGLT1, and reduces the amount of the corresponding mRNA or the expression level of the corresponding protein of SGLT2 and SGLT1.

[0013] On the other hand, this disclosure provides a composition comprising the aforementioned antisense oligonucleotide or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier.

[0014] On the other hand, this disclosure provides a cell that contains the aforementioned antisense oligonucleotides.

[0015] On the other hand, this disclosure provides a method for inhibiting SGLT2 and / or SGLT1 gene expression in vitro, the method comprising the following steps:

[0016] Contact the cells with an effective amount of the aforementioned antisense oligonucleotide and / or the aforementioned composition.

[0017] On the other hand, this disclosure provides a kit containing the aforementioned antisense oligonucleotides and / or the aforementioned compositions.

[0018] On the other hand, this disclosure provides the use of the aforementioned antisense oligonucleotide and / or the aforementioned composition in the preparation of a medicament for the prevention and / or treatment of diseases;

[0019] Preferably, the disease is an sglt1 and / or sglt2 related disease;

[0020] Preferably, the disease is type I diabetes, type II diabetes, diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, delayed wound healing, insulin resistance, hyperglycemia, hyperinsulinemia, chronic kidney disease, heart failure with preserved ejection fraction, heart failure with reduced ejection fraction, elevated blood levels of fatty acids or glycerol, hyperlipidemia, dyslipidemia, obesity, hypertriglyceridemia, syndrome X, diabetic complications or atherosclerosis, hypertension, hyperuricemia or cardiovascular disease.

[0021] On the other hand, this disclosure provides the use of the aforementioned antisense oligonucleotide and / or the aforementioned composition for the prevention and / or treatment of diseases;

[0022] Preferably, the disease is an sglt1 and / or sglt2 related disease;

[0023] Preferably, the disease is type I diabetes, type II diabetes, diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, delayed wound healing, insulin resistance, hyperglycemia, hyperinsulinemia, chronic kidney disease, heart failure with preserved ejection fraction, heart failure with reduced ejection fraction, elevated blood levels of fatty acids or glycerol, hyperlipidemia, dyslipidemia, obesity, hypertriglyceridemia, syndrome X, diabetic complications or atherosclerosis, hypertension, hyperuricemia or cardiovascular disease.

[0024] On the other hand, this disclosure provides a method for preventing and / or treating a disease, comprising administering an effective amount of the aforementioned antisense oligonucleotide and / or the aforementioned composition to a subject in need;

[0025] Preferably, the disease is an sglt1 and / or sglt2 related disease;

[0026] Preferably, the disease is type I diabetes, type II diabetes, diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, delayed wound healing, insulin resistance, hyperglycemia, hyperinsulinemia, chronic kidney disease, heart failure with preserved ejection fraction, heart failure with reduced ejection fraction, elevated blood levels of fatty acids or glycerol, hyperlipidemia, dyslipidemia, obesity, hypertriglyceridemia, syndrome X, diabetic complications or atherosclerosis, hypertension, hyperuricemia or cardiovascular disease.

[0027] On the other hand, this disclosure provides pharmaceutical compositions for the prevention and / or treatment of diseases, wherein the pharmaceutical compositions comprise the aforementioned antisense oligonucleotides and / or the aforementioned compositions;

[0028] Preferably, the disease is an sglt1 and / or sglt2 related disease;

[0029] Preferably, the disease is type I diabetes, type II diabetes, diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, delayed wound healing, insulin resistance, hyperglycemia, hyperinsulinemia, chronic kidney disease, heart failure with preserved ejection fraction, heart failure with reduced ejection fraction, elevated blood levels of fatty acids or glycerol, hyperlipidemia, dyslipidemia, obesity, hypertriglyceridemia, syndrome X, diabetic complications or atherosclerosis, hypertension, hyperuricemia or cardiovascular disease. Attached Figure Description

[0030] Figure 1 shows the hypoglycemic effect of ASO1 with different modifications in the db / db diabetic mouse model.

[0031] Figure 2 shows the distribution of ASO1-LNA in mouse tissues.

[0032] Figure 3 shows the hypoglycemic effect of dual-targeted ASO in SGLT2 humanized mice. Detailed Implementation

[0033] I. Definition

[0034] In this disclosure, unless otherwise stated, scientific and technical terms used herein have the meanings commonly understood by those skilled in the art. Furthermore, the terms and laboratory procedures related to protein and nucleic acid chemistry, molecular biology, cell and tissue culture, microbiology, and immunology used herein are all widely used terms and routine procedures in their respective fields. To better understand this disclosure, definitions and explanations of relevant terms are provided below.

[0035] As used herein, the term “about” or “approximately” when applied to one or more target values ​​means a value similar to the reference value. In some embodiments, unless otherwise stated or otherwise apparent from the context, the term “approximately” or “about” means a range of values ​​falling within 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less of the reference value in any direction (unless such a number would exceed 100% of the possible value). As used herein, “optional” or “optionally” means that the event or condition described thereafter may or may not occur, and the description includes both cases in which the event or condition occurs and cases in which it does not occur.

[0036] As used herein, the term "chain" refers to a single, continuous sequence of nucleotides linked together by internucleotide bonds (e.g., phosphodiester bonds, thiophosphate bonds). In some embodiments, the chain has two free ends, such as a 5'-end and a 3'-end.

[0037] In this art, "antisense compound" refers to an oligomeric compound capable of hybridizing with a target nucleic acid via hydrogen bonding. Examples of antisense compounds include single-stranded and double-stranded compounds, such as antisense oligonucleotides, siRNA, shRNA, ssRNA, and occupancy compounds. "Antisense inhibition" refers to a reduction in the level of the target nucleic acid in the presence of an antisense compound complementary to the target nucleic acid compared to or in the absence of the antisense compound. "Antisense mechanism" refers to any mechanism involving hybridization of a compound with a target nucleic acid, where the result or effect of hybridization is target degradation or target occupancy, accompanied by inhibition of cellular mechanisms involved, such as transcription or splicing.

[0038] As used herein, the term "antisense oligonucleotide" (ASO) refers to an oligomer or polymer of nucleotides, such as naturally occurring nucleosides or their modified forms, which are covalently linked to each other by internucleotide linkages. ASOs used in this disclosure include at least one non-naturally occurring nucleoside. The ASO is complementary to the target nucleic acid, such that the ASO hybridizes with the target nucleic acid sequence. The terms "antisense ASO," "ASO," and "oligomer" as used herein are interchangeable with the term "ASO."

[0039] As used herein, the term "complementary" refers to a structural relationship between nucleotides (e.g., two nucleotides on opposing nucleic acids or on opposing regions of a single nucleic acid strand) that allows nucleotides to form base pairs with each other. For example, a purine nucleotide complementary to a pyrimidine nucleotide of an opposing nucleic acid can be base-paired together by forming hydrogen bonds. In some embodiments, complementary nucleotides may be base-paired in a Watson-Crick manner or in any other manner that allows the formation of a stable duplex. In some embodiments, two nucleic acids may have nucleotide sequences that are complementary to each other to form complementary regions. A "complementary region" refers to a region on an antisense oligonucleotide that is completely or substantially complementary to the target mRNA sequence. The terms "complementary," "completely complementary," and "substantially complementary" can be used relative to base pairing between an antisense oligonucleotide and the target sequence.

[0040] As used herein, the term "difference" refers to a "nucleotide difference" between two nucleotide sequences. This means that the type of bases at the same position of the nucleotides has changed compared to the former. For example, if a nucleotide base in the latter is A, and the corresponding nucleotide base at the same position in the former is U, C, G, or T, then a nucleotide difference is considered to exist between the two nucleotide sequences at that position. In some embodiments, replacing the nucleotide at the original position with a baseless nucleotide or a nucleotide analog can also be considered a nucleotide difference at that position.

[0041] As used in this article, the term "mismatch" refers to a situation in double-stranded nucleic acids where corresponding bases are not paired in a complementary manner. Mismatches can occur within the molecule or at the ends, where the complementary region is not perfectly complementary to the target sequence.

[0042] As used herein, the term “cap structure” or “end-cap portion” refers to a chemical modification that has been incorporated into either end of an antisense compound.

[0043] As used herein, the terms "comprising / including" and other forms of use are not restrictive. The terms "having" and other forms of use are not restrictive. As used herein, whether in transitional phrases or in the body of the claims, the term "comprising / including" shall be construed as having an open-ended meaning. That is, the term should be interpreted synonymously with the phrases "at least having" or "at least including." For example, when used in the context of a process, the term "comprising" means that the process includes at least the listed steps, but may also include additional steps. When used in the context of a compound, composition, or device, the term "comprising" means that the compound, composition, or device includes at least the listed features or components, but may also include additional features or components.

[0044] As used herein, a "nucleoside" is a compound composed of a purine or pyrimidine base and ribose or deoxyribose; a "nucleotide" is a compound composed of a purine or pyrimidine base, ribose or deoxyribose, and a phosphate group; and an "oligonucleotide" is a nucleic acid molecule (RNA or DNA) having a length of, for example, less than 100, 200, 300, or 400 nucleotides. Oligonucleotides may contain ribonucleotides, deoxyribonucleotides, and / or modified nucleotides, including, for example, modified ribonucleotides. Oligonucleotides may be single-stranded or double-stranded. Oligonucleotides may or may not have a double-stranded region. As a set of non-limiting examples, oligonucleotides may be, but are not limited to, small interfering RNA (siRNA), microRNA (miRNA), short hairpin RNA (shRNA), cleatase substrate interfering RNA (dsiRNA), antisense oligonucleotides, short siRNA, or single-stranded siRNA.

[0045] As used in this article, a "base" is the basic building block for the synthesis of nucleosides, nucleotides, and nucleic acids. Its constituent elements include nitrogen, hence it is also called a "nitrogenous base." Unless otherwise specified, the capital letters A, U, T, G, and C in this article represent the base composition of nucleotides, namely adenine, uracil, thymine, guanine, and cytosine, respectively.

[0046] As used herein, the term "deoxyribonucleotide" refers to a nucleotide that has a hydrogen atom at the 2' position of its pentose sugar compared to a ribonucleotide. A modified deoxyribonucleotide is a deoxyribonucleotide that has one or more modifications or substitutions (including modifications or substitutions in the sugar, phosphate group, or base) other than at the 2' position.

[0047] As used herein, the term "gapmer" refers to a chimeric antisense compound in which an internal region containing multiple nucleotides supporting RNase H cleavage is located between an external region containing one or more nucleotides, wherein the nucleotides containing the internal region are chemically different from those containing the external region. The internal region may be referred to as a "gap" and the external region as a "wing". In other words, a "gapmer" is a chimeric oligomer containing a central region ("gap") and regions on each side of the central region ("wings"), wherein the gap contains at least one modification that differs from the modification in each wing. These modifications include nucleobases, monomer linkages, and sugar modifications, as well as the absence of modifications (unmodified). Thus, in some embodiments, the nucleotide linkages in each wing are different from those in the gap. In some embodiments, each wing contains a nucleotide with a high-affinity modification while the gap contains a nucleotide without that modification. In some embodiments, both the nucleotides in the gap and the nucleotides in the wings contain high-affinity modifications, but the high-affinity modifications in the gap are different from those in the wings. In some embodiments, the modifications in each wing are identical to each other. In some embodiments, the modifications in the wings are different from each other. In some embodiments, the nucleotide in the notch is unmodified while the nucleotide in the wings is modified. In some embodiments, the modifications in each wing are the same. In some embodiments, the modifications in one wing are different from those in another wing. In some embodiments, the antisense compound is a notch polymer containing a 2'-deoxynucleotide in the notch and a nucleotide with a high affinity modification in the wings. In some embodiments, the antisense compound is a notch polymer containing a nucleotide in the notch and a nucleotide with a high affinity modification in the wings.

[0048] As used herein, the term “chimeric antisense compound” refers to an antisense compound having at least two chemically dissimilar regions, each with multiple subunits.

[0049] If one of the starting materials or compounds of this disclosure contains one or more functional groups that are unstable or reactive under the reaction conditions of one or more reaction steps, suitable protecting groups can be introduced prior to the critical steps using methods well known in the art. Such protecting groups can be removed later in the synthesis using standard methods described in the literature. Examples of protecting groups are tert-butoxycarbonyl (Boc), 9-fluorenylmethylcarbamate (Fmoc), 2-trimethylsilylethylcarbamate (Teoc), carbobenzyloxy (Cbz), and p-methoxybenzyloxycarbonyl (Moz).

[0050] In this specification, the term "alkyl" refers, alone or in combination, to a straight-chain or branched alkyl group having 1 to 8 carbon atoms, particularly a straight-chain or branched alkyl group having 1 to 6 carbon atoms, and even more particularly a straight-chain or branched alkyl group having 1 to 4 carbon atoms. Examples of straight-chain and branched C1-C8 alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl isomers, hexyl isomers, heptyl isomers, and octyl isomers, especially methyl, ethyl, propyl, butyl, and pentyl isomers. Specific examples of alkyl groups are methyl, ethyl, and propyl.

[0051] The term "cycloalkyl" refers, alone or in combination, to a cycloalkyl ring having 3 to 8 carbon atoms, particularly a cycloalkyl ring having 3 to 6 carbon atoms. Examples of cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl, more particularly cyclopropyl and cyclobutyl. A specific example of "cycloalkyl" is cyclopropyl.

[0052] The term "alkoxy," used alone or in combination, denotes a group of the formula alkyl-O-, wherein the term "alkyl" has the meaning given above, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, and tert-butoxy. The particular "alkoxy" are methoxy and ethoxy. Methoxyethoxy is a specific example of "alkoxyalkoxy".

[0053] The term "oxygen group" used alone or in combination refers to the -O- group.

[0054] The term "alkenyl," alone or in combination, refers to a straight-chain or branched hydrocarbon residue containing an alkene bond and up to eight, preferably six, and particularly preferably four carbon atoms. Examples of alkenyl groups are vinyl, 1-propenyl, 2-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, and isobutenyl.

[0055] The term "alkynyl" alone or in combination refers to a straight-chain or branched hydrocarbon residue containing a triple bond and up to eight, preferably six, and particularly preferably four carbon atoms.

[0056] The term "halogen" or "halogenated," alone or in combination, refers to fluorine, chlorine, bromine, or iodine, particularly fluorine, chlorine, or bromine, and even more particularly fluorine. The term "halogen," in combination with another group, indicates that the group is substituted with at least one halogen, particularly with one to five halogens, especially with one to four halogens, i.e., one, two, three, or four halogens. The term "halogenated alkyl," alone or in combination, indicates an alkyl group substituted with at least one halogen, particularly with one to five halogens, especially with one to three halogens. Examples of halogenated alkyl groups include monofluoro-, difluoro-, or trifluoro-methyl, -ethyl, or -propyl, such as 3,3,3-trifluoropropyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, fluoromethyl, or trifluoromethylfluoromethyl, difluoromethyl, and trifluoromethyl are specific "halogenated alkyl groups." The term "halogenated cycloalkyl," alone or in combination, indicates a cycloalkyl group as defined above substituted with at least one halogen, particularly with one to five halogens, especially with one to three halogens. Specific examples of “halogenated cycloalkyl” are halogenated cyclopropyl, especially fluorocyclopropyl, difluorocyclopropyl and trifluorocyclopropyl.

[0057] The terms “hydroxyl” and “hydroxyl group”, alone or in combination, refer to the -OH group.

[0058] The terms “thiohydroxyl” and “thiohydroxyl”, alone or in combination, represent the -SH group.

[0059] The term "carbonyl", alone or in combination, refers to the -C(O)- (-C(=O)-) group.

[0060] The term "carboxy" or "carboxyl", alone or in combination, refers to the -COOH group.

[0061] The term "amino" alone or in combination refers to a primary amino group (-NH2), a secondary amino group (-NH-), or a tertiary amino group (-N-).

[0062] The term "sulfonyl group," alone or in combination, refers to the -SO2 group.

[0063] The term "thioalkyl", alone or in combination, indicates a -S- group.

[0064] The term "cyano", alone or in combination, refers to the -CN group.

[0065] The term "formyl group" refers to the -C(O)H group, either alone or in combination.

[0066] The term "carbamoyl" alone or in combination represents the -C(O)NH2 group.

[0067] The term "aryl," alone or in combination, refers to a monovalent aromatic carbocyclic monocyclic or bicyclic system comprising 6 to 10 carbon ring atoms, optionally substituted by 1 to 3 substituents independently selected from halogens, hydroxyl, alkyl, alkenyl, alkoxy, alkoxyalkyl, alkenyloxy, carboxyl, alkoxycarbonyl, alkylcarbonyl, and formyl. Examples of aryl groups include phenyl and naphthyl, particularly phenyl.

[0068] The term "heteroaryl" alone or in combination refers to a monovalent aromatic heterocyclic monocyclic or bicyclic system of 5 to 12 ring atoms, comprising 1, 2, 3, or 4 heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon, which is optionally substituted by 1 to 3 substituents independently selected from halogen, hydroxyl, alkyl, alkenyl, alkoxy, alkoxyalkyl, alkenyloxy, carboxyl, alkoxycarbonyl, alkylcarbonyl, and formyl. Examples of heteroaryl groups include pyrrole, furanyl, thiophene, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrazolyl, pyrimidinyl, triazinyl, isoxazolyl, benzofuranyl, isothiazolyl, benzothiophene, indolyl, isindolyl, isobenzofuranyl, benzimidazolyl, benzooxazolyl, benzoisooxazolyl, benzothiazolyl, benzooxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxolinyl, carbazole, or acridineyl.

[0069] The term "heterocyclic group," alone or in combination, refers to a monocyclic or bicyclic system of 4 to 12 ring atoms (especially 4 to 9 ring atoms) that is monovalently saturated or partially unsaturated, comprising 1, 2, 3, or 4 heteroatoms selected from N, O, and S, with the remaining ring atom being carbon, which is optionally substituted with 1 to 3 substituents, which are independently selected from halogens, hydroxyl groups, alkyl groups, alkenyl groups, alkoxy groups, alkoxyalkyl groups, alkenylyl groups, carboxyl groups, alkoxycarbonyl groups, alkylcarbonyl groups, and formyl groups. Examples of monocyclic saturated heterocyclic groups include azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, piperidinyl, and tetrahydropyranyl. (rahydropyranyl), tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl, azepanyl, diazepanyl, homopiperazinyl, or oxazepanyl. Examples of bicyclic saturated heterocyclic alkyl groups are 8-aza-bicyclo[3.2.1]octyl, quininecycloyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl, 9-aza-bicyclo[3.3.1]nonyl, 3-oxa-9-aza-bicyclo[3.3.1]nonyl, or 3-thia-9-aza-bicyclo[3.3.1]nonyl. Examples of partially unsaturated heterocyclic alkyl groups are dihydrofuranyl, imidazolinyl, dihydrooxazolyl, tetrahydropyridyl, or dihydropyranyl.

[0070] As used herein, the term "cleavable moiety" refers to a bond or group capable of splitting under physiological conditions. In some embodiments, the cleavable moiety is cleaved within a cellular or subcellular compartment (such as a lysosome). In some embodiments, the cleavable moiety is cleaved by an endogenous enzyme such as a nuclease. In some embodiments, the cleavable moiety comprises an atomic group having one, two, three, four, or more than four cleavable bonds.

[0071] As used herein, the term “cEt” or “restricted ethyl” refers to a bicyclic nucleotide having a sugar moiety comprising a bridge connecting a 4'-carbon and a 2'-carbon, wherein said bridge has the formula: 4'-CH(CH3)-O-2'. “cEt-modified nucleotide” (also known as “restricted ethyl nucleotide”) refers to a nucleotide containing a bicyclic sugar moiety with a 4'-CH(CH3)-O-2' bridge.

[0072] As used herein, the terms “locked nucleic acid” or “LNA” or “LNA nucleotide” refer to a nucleic acid monomer having a bridge between two carbon atoms at the 4' and 2' positions of the nucleotide sugar unit, thereby forming a bicyclic sugar. Examples of such bicyclic sugars include, but are not limited to, α-L-methyleneoxy(4'-CH2-O-2')LNA, β-D-methyleneoxy(4'-CH2-O-2')LNA, ethoxy(4'-(CH2)2-O-2')LNA, aminooxy(4'-CH2-ON(R)-2')LNA, and oxyamino(4'-CH2-N(R)-O-2')LNA, including but not limited to the structures shown below:

[0073] For example, R3 is independently a protecting group or a C1-C3 alkyl group.

[0074] In this disclosure, "Base" means base.

[0075] As used herein, LNA compounds include, but are not limited to, compounds having at least one bridge between the 4' and 2' positions of a sugar, wherein each of said bridges independently comprises one or two to four linking groups independently selected from the following: -[C(R1)(R2)]n-, -C(R1)=C(R2)-, -C(R1)=N-, -C(=NR1)-, -C(=O)-, -C(=S)-, -O-, -Si(R1)2-, -S(=O)x-, and -N(R1)-; wherein: x is 0, 1, or 2; n is 1, 2, 3, or 4; and R1 and R2 are each independently H, a protecting group, a hydroxyl group, or a C1-C2 group. 12 Alkyl, substituted C1-C 12 Alkyl, C2-C 12 Alkenyl, substituted C2-C 12 alkenyl, C2-C 12 Alkyne group, substituted C2-C 12 alkynyl group, C5-C 20 Aryl, substituted C5-C 20Aryl, heterocyclic, substituted heterocyclic, heteroaryl, substituted heteroaryl, C5-C7 alicyclic, substituted C5-C7 alicyclic, halogen, OJ1, NJ1J2, SJ1, N3, COOJ1, acyl (C(=O)-J1), substituted acyl, CN, sulfonyl (S(=O)2-J1) or sulfonic acid oxy (S(=O)-J1); and J1 and J2 are each independently H, C1-C 12 Alkyl, substituted C1-C 12 Alkyl, C2-C 12 Alkenyl, substituted C2-C 12 alkenyl, C2-C 12 Alkyne group, substituted C2-C 12 alkynyl group, C5-C 20 Aryl, substituted C5-C 20 Aryl, acyl (C(=O)-J1), substituted acyl, heterocyclic, substituted heterocyclic, C1-C 12 Aminoalkyl, substituted C1-C 12 Aminoalkyl groups or protecting groups.

[0076] As used herein, the term "chemically distinct region" refers to a region of an antisense compound that is chemically different in some way from another region of the same antisense compound. For example, a region having a 2'-O-methoxyethyl nucleoside is chemically different from a region having a nucleoside without 2'-O-methoxyethyl modification.

[0077] As used herein, the term "chemical modification" refers to a chemical difference in a compound when compared to its naturally occurring counterpart. Chemical modifications of oligonucleotides include nucleoside modifications (including sugar moiety modifications and nucleobase modifications) and inter-nucleoside linkage modifications. For the purposes of oligonucleotides, chemical modifications do not include differences in nucleobase sequence only.

[0078] As used herein, the term “modified nucleoside linkage” refers to substitution or any change from naturally occurring nucleoside linkages (i.e., phosphodiester nucleoside linkages).

[0079] As used herein, the term "modified nucleobase" means any nucleobase other than adenine, cytosine, guanine, thymine (also known as 5-methyluracil), or uracil. "Unmodified nucleobase" means the purine bases adenine (A) and guanine (G), and the pyrimidine bases thymine (T), cytosine (C), and uracil (U).

[0080] As used herein, the term "modified nucleoside" refers to a nucleoside that independently has a modified sugar moiety and / or a modified nucleic acid base.

[0081] As used herein, the term "modified nucleotide" means a nucleotide that has a modified sugar moiety, a modified internucleotide link, and / or a modified nucleobase.

[0082] As used herein, the term "modified oligonucleotide" means an oligonucleotide containing at least one modified nucleoside link, a modified sugar, and / or a modified nucleic acid base.

[0083] As used herein, the term "modified sugar" means that there is substitution and / or any change compared to the natural sugar portion.

[0084] As used in this article, the term "motif" refers to a modification pattern. In antisense oligonucleotides (ASOs), a modification pattern is a specific arrangement and combination of chemical modifications in the ASO. Different modification patterns can have different effects on the stability, affinity, pharmacokinetic properties, and biological activity of the ASO.

[0085] As used herein, a "nucleotide difference" between two nucleotide sequences refers to a change in the type of bases at the same position of the nucleotides compared to the latter. For example, if a nucleotide base in the latter is A, and the corresponding nucleotide base at the same position in the former is U, G, C, or T, then a nucleotide difference is considered to exist between the two nucleotide sequences at that position. In some embodiments, replacing the nucleotide at the original position with a baseless nucleotide or its equivalent can also be considered a nucleotide difference at that position.

[0086] "2'-O-methoxyethyl" (also known as 2'-MOE, 2'-OCH2CH2-OCH3, and MOE) refers to the O-methoxyethyl modification at the 2' position of the furanose ring. Sugars modified with 2'-O-methoxyethyl are modified sugars.

[0087] "2'-O-methoxyethyl modified nucleosides" (also known as "2'-MOE nucleosides") refers to nucleosides containing a 2'-MOE modified sugar moiety.

[0088] "2'-substituted nucleosides" refers to nucleosides containing a substituent other than H or OH at the 2' position of the furanose ring. In some embodiments, 2'-substituted nucleosides include nucleosides modified with bicyclic sugars.

[0089] "2'-deoxynucleoside" means a nucleoside that contains a hydrogen atom at the 2' position of the sugar moiety.

[0090] "3' target site" refers to the nucleotide of the target nucleic acid that is complementary to the 3' nucleotide of a specific antisense compound.

[0091] "5' target site" refers to the nucleotide of the target nucleic acid that is complementary to the 5' nucleotide of a specific antisense compound.

[0092] "5-Methylcytosine" means cytosine modified with a methyl group attached to the 5-position. 5-Methylcytosine is a modified nucleobase.

[0093] "Conjugate" or "conjugate group" refers to an atom or atomic group that is bound to an oligonucleotide or oligomer compound. Typically, conjugate groups alter one or more properties of the compound to which they are attached, including but not limited to pharmacodynamics, pharmacokinetics, binding, absorption, cellular distribution, cellular uptake, charge, and / or clearance properties.

[0094] In the context of a conjugate group, “conjugate connector” or “connector” means a part of a conjugate group that contains any atom or atomic group and that (1) covalently connects an oligonucleotide to another part of the conjugate group or (2) covalently connects two or more parts of the conjugate group.

[0095] The conjugation group, referred to herein as a group, provides a bond for forming a covalent link to an oligomer compound such as an antisense oligonucleotide. In some embodiments, the linking site on the oligomer compound is the 3'-oxygen atom of the 3'-hydroxyl group of the 3'-terminal nucleoside of the oligomer compound. In some embodiments, the linking site on the oligomer compound is the 5'-oxygen atom of the 5'-hydroxyl group of the 5'-terminal nucleoside of the oligomer compound. In some embodiments, the bond for forming the link to the oligomer compound is a cleavable bond. In some of the embodiments described, the cleavable bond constitutes all or part of the cleavable portion.

[0096] In some embodiments, the conjugation group comprises a cleavable moiety (e.g., a cleavable bond or cleavable nucleoside) and a carbohydrate cluster moiety, such as the GalNAc cluster moiety. This carbohydrate cluster moiety comprises a targeting moiety and optionally a conjugation linker. In some embodiments, the carbohydrate cluster moiety is identified by the number and identity of the ligands. The carbohydrate cluster fragment is linked to an oligomer compound via the cleavable moiety (e.g., a cleavable bond or cleavable nucleoside).

[0097] As used herein, the term "diabetes" includes type 1 and type 2. In some embodiments, diabetes refers to type 1 diabetes. In other embodiments, diabetes refers to type 2 diabetes. Those skilled in the art understand type 1 and type 2 diabetes. In a patient with type 1 diabetes, the patient's immune system attacks and destroys the beta cells in the pancreas that produce insulin. Therefore, patients with type 1 diabetes do not produce insulin. In a patient with type 2 diabetes, the patient's body cannot use insulin effectively. Therefore, patients with type 2 diabetes do not respond to the insulin produced in their body.

[0098] As used herein, the terms “type 2 diabetes” and “type II diabetes” are interchangeable and are defined as follows: a patient’s fasting (i.e., no caloric intake over approximately 8 hours) blood glucose or serum glucose concentration is greater than approximately 125 mg / dL (approximately 6.94 mmol / L) on at least two independent measurements. Type 2 diabetes is also defined as a condition in which a patient has an HbA1c level equal to or greater than approximately 6.5%. 1c (hemoglobin A) 1c Diabetes is defined as a non-enzymatic glycation product of the hemoglobin B chain, a two-hour plasma glucose level equal to or greater than approximately 200 mg / dL (approximately 11.1 mmol / L) during an oral glucose tolerance test (OGTT), or a random glucose concentration equal to or greater than approximately 200 mg / dL (approximately 11.1 mmol / L), accompanied by classic symptoms of hyperglycemia or hyperglycemic crisis. In the absence of clear symptoms of hyperglycemia, as with most diagnostic tests, the test results diagnosing diabetes should be repeated to rule out laboratory errors.

[0099] As used herein, the term "pharmaceutically acceptable carrier" is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents, and absorption delay agents compatible with drug administration. The use of such media and reagents for pharmaceutically active substances is well known in the art. Its use in these compositions is covered unless any conventional media or reagent is incompatible with the active compound. Pharmaceutically acceptable carriers include diluents, fillers, salts, buffers, stabilizers, solubilizers, and other materials known in the art. Such formulations may typically contain salts, buffers, preservatives, compatible carriers, and optionally other therapeutic agents. When used in medicine, the salt should be pharmaceutically acceptable, but non-pharmaceutically acceptable salts may be readily used to prepare their pharmaceutically acceptable salts, without exclusion from the scope of this invention. Such pharmacologically and pharmaceutically acceptable salts include, but are not limited to, salts prepared from the following acids: hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, maleic acid, acetic acid, salicylic acid, citric acid, formic acid, malonic acid, succinic acid, etc. In addition, pharmaceutically acceptable salts can be prepared as alkali metal salts or alkaline earth metal salts, such as sodium salts, potassium salts, or calcium salts.

[0100] As used herein, the term “inhibition” is used interchangeably with “reduction,” “silence,” “downregulation,” and other similar terms, and includes any level of inhibition.

[0101] As used herein, the term "treatment" includes suppressing, slowing, stopping, or reversing the progression or severity of existing symptoms or a patient's condition. Therefore, treatment includes prevention, cure, and / or eradication. Furthermore, "treatment method," "treatment," "relief," or "improvement" may be used interchangeably herein. Prevention refers to preventing potential disease and / or preventing the worsening of symptoms or the development of disease. "Improvement" refers to at least one indicator of the reduction, slowing, cessation, or reversal of symptoms or the severity of a disease. The severity of an indicator can be determined by subjective or objective measures known to those skilled in the art. As used herein, "efficacy" refers to the effect resulting from treatment of an individual that alters, generally improves, or enhances the symptoms of a disease or condition, or cures a disease or condition. As used herein, "therapeutic effective amount" or "therapeutic effective dose" refers to the amount of a substance, compound, material, or composition containing a compound that, when applied to a subject, is at least sufficient to produce a therapeutic effect. Therefore, it is the amount necessary to prevent, cure, improve, block, or partially block the symptoms of a disease or condition. As used herein, "preventive effective dose" or "preventive effective amount" refers to the amount of a substance, compound, material, or composition containing a compound that, when applied to a subject, would have the intended preventive effect, such as preventing or delaying the onset or recurrence of a disease or symptom, or reducing the likelihood of the onset or recurrence of a disease or symptom. A fully preventive effective dose does not necessarily occur through the administration of a single dose and can occur only after a series of doses have been administered. Therefore, a preventive effective dose can be administered in one or more applications.

[0102] As used herein, the term "patient" refers to any animal, such as a mammal or marsupial. The subject matter of this disclosure includes, but is not limited to, humans, non-human primates (e.g., rhesus monkeys or other types of macaques), mice, pigs, horses, donkeys, cattle, sheep, rats, and any kind of poultry. In some embodiments, the patients described herein suffer from chronic kidney disease, thus increasing their risk of developing renal events.

[0103] As used herein, the term "renal event" refers to an impairment related to or affecting renal function and / or renal hyperfiltration. Renal impairments include, but are not limited to, high urinary albumin levels, high serum creatinine, high serum albumin / creatinine ratio (ACR), renal hyperfiltration injury, diabetic nephropathy (including but not limited to hyperfiltration diabetic nephropathy), renal hyperfiltration, glomerular hyperfiltration, renal allogeneic transplantation hyperfiltration, compensatory hyperfiltration, chronic hyperfiltration kidney disease, acute hyperfiltration renal failure, obesity, end-stage renal disease (ESKD), or renal death.

[0104] As used herein, “prevention” and “protection” are used interchangeably. These terms refer to methods for obtaining beneficial or desired results, including but not limited to preventive benefits. To obtain a “preventive benefit,” the conjugate or composition may be given to a patient at risk of developing a specific disease, or to a patient who reports one or more pathological symptoms of a disease, even if a diagnosis of the disease may not have been made. In some embodiments, the products or methods described herein are used to reduce or prevent the occurrence of one or more cardiovascular events in a patient.

[0105] As used herein, unless otherwise stated, the terms "cardiovascular event" or "cardiovascular disease" shall include, but are not limited to, cardiovascular death, nonfatal myocardial infarction, nonfatal stroke (ischemic), peripheral artery disease, hypertensive cardiomyopathy, ischemic cardiomyopathy, coronary artery disease, peripheral vascular disease, cerebrovascular disease, arrhythmia (other than sinus tachycardia), cardiomyopathy, angina (including but not limited to unstable angina), heart failure (including but not limited to heart failure requiring hospitalization, heart failure, etc.), and coronary valve disease. In some embodiments, a cardiovascular event is cardiovascular death, hospitalized heart failure, nonfatal myocardial infarction, or nonfatal stroke, or any combination thereof. In other embodiments, a cardiovascular event is cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. In yet another embodiment, a cardiovascular event or disease is nonfatal myocardial infarction. In yet another embodiment, a cardiovascular event is nonfatal stroke. In yet another embodiment, a cardiovascular event is cardiovascular death. In yet another embodiment, a cardiovascular event is hospitalized heart failure.

[0106] In other implementations, a patient may also be diagnosed with one or more cardiovascular risk factors that could lead to a cardiovascular event. Cardiovascular risk factors may include, but are not limited to, syncope, transient ischemic events or stroke (excluding intracranial hemorrhage), cardiovascular procedures such as heart transplantation, implantation of cardiac devices such as cardiac stimulators (pacemakers) or defibrillators (“ICDs”), cerebrovascular or peripheral interventions, pulmonary embolism or deep vein thrombosis, acute pulmonary edema or dyspnea due to cardiac causes, stable angina or atypical chest pain, supraventricular arrhythmias such as atrial fibrillation, changes in arterial pressure (e.g., hypotension, hypertension, excluding syncope), cardiovascular infection, major bleeding / blood loss (requiring two or more blood clots or any intracranial hemorrhage), and high cholesterol (hyperlipidemia) such as high... LDL, low HDL, high triglycerides, obesity, microalbuminuria, peripheral vascular disease, underlying structural heart disease, atherosclerosis, atrial fibrillation, tachycardia, coronary artery disease, non-rheumatic valvular heart disease, ischemic dilated cardiomyopathy, ablation, supraventricular tachycardia other than atrial fibrillation or fibrillation, history of heart valve surgery, non-ischemic dilated cardiomyopathy, hypertrophic cardiomyopathy, rheumatic valvular disease, sustained ventricular tachycardia, congenital heart disease, ventricular fibrillation, at least one cardiac device (including but not limited to a cardiac stimulator, implantable defibrillator, etc.), current or past smoking history, male sex, or any combination thereof.

[0107] II. Detailed Description of Implementation Methods

[0108] In one aspect, this disclosure provides a dual-targeting antisense oligonucleotide for SGLT2 and SGLT1, the antisense oligonucleotide being 10-18 nucleotides in length, wherein the antisense oligonucleotide is at least partially complementary to a segment of nucleotides in the respective transcribed mRNA of SGLT2 and SGLT1, and reduces the amount of the corresponding mRNA or the expression level of the corresponding protein of SGLT2 and SGLT1.

[0109] In some embodiments, the antisense oligonucleotide comprises at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, or at least 16 consecutive nucleotide sequences that differ from the nucleotide sequences shown in any of SEQ ID NO:1-166 by no more than 4, 3, 2, or 1 nucleotides.

[0110] In some implementations, the transcribed mRNA sequence of the SGLT1 is shown in SEQ ID NO:167.

[0111] In some implementations, the transcribed mRNA sequence of the SGLT2 is shown in SEQ ID NO:168.

[0112] In some embodiments, the antisense oligonucleotide is complementary to an equal-length portion or a portion of the nucleobase fragment 1 in the sequence shown in SEQ ID NO:167, and the nucleobase fragment 1 complementary to the antisense oligonucleotide is selected from the following regions or fragments thereof:

[0113] (1) Segment 1231-1244 of SEQ ID NO:167;

[0114] (2) Segment 195-206 of SEQ ID NO:167;

[0115] (3) Segment 1136-1148 of SEQ ID NO:167;

[0116] (4) Segment 484-497 of SEQ ID NO:167;

[0117] (5) Segment 1205-1221 of SEQ ID NO:167;

[0118] (6) Segment 1231-1251 of SEQ ID NO:167;

[0119] (7) Segment 1375-1388 of SEQ ID NO:167;

[0120] (8) Segment 1018-1038 of SEQ ID NO:167;

[0121] (9) Segment 1174-1185 of SEQ ID NO:167;

[0122] (10) Segment 1375-1392 of SEQ ID NO:167;

[0123] (11) Segment 262-278 of SEQ ID NO:167;

[0124] (12) Segment 620-631 of SEQ ID NO:167;

[0125] (13) Segment 886-898 of SEQ ID NO:167; or

[0126] (14) Segment 913-926 of SEQ ID NO:167.

[0127] In some embodiments, the antisense oligonucleotide is complementary to an equal-length portion or a portion of the nucleobase fragment 2 in the sequence shown in SEQ ID NO:168, and the nucleobase fragment 2 complementary to the antisense oligonucleotide is selected from the following regions or fragments thereof:

[0128] (1) Segment 1224-1237 of SEQ ID NO:168;

[0129] (2) Segment 179-190 of SEQ ID NO:168;

[0130] (3) Segment 1129-1141 of SEQ ID NO:168;

[0131] (4) Segment 468-481 of SEQ ID NO:168;

[0132] (5) Segment 1198-1214 of SEQ ID NO:168;

[0133] (6) Segment 1224-1244 of SEQ ID NO:168;

[0134] (7) Segment 1368-1381 of SEQ ID NO:168;

[0135] (8) Segment 1011-1031 of SEQ ID NO:168;

[0136] (9) Segment 1167-1178 of SEQ ID NO:168;

[0137] (10) Segment 1368-1385 of SEQ ID NO:168;

[0138] (11) Segment 246-262 of SEQ ID NO:168;

[0139] (12) Segment 571-582 of SEQ ID NO:168;

[0140] (13) Segment 879-891 of SEQ ID NO:168; or

[0141] (14) Segment 906-919 of SEQ ID NO:168.

[0142] In some embodiments, the antisense oligonucleotide is complementary to an equal-length portion or a portion of the sequence of nucleobase fragment 1 in the sequence shown in SEQ ID NO:167, and is also complementary to an equal-length portion or a portion of the sequence of nucleobase fragment 2 in the sequence shown in SEQ ID NO:168. Nucleobase fragments 1 and 2, which are complementary to the antisense oligonucleotide, are selected from any of the following combinations:

[0143] (1) Nucleobase fragment 1 is the 1231-1242 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1224-1235 segment of SEQ ID NO:168;

[0144] (2) Nucleobase fragment 1 is the 1231-1243 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1224-1236 segment of SEQ ID NO:168;

[0145] (3) Nucleobase fragment 1 is the 1232-1243 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1225-1236 segment of SEQ ID NO:168;

[0146] (4) Nucleobase fragment 1 is the 1231-1244 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1224-1237 segment of SEQ ID NO:168;

[0147] (5) Nucleobase fragment 1 is the 1232-1244 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1225-1237 segment of SEQ ID NO:168;

[0148] (6) Nucleobase fragment 1 is the 1233-1244 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1226-1237 segment of SEQ ID NO:168;

[0149] (7) Nucleobase fragment 1 is the 195-206 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 179-190 segment of SEQ ID NO:168;

[0150] (8) Nucleobase fragment 1 is the 1136-1147 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1129-1140 segment of SEQ ID NO:168;

[0151] (9) Nucleobase fragment 1 is segment 1136-1148 of SEQ ID NO:167; Nucleobase fragment 2 is segment 1129-1141 of SEQ ID NO:168;

[0152] (10) Nucleobase fragment 1 is segment 1137-1148 of SEQ ID NO:167; Nucleobase fragment 2 is segment 1130-1141 of SEQ ID NO:168;

[0153] (11) Nucleobase fragment 1 is the 484-495 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 468-479 segment of SEQ ID NO:168;

[0154] (12) Nucleobase fragment 1 is the 484-496 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 468-480 segment of SEQ ID NO:168;

[0155] (13) Nucleobase fragment 1 is the 485-496 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 469-480 segment of SEQ ID NO:168;

[0156] (14) Nucleobase fragment 1 is the 484-497 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 468-481 segment of SEQ ID NO:168;

[0157] (15) Nucleobase fragment 1 is the 485-497 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 469-481 segment of SEQ ID NO:168;

[0158] (16) Nucleobase fragment 1 is segment 486-497 of SEQ ID NO:167; Nucleobase fragment 2 is segment 470-481 of SEQ ID NO:168;

[0159] (17) Nucleobase fragment 1 is the 1205-1216 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1198-1209 segment of SEQ ID NO:168;

[0160] (18) Nucleobase fragment 1 is the 1205-1217 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1198-1210 segment of SEQ ID NO:168;

[0161] (19) Nucleobase fragment 1 is the 1206-1217 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1199-1210 segment of SEQ ID NO:168;

[0162] (20) Nucleobase fragment 1 is the 1205-1218 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1198-1211 segment of SEQ ID NO:168;

[0163] (21) Nucleobase fragment 1 is the 1206-1218 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1199-1211 segment of SEQ ID NO:168;

[0164] (22) Nucleobase fragment 1 is the 1207-1218 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1200-1211 segment of SEQ ID NO:168;

[0165] (23) Nucleobase fragment 1 is the 1205-1219 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1198-1212 segment of SEQ ID NO:168;

[0166] (24) Nucleobase fragment 1 is the 1206-1219 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1199-1212 segment of SEQ ID NO:168;

[0167] (25) Nucleobase fragment 1 is the 1207-1219 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1200-1212 segment of SEQ ID NO:168;

[0168] (26) Nucleobase fragment 1 is the 1208-1219 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1201-1212 segment of SEQ ID NO:168;

[0169] (27) Nucleobase fragment 1 is the 1205-1220 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1198-1213 segment of SEQ ID NO:168;

[0170] (28) Nucleobase fragment 1 is the 1206-1220 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1199-1213 segment of SEQ ID NO:168;

[0171] (29) Nucleobase fragment 1 is the 1207-1220 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1200-1213 segment of SEQ ID NO:168;

[0172] (30) Nucleobase fragment 1 is the 1208-1220 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1201-1213 segment of SEQ ID NO:168;

[0173] (31) Nucleobase fragment 1 is the 1209-1220 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1202-1213 segment of SEQ ID NO:168;

[0174] (32) Nucleobase fragment 1 is the 1206-1221 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1199-1214 segment of SEQ ID NO:168;

[0175] (33) Nucleobase fragment 1 is the 1207-1221 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1200-1214 segment of SEQ ID NO:168;

[0176] (34) Nucleobase fragment 1 is the 1208-1221 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1201-1214 segment of SEQ ID NO:168;

[0177] (35) Nucleobase fragment 1 is the 1209-1221 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1202-1214 segment of SEQ ID NO:168;

[0178] (36) Nucleobase fragment 1 is the 1210-1221 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1203-1214 segment of SEQ ID NO:168;

[0179] (37) Nucleobase fragment 1 is the 1231-1245 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1224-1238 segment of SEQ ID NO:168;

[0180] (38) Nucleobase fragment 1 is the 1232-1245 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1225-1238 segment of SEQ ID NO:168;

[0181] (39) Nucleobase fragment 1 is the 1233-1245 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1226-1238 segment of SEQ ID NO:168;

[0182] (40) Nucleobase fragment 1 is the 1234-1245 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1227-1238 segment of SEQ ID NO:168;

[0183] (41) Nucleobase fragment 1 is the 1231-1246 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1224-1239 segment of SEQ ID NO:168;

[0184] (42) Nucleobase fragment 1 is the 1232-1246 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1225-1239 segment of SEQ ID NO:168;

[0185] (43) Nucleobase fragment 1 is the 1233-1246 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1226-1239 segment of SEQ ID NO:168;

[0186] (44) Nucleobase fragment 1 is the 1234-1246 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1227-1239 segment of SEQ ID NO:168;

[0187] (45) Nucleobase fragment 1 is the 1235-1246 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1228-1239 segment of SEQ ID NO:168;

[0188] (46) Nucleobase fragment 1 is the 1232-1247 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1225-1240 segment of SEQ ID NO:168;

[0189] (47) Nucleobase fragment 1 is the 1233-1247 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1226-1240 segment of SEQ ID NO:168;

[0190] (48) Nucleobase fragment 1 is the 1234-1247 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1227-1240 segment of SEQ ID NO:168;

[0191] (49) Nucleobase fragment 1 is the 1235-1247 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1228-1240 segment of SEQ ID NO:168;

[0192] (50) Nucleobase fragment 1 is the 1236-1247 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1229-1240 segment of SEQ ID NO:168;

[0193] (51) Nucleobase fragment 1 is segment 1233-1248 of SEQ ID NO:167; Nucleobase fragment 2 is segment 1226-1241 of SEQ ID NO:168;

[0194] (52) Nucleobase fragment 1 is segment 1234-1248 of SEQ ID NO:167; Nucleobase fragment 2 is segment 1227-1241 of SEQ ID NO:168;

[0195] (53) Nucleobase fragment 1 is the 1235-1248 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1228-1241 segment of SEQ ID NO:168;

[0196] (54) Nucleobase fragment 1 is segment 1236-1248 of SEQ ID NO:167; Nucleobase fragment 2 is segment 1229-1241 of SEQ ID NO:168;

[0197] (55) Nucleobase fragment 1 is segment 1237-1248 of SEQ ID NO:167; Nucleobase fragment 2 is segment 1230-1241 of SEQ ID NO:168;

[0198] (56) Nucleobase fragment 1 is the 1234-1249 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1227-1242 segment of SEQ ID NO:168;

[0199] (57) Nucleobase fragment 1 is the 1235-1249 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1228-1242 segment of SEQ ID NO:168;

[0200] (58) Nucleobase fragment 1 is the 1236-1249 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1229-1242 segment of SEQ ID NO:168;

[0201] (59) Nucleobase fragment 1 is segment 1237-1249 of SEQ ID NO:167; Nucleobase fragment 2 is segment 1230-1242 of SEQ ID NO:168;

[0202] (60) Nucleobase fragment 1 is segment 1238-1249 of SEQ ID NO:167; Nucleobase fragment 2 is segment 1231-1242 of SEQ ID NO:168;

[0203] (61) Nucleobase fragment 1 is the 1235-1250 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1228-1243 segment of SEQ ID NO:168;

[0204] (62) Nucleobase fragment 1 is the 1236-1250 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1229-1243 segment of SEQ ID NO:168;

[0205] (63) Nucleobase fragment 1 is the 1237-1250 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1230-1243 segment of SEQ ID NO:168;

[0206] (64) Nucleobase fragment 1 is the 1238-1250 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1231-1243 segment of SEQ ID NO:168;

[0207] (65) Nucleobase fragment 1 is the 1239-1250 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1232-1243 segment of SEQ ID NO:168;

[0208] (66) Nucleobase fragment 1 is the 1236-1251 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1229-1244 segment of SEQ ID NO:168;

[0209] (67) Nucleobase fragment 1 is the 1237-1251 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1230-1244 segment of SEQ ID NO:168;

[0210] (68) Nucleobase fragment 1 is the 1238-1251 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1231-1244 segment of SEQ ID NO:168;

[0211] (69) Nucleobase fragment 1 is the 1239-1251 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1232-1244 segment of SEQ ID NO:168;

[0212] (70) Nucleobase fragment 1 is the 1240-1251 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1233-1244 segment of SEQ ID NO:168;

[0213] (71) Nucleobase fragment 1 is the 1375-1386 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1368-1379 segment of SEQ ID NO:168;

[0214] (72) Nucleobase fragment 1 is the 1375-1387 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1368-1380 segment of SEQ ID NO:168;

[0215] (73) Nucleobase fragment 1 is the 1376-1387 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1369-1380 segment of SEQ ID NO:168;

[0216] (74) Nucleobase fragment 1 is the 1375-1388 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1368-1381 segment of SEQ ID NO:168;

[0217] (75) Nucleobase fragment 1 is the 1376-1388 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1369-1381 segment of SEQ ID NO:168;

[0218] (76) Nucleobase fragment 1 is the 1377-1388 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1370-1381 segment of SEQ ID NO:168;

[0219] (77) Nucleobase fragment 1 is segment 1018-1029 of SEQ ID NO:167; Nucleobase fragment 2 is segment 1011-1022 of SEQ ID NO:168;

[0220] (78) Nucleobase fragment 1 is the 1018-1030 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1011-1023 segment of SEQ ID NO:168;

[0221] (79) Nucleobase fragment 1 is the 1019-1030 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1012-1023 segment of SEQ ID NO:168;

[0222] (80) Nucleobase fragment 1 is the 1018-1031 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1011-1024 segment of SEQ ID NO:168;

[0223] (81) Nucleobase fragment 1 is the 1019-1031 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1012-1024 segment of SEQ ID NO:168;

[0224] (82) Nucleobase fragment 1 is the 1020-1031 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1013-1024 segment of SEQ ID NO:168;

[0225] (83) Nucleobase fragment 1 is the 1018-1032 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1011-1025 segment of SEQ ID NO:168;

[0226] (84) Nucleobase fragment 1 is the 1019-1032 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1012-1025 segment of SEQ ID NO:168;

[0227] (85) Nucleobase fragment 1 is the 1020-1032 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1013-1025 segment of SEQ ID NO:168;

[0228] (86) Nucleobase fragment 1 is segment 1021-1032 of SEQ ID NO:167; Nucleobase fragment 2 is segment 1014-1025 of SEQ ID NO:168;

[0229] (87) Nucleobase fragment 1 is the 1018-1033 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1011-1026 segment of SEQ ID NO:168;

[0230] (88) Nucleobase fragment 1 is the 1019-1033 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1012-1026 segment of SEQ ID NO:168;

[0231] (89) Nucleobase fragment 1 is the 1020-1033 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1013-1026 segment of SEQ ID NO:168;

[0232] (90) Nucleobase fragment 1 is the 1021-1033 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1014-1026 segment of SEQ ID NO:168;

[0233] (91) Nucleobase fragment 1 is the 1022-1033 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1015-1026 segment of SEQ ID NO:168;

[0234] (92) Nucleobase fragment 1 is the 1019-1034 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1012-1027 segment of SEQ ID NO:168;

[0235] (93) Nucleobase fragment 1 is the 1020-1034 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1013-1027 segment of SEQ ID NO:168;

[0236] (94) Nucleobase fragment 1 is segment 1021-1034 of SEQ ID NO:167; Nucleobase fragment 2 is segment 1014-1027 of SEQ ID NO:168;

[0237] (95) Nucleobase fragment 1 is the 1022-1034 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1015-1027 segment of SEQ ID NO:168;

[0238] (96) Nucleobase fragment 1 is the 1023-1034 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1016-1027 segment of SEQ ID NO:168;

[0239] (97) Nucleobase fragment 1 is the 1020-1035 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1013-1028 segment of SEQ ID NO:168;

[0240] (98) Nucleobase fragment 1 is the 1021-1035 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1014-1028 segment of SEQ ID NO:168;

[0241] (99) Nucleobase fragment 1 is the 1022-1035 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1015-1028 segment of SEQ ID NO:168;

[0242] (100) Nucleobase fragment 1 is the 1023-1035 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1016-1028 segment of SEQ ID NO:168;

[0243] (101) Nucleobase fragment 1 is the 1024-1035 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1017-1028 segment of SEQ ID NO:168;

[0244] (102) Nucleobase fragment 1 is the 1021-1036 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1014-1029 segment of SEQ ID NO:168;

[0245] (103) Nucleobase fragment 1 is the 1022-1036 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1015-1029 segment of SEQ ID NO:168;

[0246] (104) Nucleobase fragment 1 is the 1024-1036 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1017-1029 segment of SEQ ID NO:168;

[0247] (105) Nucleobase fragment 1 is the 1023-1036 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1016-1029 segment of SEQ ID NO:168;

[0248] (106) Nucleobase fragment 1 is the 1025-1036 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1018-1029 segment of SEQ ID NO:168;

[0249] (107) Nucleobase fragment 1 is the 1022-1037 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1015-1030 segment of SEQ ID NO:168;

[0250] (108) Nucleobase fragment 1 is the 1023-1037 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1016-1030 segment of SEQ ID NO:168;

[0251] (109) Nucleobase fragment 1 is the 1024-1037 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1017-1030 segment of SEQ ID NO:168;

[0252] (110) Nucleobase fragment 1 is the 1025-1037 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1018-1030 segment of SEQ ID NO:168;

[0253] (111) Nucleobase fragment 1 is the 1026-1037 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1019-1030 segment of SEQ ID NO:168;

[0254] (112) Nucleobase fragment 1 is the 1023-1038 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1016-1031 segment of SEQ ID NO:168;

[0255] (113) Nucleobase fragment 1 is segment 1024-1038 of SEQ ID NO:167; Nucleobase fragment 2 is segment 1017-1031 of SEQ ID NO:168;

[0256] (114) Nucleobase fragment 1 is the 1025-1038 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1018-1031 segment of SEQ ID NO:168;

[0257] (115) Nucleobase fragment 1 is the 1026-1038 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1019-1031 segment of SEQ ID NO:168;

[0258] (116) Nucleobase fragment 1 is the 1027-1038 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1020-1031 segment of SEQ ID NO:168;

[0259] (117) Nucleobase fragment 1 is the 1174-1185 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1167-1178 segment of SEQ ID NO:168;

[0260] (118) Nucleobase fragment 1 is the 1375-1389 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1368-1382 segment of SEQ ID NO:168;

[0261] (119) Nucleobase fragment 1 is the 1376-1389 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1369-1382 segment of SEQ ID NO:168;

[0262] (120) Nucleobase fragment 1 is the 1377-1389 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1370-1382 segment of SEQ ID NO:168;

[0263] (121) Nucleobase fragment 1 is the 1378-1389 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1371-1382 segment of SEQ ID NO:168;

[0264] (122) Nucleobase fragment 1 is the 1375-1390 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1368-1383 segment of SEQ ID NO:168;

[0265] (123) Nucleobase fragment 1 is the 1376-1390 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1369-1383 segment of SEQ ID NO:168;

[0266] (124) Nucleobase fragment 1 is the 1377-1390 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1370-1383 segment of SEQ ID NO:168;

[0267] (125) Nucleobase fragment 1 is the 1378-1390 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1371-1383 segment of SEQ ID NO:168;

[0268] (126) Nucleobase fragment 1 is the 1379-1390 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1372-1383 segment of SEQ ID NO:168;

[0269] (127) Nucleobase fragment 1 is the 1376-1391 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1369-1384 segment of SEQ ID NO:168;

[0270] (128) Nucleobase fragment 1 is the 1377-1391 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1370-1384 segment of SEQ ID NO:168;

[0271] (129) Nucleobase fragment 1 is the 1378-1391 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1371-1384 segment of SEQ ID NO:168;

[0272] (130) Nucleobase fragment 1 is the 1379-1391 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1372-1384 segment of SEQ ID NO:168;

[0273] (131) Nucleobase fragment 1 is the 1380-1391 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1373-1384 segment of SEQ ID NO:168;

[0274] (132) Nucleobase fragment 1 is the 1377-1392 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1370-1385 segment of SEQ ID NO:168;

[0275] (133) Nucleobase fragment 1 is the 1378-1392 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1371-1385 segment of SEQ ID NO:168;

[0276] (134) Nucleobase fragment 1 is the 1379-1392 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1372-1385 segment of SEQ ID NO:168;

[0277] (135) Nucleobase fragment 1 is the 1380-1392 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1373-1385 segment of SEQ ID NO:168;

[0278] (136) Nucleobase fragment 1 is segment 1381-1392 of SEQ ID NO:167; Nucleobase fragment 2 is segment 1374-1385 of SEQ ID NO:168;

[0279] (137) Nucleobase fragment 1 is segment 262-273 of SEQ ID NO:167; Nucleobase fragment 2 is segment 246-257 of SEQ ID NO:168;

[0280] (138) Nucleobase fragment 1 is segment 262-274 of SEQ ID NO:167; Nucleobase fragment 2 is segment 246-258 of SEQ ID NO:168;

[0281] (139) Nucleobase fragment 1 is segment 263-274 of SEQ ID NO:167; Nucleobase fragment 2 is segment 247-258 of SEQ ID NO:168;

[0282] (140) Nucleobase fragment 1 is the 262-275 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 246-259 segment of SEQ ID NO:168;

[0283] (141) Nucleobase fragment 1 is segment 263-275 of SEQ ID NO:167; Nucleobase fragment 2 is segment 247-259 of SEQ ID NO:168;

[0284] (142) Nucleobase fragment 1 is the 264-275 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 248-259 segment of SEQ ID NO:168;

[0285] (143) Nucleobase fragment 1 is the 262-276 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 246-260 segment of SEQ ID NO:168;

[0286] (144) Nucleobase fragment 1 is the 263-276 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 247-260 segment of SEQ ID NO:168;

[0287] (145) Nucleobase fragment 1 is the 264-276 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 248-260 segment of SEQ ID NO:168;

[0288] (146) Nucleobase fragment 1 is the 265-276 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 249-260 segment of SEQ ID NO:168;

[0289] (147) Nucleobase fragment 1 is the 262-277 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 246-261 segment of SEQ ID NO:168;

[0290] (148) Nucleobase fragment 1 is the 263-277 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 247-261 segment of SEQ ID NO:168;

[0291] (149) Nucleobase fragment 1 is the 264-277 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 248-261 segment of SEQ ID NO:168;

[0292] (150) Nucleobase fragment 1 is the 265-277 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 249-261 segment of SEQ ID NO:168;

[0293] (151) Nucleobase fragment 1 is the 266-277 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 250-261 segment of SEQ ID NO:168;

[0294] (152) Nucleobase fragment 1 is segment 263-278 of SEQ ID NO:167; Nucleobase fragment 2 is segment 247-262 of SEQ ID NO:168;

[0295] (153) Nucleobase fragment 1 is segment 264-278 of SEQ ID NO:167; Nucleobase fragment 2 is segment 248-262 of SEQ ID NO:168;

[0296] (154) Nucleobase fragment 1 is segment 265-278 of SEQ ID NO:167; Nucleobase fragment 2 is segment 249-262 of SEQ ID NO:168;

[0297] (155) Nucleobase fragment 1 is segment 266-278 of SEQ ID NO:167; Nucleobase fragment 2 is segment 250-262 of SEQ ID NO:168;

[0298] (156) Nucleobase fragment 1 is segment 267-278 of SEQ ID NO:167; Nucleobase fragment 2 is segment 251-262 of SEQ ID NO:168;

[0299] (157) Nucleobase fragment 1 is segment 620-631 of SEQ ID NO:167; Nucleobase fragment 2 is segment 571-582 of SEQ ID NO:168;

[0300] (158) Nucleobase fragment 1 is the 886-897 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 879-890 segment of SEQ ID NO:168;

[0301] (159) Nucleobase fragment 1 is the 886-898 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 879-891 segment of SEQ ID NO:168;

[0302] (160) Nucleobase fragment 1 is the 887-898 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 880-891 segment of SEQ ID NO:168;

[0303] (161) Nucleobase fragment 1 is the 913-924 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 906-917 segment of SEQ ID NO:168;

[0304] (162) Nucleobase fragment 1 is the 913-925 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 906-918 segment of SEQ ID NO:168;

[0305] (163) Nucleobase fragment 1 is the 914-925 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 907-918 segment of SEQ ID NO:168;

[0306] (164) Nucleobase fragment 1 is the 913-926 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 906-919 segment of SEQ ID NO:168;

[0307] (165) Nucleobase fragment 1 is region 914-926 of SEQ ID NO:167; nucleobase fragment 2 is region 907-919 of SEQ ID NO:168; or

[0308] (166) Nucleobase fragment 1 is segment 915-926 of SEQ ID NO:167; nucleobase fragment 2 is segment 908-919 of SEQ ID NO:168.

[0309] In some embodiments, the antisense oligonucleotide is 10-16 nucleotides in length. In some embodiments, the antisense oligonucleotide is 12-16 nucleotides in length.

[0310] In some embodiments, the antisense oligonucleotide consists of X to Y consecutive nucleotides, where X represents the minimum number of nucleotides in the range and Y represents the maximum number of nucleotides in the range. In some embodiments, X and Y are each independently selected from 10, 11, 12, 13, 14, 15, and 16, provided that X ≤ Y. For example, in some embodiments, the antisense oligonucleotide consists of 12 to 13, 12 to 14, 12 to 15, 12 to 16, 13 to 14, 13 to 15, 13 to 16, 14 to 15, 14 to 16, and 15 to 16 consecutive nucleotides.

[0311] In some embodiments, the antisense oligonucleotide comprises:

[0312] A spacer segment consisting of 8-10 consecutive deoxynucleotides;

[0313] The 5' wing region consists of 1-3 consecutive nucleotides; and

[0314] A 3' wing region consisting of 1-3 consecutive nucleotides;

[0315] The spacer segment is located between the 5' wing region and the 3' wing region, and the 5' wing region and the 3' wing region contain modified nucleotides.

[0316] In some implementations, each nucleotide in the 5' wing region and the 3' wing region is a modified nucleotide.

[0317] In some implementations, the spacer segment contains modified nucleotides.

[0318] In some embodiments, the modified nucleotide is a base-modified nucleotide, a sugar-modified nucleotide, and / or a phosphate backbone-modified nucleotide.

[0319] In some implementations, the modified nucleotide is a base-modified nucleotide.

[0320] In some embodiments, the antisense oligonucleotide comprises one or more nucleotides containing unmodified bases, such as nucleotides containing adenine (A), thymine (T), cytosine (C), uracil (U), or guanine (G). In some embodiments, the antisense oligonucleotide comprises one or more nucleotides containing modified bases (such as 5-methylcytosine, 5mC). In some embodiments, the antisense oligonucleotide comprises one or more nucleotides without bases (i.e., base-free nucleotides). In some embodiments, the antisense oligonucleotide comprises one or more inosine nucleotides (i.e., nucleotides containing hypoxanthine bases).

[0321] In some implementations, the modified adenine has structure (I):

[0322] Among them, R 2A H, C1-C6 alkyl, substituted C1-C6 alkyl, C1-C6 thioalkyl, or substituted C1-C6 thioalkyl, C1-C6 alkoxy, or substituted C1-C6 alkoxy; R 6A For H, N(R) a (R) b ), acetyl, formyl, or O-phenyl; Y 7A For N and R 7A It either does not exist or is a C1-C6 alkyl group; or Y 7A For C and R 7A Selected from H, C1-C6 alkyl, or CN(R) a (R) b );Y 8A For N and R 8A Does not exist, or Y 8A For C and R 8A Selected from H, halogens, OH, C1-C6 alkyl groups, or substituted C1-C6 alkyl groups; R a and R b Independently selected from H, C1-C6 alkyl, substituted C1-C6 alkyl, C1-C6 alkenyl, substituted C1-C6 alkenyl, acetyl, formyl, or together forming a 5-7 membered heterocycle; excluding Y. 7A For N, Y 8A For C, R8A For H, R 2A Let H be the number of 'R', and R be the number of 'R'. 6A This refers to the case of NH2 (unmodified adenine).

[0323] In some implementations, the modified guanine has structure (II):

[0324] Among them, R 2G For N(R) a (R) b ); R 6G It is an oxygen-substituted (=O) and R 1G For H, or R 6G Selected from O-C1-C6 alkyl or S-C1-C6 alkyl and R 1G Does not exist; Y 7G For N and R 7A It is absent or is a C1-C6 alkyl group; or Y 7G For C and R 7G Selected from H, C1-C6 alkyl, or CN(R) a (R) b );Y 8G For N and R 8G Does not exist, or Y 8G For C and R 8G Selected from H, halogens, OH, C1-C6 alkyl groups, or substituted C1-C6 alkyl groups; R a and R b Independently selected from H, C1-C6 alkyl, substituted C1-C6 alkyl, C1-C6 alkenyl, substituted C1-C6 alkenyl, acetyl, formyl, or together forming a 5-7 membered heterocycle; excluding Y. 7G For N, Y 8G For C, R 8G For H, R 2G It is NH2 and R 6G This is the case where it equals O (unmodified guanine).

[0325] In some embodiments, the modified thymine or modified uracil has structure (III):

[0326] Where X is selected from O or S, and R 5U Selected from H, OH, halogens, O-Cl-C 12 Alkyl, O-C1-C 12 Substituted alkyl, C1-C 12 Alkyl, substituted C1-C 12 Alkyl, C1-C 12 Alkenyl, substituted C1-C 12 Alkenyl; where if each X is O, then R5U It is neither H nor CH3 (unmodified uracil and unmodified thymine, respectively).

[0327] In some implementations, those skilled in the art can, depending on whether the nucleotide is RNA or DNA, add R... 5U H is replaced with CH3 or CH3 is replaced with H (that is, the thymine and uracil are interchanged).

[0328] In some implementations, the modified cytosine has structure (IV):

[0329] Where X is selected from O or S, R 4C For N(R) a (R) b ); R 5C Selected from H, OH, halogens, O-Cl-C 12 Alkyl, O-C1-C 12 Substituted alkyl, C1-C 12 Alkyl, substituted C1-C 12 Alkyl, C1-C 12 Alkenyl, substituted C1-C 12 alkenyl; R a and R b Independently selected from H, C1-C6 alkyl, substituted C1-C6 alkyl, C1-C6 alkenyl, substituted C1-C6 alkenyl, acetyl, formyl, or together forming a 5-7 membered heterocycle; excluding X being O, R 4C It is NH2 and R 5C The case is H (unmodified cytosine).

[0330] In some embodiments, the modified nucleobase is selected from: 5-substituted pyrimidines, 6-azapyrimidines, alkyl or alkynyl-substituted pyrimidines, alkyl-substituted purines, and N-2, N-6, and O-6-substituted purines. In some embodiments, the modified nucleobase is selected from: 5-methylcytosine, 2-aminopropyladenine, 5-hydroxymethylcytosine, xanthine, hypoxanthine, 2-aminoadenine, 6-N-methylguanine, 6-N-methyladenine, 2-propyladenine, 2-thiouracil, 2-thiothymidine and 2-thiocytosine, 5-propynyl(-C≡C-CH3)uracil, 5-propynylcytosine, 6-azauracil, 6-azacytosine, 6-azathymidine, 5-ribosyluracil (pseudouracil), 4-thiouracil, 8-halogenated, 8-amino, 8-thiol, 8-thioalkyl, 8-hydroxy, 8-aza and others. It includes 8-substituted purines, 5-halogenated (especially 5-bromine), 5-trifluoromethyl, 5-halogenated uracil, and 5-halogenated cytosine, 7-methylguanine, 7-methyladenine, 2-F-adenine, 2-aminoadenine, 7-deazoguanine, 7-deazoadenine, 3-deazoguanine, 3-deazoadenine, 6-N-benzoyladenine, 2-N-isobutyrylguanine, 4-N-benzoylcytosine, 4-N-benzoyluracil, 5-methyl-4-N-benzoylcytosine, 5-methyl-4-N-benzoyluracil, universal bases, hydrophobic bases, hybrid bases, size-amplified bases, and fluorinated bases.

[0331] In some embodiments, the modified nucleobases include tricyclic pyrimidines, such as 1,3-diazaphenoxazin-2-one, 1,3-diazaphenthiazin-2-one, and 9-(2-aminoethoxy)-1,3-diazaphenoxazin-2-one (G-clamp). Modified nucleobases may also include those bases where the purine or pyrimidine base is replaced by another heterocyclic ring, such as 7-deadenine, 7-deadenine, 2-aminopyridine, and 2-pyridone.

[0332] In some embodiments, each nucleobase of the antisense oligonucleotide is selected from A, G, C, T, U, and 5mC. In some embodiments, each nucleobase of the antisense oligonucleotide is selected from A, G, T, and 5mC (i.e., unmodified purines and 5-methylpyrimidines).

[0333] In some embodiments, the modified nucleotide is a sugar-modified nucleotide.

[0334] In some embodiments, the modified glycosyl moiety in the sugar-modified nucleotide is a non-bicyclic modified glycosyl moiety. In some embodiments, the modified glycosyl moiety is a bicyclic or tricyclic glycosyl moiety.

[0335] In some embodiments, the sugar-modified nucleotide contains a cyclopropyl group at the 5' carbon of the sugar. In some embodiments, the sugar-modified nucleotide contains a bridge between the 4'-carbon and the 2'-carbon of the sugar, and the sugar-modified nucleotide is a 4'-2'-bridged bicyclic nucleotide.

[0336] In some embodiments, the modified glycosyl moiety is a non-bicyclic modified furanyl glycosyl moiety comprising one or more acyclic substituents, including but not limited to substituents at the 2', 3', 4', and / or 5' positions. In some embodiments, the furanyl glycosyl moiety is a ribosyl glycosyl moiety. In some embodiments, one or more acyclic substituents of the non-bicyclic modified glycosyl moiety are branched. In some embodiments, the modified glycosyl moiety comprises one or more unbridged sugar substituents and one or more bridging sugar substituents (e.g., 5'-substituted and 4'-2'-bridged sugars).

[0337] In some embodiments, the sugar-modified nucleotide contains a 2' substituent other than H or OH, the 2' substituent being independently selected from substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, or halogen.

[0338] In some embodiments, the 2'-substituent is selected from: halogenated, allyl, amino, azide, SH, CN, OCN, CF3, OCF3, O-C1-C. 10 Alkoxy, O-C1-C10 substituted alkoxy, O-C1-C 10 Alkyl, O-C1-C 10 Substituted alkyl, S-alkyl, N(R) m )-alkyl, O-alkenyl, S-alkenyl, N(R m )-Alkenyl, O-alkynyl, S-alkynyl, N(R m )-Alkyne, O-alkylene-O-alkyl, Alkyne, Alkaryl, Arylalkyl, O-Alkaryl, O-Arylalkyl, O(CH2)2SCH3, O(CH2)2ON(R m (R) n ) or OCH2C(=O)-N(R m (R) n ), where each R m and R n Independently, it is H, an amino protecting group, or a substituted or unsubstituted C1-C. 10Alkyl, -O(CH2)2ON(CH3)2 ("DMAOE"), or 2'-O(CH2)2O(CH2)2N(CH3)2 ("DMAEOE"). Some embodiments of the above 2'-substituents may be further substituted by one or more substituents independently selected from the following: hydroxyl, amino, alkoxy, carboxyl, benzyl, phenyl, nitro(NO2), thiol, thioalkoxy, thioalkyl, halogen, alkyl, aryl, alkenyl, and alkynyl.

[0339] In some embodiments, the bridge independently comprises one or two to four linking groups, the linking groups being independently selected from -R-[C(R1)(R2)] n -R'-、-[C(R1)(R2)] n -R-R'-,-R-R'-[C(R1)(R2)] n -, -RC(R1)=C(R2)-R'-, -R-R'-C(R1)=C(R2)-, -C(R1)=C(R2)-R-R'-, -C(R1)=N-; R and R' are each independently selected from single bonds, -N(R3)-, -O-, -S-, -Se-, -Si(R4)(R5)-, -C(=O)-, -C(=S)-, -C(=NR3)-.

[0340] In some embodiments, the linking group is independently selected from -[C(R1)(R2)] n -、-[C(R1)(R2)] n -O-、-[C(R1)(R2)] n -N(R3)-、-[C(R1)(R2)] n -N(R3)-O-、-[C(R1)(R2)] n -ON(R3)-、-[C(R1)(R2)] n -S-, -C(R1)=C(R2)-, -C(R1)=N-.

[0341] Where n is 1, 2, 3 or 4.

[0342] Each R1, R2, R4, R5 is independently selected from H, protecting group, hydroxyl group, substituted or unsubstituted C1-C. 12 Alkyl, substituted or unsubstituted C2-C 12 alkenyl, substituted or unsubstituted C2-C 12 Alkyne, substituted or unsubstituted C5-C 20Aryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heteroaryl, substituted or unsubstituted C5-C7 alicyclic group, halogen, OJ1, NJ1J2, SJ1, N3, COOJ1, acyl (C(=O)-H or C(=O)-J1), substituted acyl, CN, sulfonyl (S(=O)2-J1) or sulfonyloxy (S(=O)-J1), or R1 and R2 linked together to form C3-C6 cycloalkyl or heterocyclic alkyl;

[0343] R3 is selected from H, protecting group, hydroxyl group, substituted or unsubstituted C1-C. 12 Alkyl, substituted or unsubstituted C2-C 12 alkenyl, substituted or unsubstituted C2-C 12 Alkyne, substituted or unsubstituted C5-C 20 Aryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heteroaryl, substituted or unsubstituted C5-C7 alicyclic group, halogen, OJ1, NJ1J2, SJ1, N3, COOJ1, acyl (C(=O)-H or C(=O)-J1), substituted acyl, CN, sulfonyl (S(=O)2-J1), sulfonic acid oxy (S(=O)-J1) or -C(=NH)-NH2-;

[0344] Each J1 and J2 is independently H, substituted or unsubstituted C1-C. 12 Alkyl, substituted or unsubstituted C2-C 12 alkenyl, substituted or unsubstituted C2-C 12 Alkyne, substituted or unsubstituted C5-C 20 Aryl, substituted or unsubstituted acyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted C1-C 12 Aminoalkyl or protecting group.

[0345] In some embodiments, the bridge is independently 4'-CH2-2', 4'-(CH2)2-2', 4'-CH2-O-2', 4'-CH(CH3)-O-2', 4'-C(C3H5)-O-2', 4'-CH2-ON(R3)-2', 4'-CH2-N(R3)-O-2', 4'-CH2-N(R3)-2', 4'-CH(R1)-NH-2', 4'-CH(R1)-N(R3)-2', 4'-CH2-S-2', 4'-CH(CH3)-S-2', 4'-CH2-R4-2', or 4'-C(=O)-N(R3)-2', wherein each R1, R2, R3 is independently a protecting group or a C1-C3 alkyl group.

[0346] In some embodiments, the bridge is independently 4'-CH2-2', 4'-(CH2)2-2', 4'-CH2-O-2', 4'-CH(CH3)-O-2', 4'-C(C3H6)-O-2', 4'-C(C2H4)-O-2', 4'-CH2-ON(R3)-2', 4'-CH2-N(R3)-O-2', 4'-CH2-N (R3)-2', 4'-CH(R1)-NH-2', 4'-CH(R1)-N(R3)-2', 4'-CH2-S-2', 4'-CH(CH3)-S-2', 4'-CH2-R4-2', or 4'-C(=O)-N(R3)-2', wherein each R1, R2, R3 is independently a protecting group or a C1-C3 alkyl group, and R4 is independently an alkylene group. In some embodiments, the sugar-modified nucleotide is LNA, cET, ENA, a 2'-fluorine-modified nucleotide, a 2'-O-methyl-modified nucleotide, or a combination thereof.

[0347] In some embodiments, the sugar-modified nucleotide is 2'-O-methyl (2'-OMe), 2'-methoxyethyl (2'-MOE), LNA, restricted ethyl (cEt), ENA, or a 2'-fluorine-modified nucleotide, or a combination thereof.

[0348] In some embodiments, the sugar-modified nucleotide is an LNA nucleotide selected from the following structures:

[0349] The definitions of R1, R2, and R are as described above.

[0350] In some embodiments, the sugar-modified nucleotide is an LNA nucleotide selected from the following structures:

[0351] R3 is defined as described above.

[0352] In some embodiments, the sugar-modified nucleotide is an LNA nucleotide selected from the following structures:

[0353] Where R is selected from O, S or N-R3, R1, R2 and R3 are defined as described above, and Base is a base.

[0354] In some embodiments, the sugar-modified nucleotide is an LNA nucleotide selected from the following structures:

[0355] R3 is defined as described above, and Base is a base.

[0356] In some implementations, the LNA used in this disclosure has the following structure:

[0357] In some embodiments, the glycosyl moiety and the nucleoside containing such glycosyl moiety have isomer configurations. For example, LNA nucleoside can be in the α-L configuration or the β-D configuration. When a particular bicyclic nucleoside (e.g., LNA or cEt) is specified in the embodiments herein, it may be in the α-L configuration or the β-D configuration unless otherwise stated.

[0358] In some embodiments, the glycosyl moiety is a sugar substitute. Such sugar substitutes may contain one or more substituents corresponding to substituents in other types of modifications to the glycosyl moiety.

[0359] In some embodiments, the oxygen atom of the glycosyl moiety is substituted, for example, with a sulfur, carbon, or nitrogen atom. In such embodiments, the modified glycosyl moiety also contains bridging and / or unbridging substituents. For example, some sugar substitutes contain a 4'-sulfur atom and substitutions at the 2'- and / or 5'-positions.

[0360] In some embodiments, the sugar substitute comprises a ring having a number of atoms other than five. For example, in some embodiments, the sugar substitute comprises a six-membered tetrahydropyran (THP) or a modified or substituted THP.

[0361] In some embodiments, the modified THP nucleoside is represented by the following general formula:

[0362] Wherein, Bx is the nucleobase moiety; T3 and T4 are each independently an internucleotide linker group that connects the modified THP nucleoside to the rest of the oligonucleotide, or one of T3 and T4 is an internucleotide linker group that connects the modified THP nucleoside to the rest of the oligonucleotide, and the other T3 or T4 is H, a hydroxyl protecting group, a linked conjugation group, or a 5' or 3'-terminal group; q1, q2, q3, q4, q5, q6 and q7 are each independently H, C1-C6 alkyl, substituted The C1-C6 alkyl, C2-C6 alkenyl, substituted C2-C6 alkenyl, C2-C6 alkynyl, or substituted C2-C6 alkynyl; and R1 and R2 are each independently selected from: hydrogen, halogen, substituted or unsubstituted alkoxy, NJ1J2, SJ1, N3, OC(=X)J1, OC(=X)NJ1J2, NJ3C(=X)NJ1J2, and CN, wherein X is O, S or NJ1, and each J1, J2 and J3 is independently H or C1-C6 alkyl.

[0363] In some embodiments, q1, q2, q3, q4, q5, q6, and q7 of the modified THP nucleoside are each H. In some embodiments, at least one of q1, q2, q3, q4, q5, q6, and q7 is not H. In some embodiments, at least one of q1, q2, q3, q4, q5, q6, and q7 is methyl. In some embodiments, one of R1 and R2 of the modified THP nucleoside is F. In some embodiments, R1 is F and R2 is H; in some embodiments, R1 is methoxy and R2 is H; in some embodiments, R1 is methoxyethoxy and R2 is H.

[0364] In some embodiments, the sugar substitute comprises a ring having more than five atoms and more than one heteroatom. For example, a nucleoside comprising a morpholine glycosyl moiety. The term "morpholine" refers to a sugar substitute having the following structure:

[0365] Wherein, Bx is the nucleobase moiety; the morpholine structure can be further modified, for example, by adding or changing various substituents to the above morpholine structure.

[0366] In some embodiments, the sugar substitute comprises an acyclic moiety. Examples of nucleosides and oligonucleotides comprising such acyclic sugar substitutes include, but are not limited to, peptide nucleic acids (PNAs), acyclic butyl nucleic acids, and other nucleosides and oligonucleotides described herein.

[0367] In some implementations, the sugar substitute is an unlocked nucleic acid nucleotide (UNA) or a glycol nucleic acid nucleotide (GNA).

[0368] In some embodiments, the modified nucleotide is a phosphate backbone modified nucleotide, the phosphate backbone including phosphate backbone modification of spacer regions and phosphate backbone modification of wing regions.

[0369] In some embodiments, the nucleosides of the antisense oligonucleotide can be linked using one or more modified internucleotide linkages. Representative phosphorus-containing internucleotide linkages include, but are not limited to, phosphodiester (containing a phosphodiester bond), phosphotriester, methylphosphonate, phosphoramide ester, thiophosphate, and dithiophosphate. Representative non-phosphodiester linkages include, but are not limited to, methylmethylimino (-CH2-N(CH3)-O-CH2-), thiodiester, thiocarbamate (-OC(=O)(NH)-S-); siloxane (-O-SiH2-O-); and N,N'-dimethylhydrazine (-CH2-N(CH3)-N(CH3)-). Compared to natural phosphodiester internucleotide linkages, modified internucleotide linkages can be used to alter (generally increase) the nuclease resistance of the oligonucleotide. This disclosure uses different modified internucleotide linkages, such as thiophosphate and / or methanesulfonylphosphonamide linkages, to achieve the technical effect of simultaneously targeting SGLT2 and SGLT2.

[0370] In some embodiments, the internucleotide linker with chiral atoms can be prepared as a racemic mixture or as individual enantiomers. Methods for preparing phosphorus-containing and non-phosphorus-containing internucleotide links are well known to those skilled in the art.

[0371] In some implementations, the modified nucleoside linker has the general formula Z1, Z2, or Z3:

[0372] Where each X 1 Independently selected from O and S; X 2 Selected from O, NR1, CH2 and S; X 3 Selected from O, NR 1 CH2 and S; L does not exist, or NR 1 、N(R 1 SO2, –N=, O, C1-C6 alkylene, or C1-C6 heteroalkylene; each R 1 Independently selected from H, C1-C6 alkyl, and substituted C1-C6 alkyl, or two R on the same atom. 1 Together they form = O; and R 2 Selected from -OH, -SH, Cl-C 22 Alkyl, substituted C1-C 22 Alkyl, C2-C 22 Alkenyl, substituted C2-C 22 Alkenyl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, heteroaryl, substituted heteroaryl, aryl, and substituted aryl; wherein when the group is substituted, it contains one or more substituents selected from: halogen, -OH, N(R) 1 )2、-O-C1-C6 alkyl、C1-C22 Alkyl, C2-C 22 Alkenyl, cycloalkyl, heterocyclic, heteroaryl, and aryl.

[0373] In some implementations, the modified nucleoside linker comprises the general formula Z4:

[0374] Wherein, X is selected from O or S; R1 is selected from H, C1-C6 alkyl, and substituted C1-C6 alkyl; and T is selected from SO2R2, C(=O)R3, and P(=O)R4R5, wherein: R2 is selected from aryl, substituted aryl, heterocyclic, substituted heterocyclic, aromatic heterocyclic, substituted aromatic heterocyclic, diazole, substituted diazole, C1-C6 alkoxy, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, substituted C1-C6 alkyl, substituted C1-C6 alkenyl, substituted C1-C6 alkynyl, and conjugated groups; R3 is selected from aryl, substituted aryl, CH3, N(CH3)2, OCH3 and conjugated groups; R4 is selected from OCH3, OH, C1-C6 alkyl, substituted C1-C6 alkyl and conjugated groups; and R5 is selected from OCH3, OH, C1-C6 alkyl, and substituted C1-C6 alkyl.

[0375] In some embodiments, the modified internucleotide linkage comprises a mesylate phosphoramidate internucleoside linkage (MsPA) group, which has the general formula:

[0376] The thiophosphate and / or methanesulfonylphosphatidyl linkage contains a chiral center.

[0377] In some embodiments, the antisense oligonucleotide comprises the general formula (R p ) and / or (S p The methanesulfonyl phosphoramide ester shown is represented by the symbol "B", where "B" indicates a nucleobase.

[0378] In some embodiments, the antisense oligonucleotide comprises the general formula (R p ) and / or (S p The thiophosphate ester shown is an example where "B" represents a nucleobase:

[0379] In some embodiments, representative internucleotide linkages with chiral centers include, but are not limited to, alkylphosphonates and thiophosphates. Modified oligonucleotides containing internucleotide linkages with chiral centers can be prepared as antisense oligonucleotides containing stereorandom internucleotide linkages, or as antisense oligonucleotides containing such internucleotide linkages having a specific stereochemical configuration.

[0380] In some embodiments, the internucleotide linker with chiral atoms can be prepared as a racemic mixture or as individual enantiomers. Methods for preparing phosphorus-containing and non-phosphorus-containing internucleotide links are well known to those skilled in the art.

[0381] In some embodiments, the antisense oligonucleotide comprises phosphate thioester (PS) nucleoside linkages, wherein all phosphate thioester nucleoside linkages are stereorandom. In some embodiments, the antisense oligonucleotide comprises methanesulfonylphosphatidyl ester nucleoside linkages, wherein all methanesulfonylphosphatidyl ester nucleoside linkages are stereorandom. Such modified oligonucleotides can be produced using synthetic methods that result in random selection of the stereoconfiguration of each nucleoside linkage with a chiral center. Nevertheless, each nucleoside linkage with a chiral center in each individual oligonucleotide molecule has a defined stereoconfiguration.

[0382] In some embodiments, the antisense oligonucleotide is enriched with a modified oligonucleotide comprising one or more specific thiophosphate and / or methanesulfonylphosphatidyl ester nucleoside linkages, each linkage being independently in a specific, independently selected stereochemical configuration. In some embodiments, the specific configuration of the specific thiophosphate and / or methanesulfonylphosphatidyl ester linkage is present in at least 65% of the molecules in the population. In some embodiments, the specific configuration is present in at least 70% of the molecules in the population. In some embodiments, the specific configuration is present in at least 80% of the molecules in the population. In some embodiments, the specific configuration is present in at least 90% of the molecules in the population. In some embodiments, the specific configuration is present in at least 99% of the molecules in the population. Such chiral-enriched antisense oligonucleotides can be produced using synthetic methods known in the art.

[0383] In some embodiments, the antisense oligonucleotide is enriched with at least one designated thiophosphate ester and / or methanesulfonylphosphatidyl ester in (S p Modified oligonucleotides with a (R) configuration. In some embodiments, the antisense oligonucleotide is enriched with at least one thiophosphate ester and / or methanesulfonylphosphatidyl ester in the (R) configuration. p Oligonucleotides with modified configurations.

[0384] Unless otherwise stated, the internucleotide linkages with chiral centers in the antisense oligonucleotides described herein may be stereo-random or in a specific stereochemical configuration.

[0385] In some embodiments, the antisense oligonucleotide comprises a neutral nucleoside linker, including but not limited to, phosphate triesters, methylphosphonates, MMI (3'-CH2-N(CH3)-O-5'), amide-3 (3'-CH2-C(=O)-N(H)-5'), amide-4 (3'-CH2-N(H)-C(=O)-5'), methyl acetal (3'-O-CH2-O-5'), methoxypropyl (MOP), and thiomethyl acetal (3'-S-CH2-O-5'). Further neutral nucleoside linkers include nonionic links comprising siloxanes (dialkylsiloxanes), carboxylic esters, carboxamides, sulfides, sulfonates, and amides. Further neutral nucleoside linkers include nonionic links comprising a mixture of N, O, S, and CH2 components.

[0386] In some embodiments, the antisense oligonucleotide comprises one or more reverse nucleosides, as shown below:

[0387] Each Bx represents any nucleobase independently.

[0388] In some implementations, nucleotides can be linked by 2'-5' bonds, as shown below:

[0389] Each Bx represents any nucleobase independently.

[0390] In some embodiments, the phosphate backbone modification includes 5'-phosphate mimicry modification. In some embodiments, the 5'-phosphate mimicry is selected from 5'-oxymethylphosphonate, 5'-vinylphosphonic acid, 5'-vinylphosphonate-2'-N-acetyl, or 5'-malonylphosphonate.

[0391] In some embodiments, the antisense oligonucleotide has a modification pattern selected from 2-8-2, 2-8-3, 3-8-3, 3-9-3, and 3-10-3, wherein the first number represents the number of nucleotides in the 5' wing region, the second number represents the number of deoxynucleotides in the spacer region, and the third number represents the number of nucleotides in the 3' wing region.

[0392] In some embodiments, the antisense nucleotide sequence is selected from any of the following modified sequences:

[0393] (1) It has the nucleotide sequence shown in SEQ ID NO:1 and the modification pattern shown in 2-8-2;

[0394] (2) It has the nucleotide sequence shown in SEQ ID NO:2 and the modification pattern shown in 2-8-3;

[0395] (3) It has a nucleotide sequence as shown in SEQ ID NO:3 and a modification pattern as shown in 2-8-2;

[0396] (4) Having a nucleotide sequence as shown in SEQ ID NO:4 and a modification pattern as shown in 3-8-3;

[0397] (5) Having a nucleotide sequence as shown in SEQ ID NO:5 and a modification pattern as shown in 2-8-3;

[0398] (6) Having a nucleotide sequence as shown in SEQ ID NO:6 and a modification pattern as shown in 2-8-2;

[0399] (7) Having a nucleotide sequence as shown in SEQ ID NO:7 and a modification pattern as shown in 2-8-2;

[0400] (8) Having a nucleotide sequence as shown in SEQ ID NO:8 and a modification pattern as shown in 2-8-2;

[0401] (9) Having a nucleotide sequence as shown in SEQ ID NO:9 and a modification pattern as shown in 2-8-3;

[0402] (10) Having a nucleotide sequence as shown in SEQ ID NO:10 and a modification pattern as shown in 2-8-2;

[0403] (11) Having a nucleotide sequence as shown in SEQ ID NO:11 and a modification pattern as shown in 2-8-2;

[0404] (12) Having a nucleotide sequence as shown in SEQ ID NO:12 and a modification pattern as shown in 2-8-3;

[0405] (13) Having a nucleotide sequence as shown in SEQ ID NO:13 and a modification pattern as shown in 2-8-2;

[0406] (14) Having a nucleotide sequence as shown in SEQ ID NO:14 and a modification pattern as shown in 3-8-3;

[0407] (15) Having a nucleotide sequence as shown in SEQ ID NO:15 and a modification pattern as shown in 2-8-3;

[0408] (16) Having a nucleotide sequence as shown in SEQ ID NO:16 and a modification pattern as shown in 2-8-2;

[0409] (17) Having a nucleotide sequence as shown in SEQ ID NO:17 and a modification pattern as shown in 2-8-2;

[0410] (18) Having a nucleotide sequence as shown in SEQ ID NO:18 and a modification pattern as shown in 2-8-3;

[0411] (19) Having a nucleotide sequence as shown in SEQ ID NO:19 and a modification pattern as shown in 2-8-2;

[0412] (20) Having a nucleotide sequence as shown in SEQ ID NO:20 and a modification pattern as shown in 3-8-3;

[0413] (21) Having a nucleotide sequence as shown in SEQ ID NO:21 and a modification pattern as shown in 2-8-3;

[0414] (22) Having a nucleotide sequence as shown in SEQ ID NO:22 and a modification pattern as shown in 2-8-2;

[0415] (23) Having a nucleotide sequence as shown in SEQ ID NO:23 and a modification pattern as shown in 3-9-3;

[0416] (24) Having a nucleotide sequence as shown in SEQ ID NO:24 and a modification pattern as shown in 3-8-3;

[0417] (25) Having a nucleotide sequence as shown in SEQ ID NO:25 and a modification pattern as shown in 2-8-3;

[0418] (26) Having a nucleotide sequence as shown in SEQ ID NO:26 and a modification pattern as shown in 2-8-2;

[0419] (27) Having a nucleotide sequence as shown in SEQ ID NO:27 and a modification pattern as shown in 3-10-3;

[0420] (28) Having a nucleotide sequence as shown in SEQ ID NO:28 and a modification pattern as shown in 3-9-3;

[0421] (29) Having a nucleotide sequence as shown in SEQ ID NO:29 and a modification pattern as shown in 3-8-3;

[0422] (30) Having a nucleotide sequence as shown in SEQ ID NO:30 and a modification pattern as shown in 2-8-3;

[0423] (31) Having a nucleotide sequence as shown in SEQ ID NO:31 and a modification pattern as shown in 2-8-2;

[0424] (32) Having a nucleotide sequence as shown in SEQ ID NO:32 and a modification pattern as shown in 3-10-3;

[0425] (33) Having a nucleotide sequence as shown in SEQ ID NO:33 and a modification pattern as shown in 3-9-3;

[0426] (34) Having a nucleotide sequence as shown in SEQ ID NO:34 and a modification pattern as shown in 3-8-3;

[0427] (35) Having a nucleotide sequence as shown in SEQ ID NO:35 and a modification pattern as shown in 2-8-3;

[0428] (36) Having a nucleotide sequence as shown in SEQ ID NO:36 and a modification pattern as shown in 2-8-2;

[0429] (37) Having a nucleotide sequence as shown in SEQ ID NO:37 and a modification pattern as shown in 3-9-3;

[0430] (38) Having a nucleotide sequence as shown in SEQ ID NO:38 and a modification pattern as shown in 3-8-3;

[0431] (39) Having a nucleotide sequence as shown in SEQ ID NO:39 and a modification pattern as shown in 2-8-3;

[0432] (40) Having a nucleotide sequence as shown in SEQ ID NO:40 and a modification pattern as shown in 2-8-2;

[0433] (41) Having a nucleotide sequence as shown in SEQ ID NO:41 and a modification pattern as shown in 3-10-3;

[0434] (42) Having a nucleotide sequence as shown in SEQ ID NO:42 and a modification pattern as shown in 3-9-3;

[0435] (43) Having a nucleotide sequence as shown in SEQ ID NO:43 and a modification pattern as shown in 3-8-3;

[0436] (44) Having a nucleotide sequence as shown in SEQ ID NO:44 and a modification pattern as shown in 2-8-3;

[0437] (45) Having a nucleotide sequence as shown in SEQ ID NO:45 and a modification pattern as shown in 2-8-2;

[0438] (46) Having a nucleotide sequence as shown in SEQ ID NO:46 and a modification pattern as shown in 3-10-3;

[0439] (47) Having a nucleotide sequence as shown in SEQ ID NO:47 and a modification pattern as shown in 3-9-3;

[0440] (48) Having a nucleotide sequence as shown in SEQ ID NO:48 and a modification pattern as shown in 3-8-3;

[0441] (49) Having a nucleotide sequence as shown in SEQ ID NO:49 and a modification pattern as shown in 2-8-3;

[0442] (50) Having a nucleotide sequence as shown in SEQ ID NO:50 and a modification pattern as shown in 2-8-2;

[0443] (51) Having a nucleotide sequence as shown in SEQ ID NO:51 and a modification pattern as shown in 3-10-3;

[0444] (52) Having a nucleotide sequence as shown in SEQ ID NO:52 and a modification pattern as shown in 3-9-3;

[0445] (53) Having a nucleotide sequence as shown in SEQ ID NO:53 and a modification pattern as shown in 3-8-3;

[0446] (54) Having a nucleotide sequence as shown in SEQ ID NO:54 and a modification pattern as shown in 2-8-3;

[0447] (55) Having a nucleotide sequence as shown in SEQ ID NO:55 and a modification pattern as shown in 2-8-2;

[0448] (56) Having a nucleotide sequence as shown in SEQ ID NO:56 and a modification pattern as shown in 3-10-3;

[0449] (57) Having a nucleotide sequence as shown in SEQ ID NO:57 and a modification pattern as shown in 3-9-3;

[0450] (58) Having a nucleotide sequence as shown in SEQ ID NO:58 and a modification pattern as shown in 3-8-3;

[0451] (59) Having a nucleotide sequence as shown in SEQ ID NO:59 and a modification pattern as shown in 2-8-3;

[0452] (60) Having a nucleotide sequence as shown in SEQ ID NO:60 and a modification pattern as shown in 2-8-2;

[0453] (61) Having a nucleotide sequence as shown in SEQ ID NO:61 and a modification pattern as shown in 3-10-3;

[0454] (62) Having a nucleotide sequence as shown in SEQ ID NO:62 and a modification pattern as shown in 3-9-3;

[0455] (63) Having a nucleotide sequence as shown in SEQ ID NO:63 and a modification pattern as shown in 3-8-3;

[0456] (64) Having a nucleotide sequence as shown in SEQ ID NO:64 and a modification pattern as shown in 2-8-3;

[0457] (65) Having a nucleotide sequence as shown in SEQ ID NO:65 and a modification pattern as shown in 2-8-2;

[0458] (66) Having a nucleotide sequence as shown in SEQ ID NO:66 and a modification pattern as shown in 3-10-3;

[0459] (67) Having a nucleotide sequence as shown in SEQ ID NO:67 and a modification pattern as shown in 3-9-3;

[0460] (68) Having a nucleotide sequence as shown in SEQ ID NO:68 and a modification pattern as shown in 3-8-3;

[0461] (69) Having a nucleotide sequence as shown in SEQ ID NO:69 and a modification pattern as shown in 2-8-3;

[0462] (70) Having a nucleotide sequence as shown in SEQ ID NO:70 and a modification pattern as shown in 2-8-2;

[0463] (71) Having a nucleotide sequence as shown in SEQ ID NO:71 and a modification pattern as shown in 2-8-2;

[0464] (72) Having a nucleotide sequence as shown in SEQ ID NO:72 and a modification pattern as shown in 2-8-3;

[0465] (73) Having a nucleotide sequence as shown in SEQ ID NO:73 and a modification pattern as shown in 2-8-2;

[0466] (74) Having a nucleotide sequence as shown in SEQ ID NO:74 and a modification pattern as shown in 3-8-3;

[0467] (75) Having a nucleotide sequence as shown in SEQ ID NO:75 and a modification pattern as shown in 2-8-3;

[0468] (76) Having a nucleotide sequence as shown in SEQ ID NO:76 and a modification pattern as shown in 2-8-2;

[0469] (77) Having a nucleotide sequence as shown in SEQ ID NO:77 and a modification pattern as shown in 2-8-2;

[0470] (78) Having a nucleotide sequence as shown in SEQ ID NO:78 and a modification pattern as shown in 2-8-3;

[0471] (79) Having a nucleotide sequence as shown in SEQ ID NO:79 and a modification pattern as shown in 2-8-2;

[0472] (80) Having a nucleotide sequence as shown in SEQ ID NO:80 and a modification pattern as shown in 3-8-3;

[0473] (81) Having a nucleotide sequence as shown in SEQ ID NO:81 and a modification pattern as shown in 2-8-3;

[0474] (82) Having a nucleotide sequence as shown in SEQ ID NO:82 and a modification pattern as shown in 2-8-2;

[0475] (83) Having a nucleotide sequence as shown in SEQ ID NO:83 and a modification pattern as shown in 3-9-3;

[0476] (84) Having a nucleotide sequence as shown in SEQ ID NO:84 and a modification pattern as shown in 3-8-3;

[0477] (85) Having a nucleotide sequence as shown in SEQ ID NO:85 and a modification pattern as shown in 2-8-3;

[0478] (86) Having a nucleotide sequence as shown in SEQ ID NO:86 and a modification pattern as shown in 2-8-2;

[0479] (87) Having a nucleotide sequence as shown in SEQ ID NO:87 and a modification pattern as shown in 3-10-3;

[0480] (88) Having a nucleotide sequence as shown in SEQ ID NO:88 and a modification pattern as shown in 3-9-3;

[0481] (89) Having a nucleotide sequence as shown in SEQ ID NO:89 and a modification pattern as shown in 3-8-3;

[0482] (90) Having a nucleotide sequence as shown in SEQ ID NO:90 and a modification pattern as shown in 2-8-3;

[0483] (91) Having a nucleotide sequence as shown in SEQ ID NO:91 and a modification pattern as shown in 2-8-2;

[0484] (92) Having a nucleotide sequence as shown in SEQ ID NO:92 and a modification pattern as shown in 3-10-3;

[0485] (93) Having a nucleotide sequence as shown in SEQ ID NO:93 and a modification pattern as shown in 3-9-3;

[0486] (94) Having a nucleotide sequence as shown in SEQ ID NO:94 and a modification pattern as shown in 3-8-3;

[0487] (95) Having a nucleotide sequence as shown in SEQ ID NO:95 and a modification pattern as shown in 2-8-3;

[0488] (96) Having a nucleotide sequence as shown in SEQ ID NO:96 and a modification pattern as shown in 2-8-2;

[0489] (97) Having a nucleotide sequence as shown in SEQ ID NO:97 and a modification pattern as shown in 3-10-3;

[0490] (98) Having a nucleotide sequence as shown in SEQ ID NO:98 and a modification pattern as shown in 3-9-3;

[0491] (99) has the nucleotide sequence shown in SEQ ID NO:99 and the modification pattern shown in 3-8-3;

[0492] (100) has the nucleotide sequence shown in SEQ ID NO:100 and the modification pattern shown in 2-8-3;

[0493] (101) has the nucleotide sequence shown in SEQ ID NO:101 and the modification pattern shown in 2-8-2;

[0494] (102) Having a nucleotide sequence as shown in SEQ ID NO:102 and a modification pattern as shown in 3-10-3;

[0495] (103) has the nucleotide sequence shown in SEQ ID NO:103 and the modification pattern shown in 3-9-3;

[0496] (104) has the nucleotide sequence shown in SEQ ID NO:104 and the modification pattern shown in 3-8-3;

[0497] (105) has the nucleotide sequence shown in SEQ ID NO:105 and the modification pattern shown in 2-8-3;

[0498] (106) has the nucleotide sequence shown in SEQ ID NO:106 and the modification pattern shown in 2-8-2;

[0499] (107) has the nucleotide sequence shown in SEQ ID NO:107 and the modification pattern shown in 3-10-3;

[0500] (108) has the nucleotide sequence shown in SEQ ID NO:108 and the modification pattern shown in 3-9-3;

[0501] (109) has the nucleotide sequence shown in SEQ ID NO:109 and the modification pattern shown in 3-8-3;

[0502] (110) has the nucleotide sequence shown in SEQ ID NO:110 and the modification pattern shown in 2-8-3;

[0503] (111) has the nucleotide sequence shown in SEQ ID NO:111 and the modification pattern shown in 2-8-2;

[0504] (112) Having a nucleotide sequence as shown in SEQ ID NO:112 and a modification pattern as shown in 3-10-3;

[0505] (113) Having a nucleotide sequence as shown in SEQ ID NO:113 and a modification pattern as shown in 3-9-3;

[0506] (114) Having the nucleotide sequence shown in SEQ ID NO:114 and the modification pattern shown in 3-8-3;

[0507] (115) has the nucleotide sequence shown in SEQ ID NO:115 and the modification pattern shown in 2-8-3;

[0508] (116) has the nucleotide sequence shown in SEQ ID NO:116 and the modification pattern shown in 2-8-2;

[0509] (117) Having the nucleotide sequence shown in SEQ ID NO:117 and the modification pattern shown in 2-8-2;

[0510] (118) Having the nucleotide sequence shown in SEQ ID NO:118 and the modification pattern shown in 3-9-3;

[0511] (119) has the nucleotide sequence shown in SEQ ID NO:119 and the modification pattern shown in 3-8-3;

[0512] (120) has the nucleotide sequence shown in SEQ ID NO:120 and the modification pattern shown in 2-8-3;

[0513] (121) Having the nucleotide sequence shown in SEQ ID NO:121 and the modification pattern shown in 2-8-2;

[0514] (122) has the nucleotide sequence shown in SEQ ID NO:122 and the modification pattern shown in 3-10-3;

[0515] (123) has the nucleotide sequence shown in SEQ ID NO:123 and the modification pattern shown in 3-9-3;

[0516] (124) has the nucleotide sequence shown in SEQ ID NO:124 and the modification pattern shown in 3-8-3;

[0517] (125) has the nucleotide sequence shown in SEQ ID NO:125 and the modification pattern shown in 2-8-3;

[0518] (126) has the nucleotide sequence shown in SEQ ID NO:126 and the modification pattern shown in 2-8-2;

[0519] (127) Having a nucleotide sequence as shown in SEQ ID NO:127 and a modification pattern as shown in 3-10-3;

[0520] (128) has the nucleotide sequence shown in SEQ ID NO:128 and the modification pattern shown in 3-9-3;

[0521] (129) has the nucleotide sequence shown in SEQ ID NO:129 and the modification pattern shown in 3-8-3;

[0522] (130) has the nucleotide sequence shown in SEQ ID NO:130 and the modification pattern shown in 2-8-3;

[0523] (131) Having the nucleotide sequence shown in SEQ ID NO:131 and the modification pattern shown in 2-8-2;

[0524] (132) Having a nucleotide sequence as shown in SEQ ID NO:132 and a modification pattern as shown in 3-10-3;

[0525] (133) has the nucleotide sequence shown in SEQ ID NO:133 and the modification pattern shown in 3-9-3;

[0526] (134) has the nucleotide sequence shown in SEQ ID NO:134 and the modification pattern shown in 3-8-3;

[0527] (135) has the nucleotide sequence shown in SEQ ID NO:135 and the modification pattern shown in 2-8-3;

[0528] (136) has the nucleotide sequence shown in SEQ ID NO:136 and the modification pattern shown in 2-8-2;

[0529] (137) has the nucleotide sequence shown in SEQ ID NO:137 and the modification pattern shown in 2-8-2;

[0530] (138) has the nucleotide sequence shown in SEQ ID NO:138 and the modification pattern shown in 2-8-3;

[0531] (139) has the nucleotide sequence shown in SEQ ID NO:139 and the modification pattern shown in 2-8-2;

[0532] (140) has the nucleotide sequence shown in SEQ ID NO:140 and the modification pattern shown in 3-8-3;

[0533] (141) Having the nucleotide sequence shown in SEQ ID NO:141 and the modification pattern shown in 2-8-3;

[0534] (142) Having a nucleotide sequence as shown in SEQ ID NO:142 and a modification pattern as shown in 2-8-2;

[0535] (143) Having the nucleotide sequence shown in SEQ ID NO:143 and the modification pattern shown in 3-9-3;

[0536] (144) has the nucleotide sequence shown in SEQ ID NO:144 and the modification pattern shown in 3-8-3;

[0537] (145) has the nucleotide sequence shown in SEQ ID NO:145 and the modification pattern shown in 2-8-3;

[0538] (146) has the nucleotide sequence shown in SEQ ID NO:146 and the modification pattern shown in 2-8-2;

[0539] (147) Having a nucleotide sequence as shown in SEQ ID NO:147 and a modification pattern as shown in 3-10-3;

[0540] (148) Having the nucleotide sequence shown in SEQ ID NO:148 and the modification pattern shown in 3-9-3;

[0541] (149) has the nucleotide sequence shown in SEQ ID NO:149 and the modification pattern shown in 3-8-3;

[0542] (150) has the nucleotide sequence shown in SEQ ID NO:150 and the modification pattern shown in 2-8-3;

[0543] (151) Having a nucleotide sequence as shown in SEQ ID NO:151 and a modification pattern as shown in 2-8-2;

[0544] (152) Having a nucleotide sequence as shown in SEQ ID NO:152 and a modification pattern as shown in 3-10-3;

[0545] (153) has the nucleotide sequence shown in SEQ ID NO:153 and the modification pattern shown in 3-9-3;

[0546] (154) has the nucleotide sequence shown in SEQ ID NO:154 and the modification pattern shown in 3-8-3;

[0547] (155) has the nucleotide sequence shown in SEQ ID NO:155 and the modification pattern shown in 2-8-3;

[0548] (156) has the nucleotide sequence shown in SEQ ID NO:156 and the modification pattern shown in 2-8-2;

[0549] (157) has the nucleotide sequence shown in SEQ ID NO:157 and the modification pattern shown in 2-8-2;

[0550] (158) has the nucleotide sequence shown in SEQ ID NO:158 and the modification pattern shown in 2-8-2;

[0551] (159) has the nucleotide sequence shown in SEQ ID NO:159 and the modification pattern shown in 2-8-3;

[0552] (160) has the nucleotide sequence shown in SEQ ID NO:160 and the modification pattern shown in 2-8-2;

[0553] (161) Having the nucleotide sequence shown in SEQ ID NO:161 and the modification pattern shown in 2-8-2;

[0554] (162) has the nucleotide sequence shown in SEQ ID NO:162 and the modification pattern shown in 2-8-3;

[0555] (163) has the nucleotide sequence shown in SEQ ID NO:163 and the modification pattern shown in 2-8-2;

[0556] (164) has the nucleotide sequence shown in SEQ ID NO:164 and the modification pattern shown in 3-8-3;

[0557] (165) Having the nucleotide sequence shown in SEQ ID NO:165 and the modification pattern shown in 2-8-3; or

[0558] (166) has the nucleotide sequence shown in SEQ ID NO:166 and the modification pattern shown in 2-8-2;

[0559] In the modified pattern, the first number represents the number of nucleotides in the 5' wing region, the second number represents the number of nucleotides in the spacer region, and the third number represents the number of nucleotides in the 3' wing region.

[0560] In some embodiments, the antisense nucleotide sequence is selected from any of the following modified sequences:

[0561] (1) It has the nucleotide sequence shown in SEQ ID NO:1 and the modification pattern shown in 2-8-2;

[0562] (2) It has the nucleotide sequence shown in SEQ ID NO:2 and the modification pattern shown in 2-8-3;

[0563] (3) It has a nucleotide sequence as shown in SEQ ID NO:3 and a modification pattern as shown in 2-8-2;

[0564] (4) Having a nucleotide sequence as shown in SEQ ID NO:4 and a modification pattern as shown in 3-8-3;

[0565] (5) Having a nucleotide sequence as shown in SEQ ID NO:5 and a modification pattern as shown in 2-8-3;

[0566] (6) Having a nucleotide sequence as shown in SEQ ID NO:6 and a modification pattern as shown in 2-8-2;

[0567] (7) Having a nucleotide sequence as shown in SEQ ID NO:7 and a modification pattern as shown in 2-8-2;

[0568] (8) Having a nucleotide sequence as shown in SEQ ID NO:12 and a modification pattern as shown in 2-8-3;

[0569] (9) Having a nucleotide sequence as shown in SEQ ID NO:13 and a modification pattern as shown in 2-8-2;

[0570] (10) Having a nucleotide sequence as shown in SEQ ID NO:28 and a modification pattern as shown in 3-9-3;

[0571] (11) Having a nucleotide sequence as shown in SEQ ID NO:29 and a modification pattern as shown in 3-8-3;

[0572] (12) Having a nucleotide sequence as shown in SEQ ID NO:30 and a modification pattern as shown in 2-8-3;

[0573] (13) Having a nucleotide sequence as shown in SEQ ID NO:32 and a modification pattern as shown in 3-10-3;

[0574] (14) Having a nucleotide sequence as shown in SEQ ID NO:33 and a modification pattern as shown in 3-9-3;

[0575] (15) Having a nucleotide sequence as shown in SEQ ID NO:34 and a modification pattern as shown in 3-8-3;

[0576] (16) Having a nucleotide sequence as shown in SEQ ID NO:51 and a modification pattern as shown in 3-10-3;

[0577] (17) Having a nucleotide sequence as shown in SEQ ID NO:52 and a modification pattern as shown in 3-9-3;

[0578] (18) Having a nucleotide sequence as shown in SEQ ID NO:53 and a modification pattern as shown in 3-8-3;

[0579] (19) Having a nucleotide sequence as shown in SEQ ID NO:54 and a modification pattern as shown in 2-8-3;

[0580] (20) Having a nucleotide sequence as shown in SEQ ID NO:55 and a modification pattern as shown in 2-8-2;

[0581] (21) Having a nucleotide sequence as shown in SEQ ID NO:56 and a modification pattern as shown in 3-10-3;

[0582] (22) Having a nucleotide sequence as shown in SEQ ID NO:57 and a modification pattern as shown in 3-9-3;

[0583] (23) Having a nucleotide sequence as shown in SEQ ID NO:58 and a modification pattern as shown in 3-8-3;

[0584] (24) Having a nucleotide sequence as shown in SEQ ID NO:59 and a modification pattern as shown in 2-8-3;

[0585] (25) Having a nucleotide sequence as shown in SEQ ID NO:60 and a modification pattern as shown in 2-8-2;

[0586] (26) Having a nucleotide sequence as shown in SEQ ID NO:66 and a modification pattern as shown in 3-10-3;

[0587] (27) Having a nucleotide sequence as shown in SEQ ID NO:67 and a modification pattern as shown in 3-9-3;

[0588] (28) Having a nucleotide sequence as shown in SEQ ID NO:68 and a modification pattern as shown in 3-8-3;

[0589] (29) Having a nucleotide sequence as shown in SEQ ID NO:69 and a modification pattern as shown in 2-8-3;

[0590] (30) Having a nucleotide sequence as shown in SEQ ID NO:70 and a modification pattern as shown in 2-8-2;

[0591] (31) Having a nucleotide sequence as shown in SEQ ID NO:74 and a modification pattern as shown in 3-8-3;

[0592] (32) Having a nucleotide sequence as shown in SEQ ID NO:92 and a modification pattern as shown in 3-10-3;

[0593] (33) Having a nucleotide sequence as shown in SEQ ID NO:93 and a modification pattern as shown in 3-9-3;

[0594] (34) Having a nucleotide sequence as shown in SEQ ID NO:94 and a modification pattern as shown in 3-8-3;

[0595] (35) Having a nucleotide sequence as shown in SEQ ID NO:95 and a modification pattern as shown in 2-8-3;

[0596] (36) Having a nucleotide sequence as shown in SEQ ID NO:96 and a modification pattern as shown in 2-8-2;

[0597] (37) Having a nucleotide sequence as shown in SEQ ID NO:97 and a modification pattern as shown in 3-10-3;

[0598] (38) Having a nucleotide sequence as shown in SEQ ID NO:101 and a modification pattern as shown in 2-8-2;

[0599] (39) Having a nucleotide sequence as shown in SEQ ID NO:106 and a modification pattern as shown in 2-8-2;

[0600] (40) Having a nucleotide sequence as shown in SEQ ID NO:109 and a modification pattern as shown in 3-8-3;

[0601] (41) Having a nucleotide sequence as shown in SEQ ID NO:110 and a modification pattern as shown in 2-8-3;

[0602] (42) Having a nucleotide sequence as shown in SEQ ID NO:111 and a modification pattern as shown in 2-8-2;

[0603] (43) Having a nucleotide sequence as shown in SEQ ID NO:114 and a modification pattern as shown in 3-8-3;

[0604] (44) Having a nucleotide sequence as shown in SEQ ID NO:116 and a modification pattern as shown in 2-8-2;

[0605] (45) Having a nucleotide sequence as shown in SEQ ID NO:118 and a modification pattern as shown in 3-9-3;

[0606] (46) Having a nucleotide sequence as shown in SEQ ID NO:119 and a modification pattern as shown in 3-8-3;

[0607] (47) Having a nucleotide sequence as shown in SEQ ID NO:122 and a modification pattern as shown in 3-10-3;

[0608] (48) Having a nucleotide sequence as shown in SEQ ID NO:123 and a modification pattern as shown in 3-9-3;

[0609] (49) Having a nucleotide sequence as shown in SEQ ID NO:124 and a modification pattern as shown in 3-8-3;

[0610] (50) Having a nucleotide sequence as shown in SEQ ID NO:125 and a modification pattern as shown in 2-8-3;

[0611] (51) Having a nucleotide sequence as shown in SEQ ID NO:127 and a modification pattern as shown in 3-10-3;

[0612] (52) Having a nucleotide sequence as shown in SEQ ID NO:128 and a modification pattern as shown in 3-9-3;

[0613] (53) Having a nucleotide sequence as shown in SEQ ID NO:129 and a modification pattern as shown in 3-8-3;

[0614] (54) Having a nucleotide sequence as shown in SEQ ID NO:157 and a modification pattern as shown in 2-8-2; or

[0615] (55) Having a nucleotide sequence as shown in SEQ ID NO:158 and a modification pattern as shown in 2-8-2;

[0616] In the modified pattern, the first number represents the number of nucleotides in the 5' wing region, the second number represents the number of nucleotides in the spacer region, and the third number represents the number of nucleotides in the 3' wing region.

[0617] In some embodiments, the antisense nucleotide sequence is selected from any of the following modified sequences:

[0618] (1) It has the nucleotide sequence shown in SEQ ID NO:1 and the modification pattern shown in 2-8-2;

[0619] (2) It has a nucleotide sequence as shown in SEQ ID NO:12 and a modification pattern as shown in 2-8-3;

[0620] (3) It has a nucleotide sequence as shown in SEQ ID NO:13 and a modification pattern as shown in 2-8-2;

[0621] (4) Having a nucleotide sequence as shown in SEQ ID NO:51 and a modification pattern as shown in 3-10-3;

[0622] (5) Having a nucleotide sequence as shown in SEQ ID NO:53 and a modification pattern as shown in 3-8-3;

[0623] (6) Having a nucleotide sequence as shown in SEQ ID NO:54 and a modification pattern as shown in 2-8-3;

[0624] (7) Having a nucleotide sequence as shown in SEQ ID NO:56 and a modification pattern as shown in 3-10-3;

[0625] (8) Having a nucleotide sequence as shown in SEQ ID NO:58 and a modification pattern as shown in 3-8-3;

[0626] (9) Having a nucleotide sequence as shown in SEQ ID NO:59 and a modification pattern as shown in 2-8-3;

[0627] (10) Having a nucleotide sequence as shown in SEQ ID NO:60 and a modification pattern as shown in 2-8-2;

[0628] (11) Having a nucleotide sequence as shown in SEQ ID NO:66 and a modification pattern as shown in 3-10-3;

[0629] (12) Having a nucleotide sequence as shown in SEQ ID NO:67 and a modification pattern as shown in 3-9-3;

[0630] (13) Having a nucleotide sequence as shown in SEQ ID NO:68 and a modification pattern as shown in 3-8-3;

[0631] (14) Having a nucleotide sequence as shown in SEQ ID NO:69 and a modification pattern as shown in 2-8-3;

[0632] (15) Having a nucleotide sequence as shown in SEQ ID NO:74 and a modification pattern as shown in 3-8-3;

[0633] (16) Having a nucleotide sequence as shown in SEQ ID NO:106 and a modification pattern as shown in 2-8-2;

[0634] (17) Having a nucleotide sequence as shown in SEQ ID NO:109 and a modification pattern as shown in 3-8-3;

[0635] (18) Having a nucleotide sequence as shown in SEQ ID NO:110 and a modification pattern as shown in 2-8-3;

[0636] (19) Having a nucleotide sequence as shown in SEQ ID NO:111 and a modification pattern as shown in 2-8-2;

[0637] (20) Having a nucleotide sequence as shown in SEQ ID NO:116 and a modification pattern as shown in 2-8-2;

[0638] (21) Having a nucleotide sequence as shown in SEQ ID NO:118 and a modification pattern as shown in 3-9-3;

[0639] (22) Having a nucleotide sequence as shown in SEQ ID NO:119 and a modification pattern as shown in 3-8-3;

[0640] (23) Having a nucleotide sequence as shown in SEQ ID NO:122 and a modification pattern as shown in 3-10-3;

[0641] (24) Having a nucleotide sequence as shown in SEQ ID NO:123 and a modification pattern as shown in 3-9-3;

[0642] (25) Having a nucleotide sequence as shown in SEQ ID NO:124 and a modification pattern as shown in 3-8-3;

[0643] (26) Having a nucleotide sequence as shown in SEQ ID NO:125 and a modification pattern as shown in 2-8-3;

[0644] (27) Having a nucleotide sequence as shown in SEQ ID NO:127 and a modification pattern as shown in 3-10-3; or

[0645] (28) Having a nucleotide sequence as shown in SEQ ID NO:128 and a modification pattern as shown in 3-9-3;

[0646] In the modified pattern, the first number represents the number of nucleotides in the 5' wing region, the second number represents the number of nucleotides in the spacer region, and the third number represents the number of nucleotides in the 3' wing region.

[0647] In some embodiments, the nucleotides in the 5' and 3' wings of the modified pattern are LNA nucleotides or cEt nucleotides.

[0648] In some embodiments, the antisense oligonucleotide is selected from any of the following combinations of modifications:

[0649] (1)LNA-(5m)C* / LNA-A* / dT* / dG* / dG* / dT* / dG* / dA* / dA* / dG* / LNA-A* / LNA-G(SEQ ID NO.169);

[0650] (2)LNA-(5m)C* / LNA-(5m)C* / dA* / dT* / dG* / dG* / dT* / dG* / dA* / dA* / LNA-G* / LNA-A* / LNA-G(SEQ ID NO.170);

[0651] (3)LNA-(5m)C* / LNA-(5m)C* / dA* / dT* / dG* / dG* / dT* / dG* / dA* / dA* / LNA-G* / LNA-A(SEQ ID NO.171);

[0652] (4)LNA-T* / LNA-(5m)C* / LNA-(5m)C* / dA* / dT* / dG* / dG* / dT* / dG* / dA* / dA* / LNA-G* / LNA-A* / LNA-G(SEQ ID NO.172);

[0653] (5)LNA-T* / LNA-(5m)C* / d(5m)C* / dA* / dT* / dG* / dG* / dT* / dG* / dA* / LNA-A* / LNA-G* / LNA-A(SEQ ID NO.173);

[0654] (6)LNA-T* / LNA-(5m)C* / d(5m)C* / dA* / dT* / dG* / dG* / dT* / dG* / dA* / LNA-A* / LNA-G(SEQ ID NO.174);

[0655] (7)LNA-(5m)C* / LNA-(5m)C* / dT* / dG* / d(5m)C* / d(5m)C* / dA* / dG* / dG* / dA* / LNA-A* / LNA-G(SEQ ID NO.175);

[0656] (8)LNA-T* / LNA-G* / dG* / dG* / d(5m)C* / dA* / dT* / dG* / dA* / dG* / LNA-(5m)C* / LNA-T(SEQ ID NO.176);

[0657] (9)LNA-T* / LNA-T* / dG* / dG* / dG* / d(5m)C* / dA* / dT* / dG* / dA* / LNA-G* / LNA-(5m)C* / LNA-T(SEQ ID NO.177);

[0658] (10)LNA-T* / LNA-T* / dG* / dG* / dG* / d(5m)C* / dA* / dT* / dG* / dA* / LNA-G* / LNA-(5m)C(SEQ ID NO.178);

[0659] (11)LNA-G* / LNA-A* / dT* / d(5m)C* / dT* / dT* / dG* / dG* / dT* / dG* / LNA-A* / LNA-A(SEQ ID NO.179);

[0660] (12)LNA-A* / LNA-G* / dA* / dT* / d(5m)C* / dT* / dT* / dG* / dG* / dT* / LNA-G* / LNA-A* / LNA-A(SEQ ID NO.180);

[0661] (13)LNA-A* / LNA-G* / dA* / dT* / d(5m)C* / dT* / dT* / dG* / dG* / dT* / LNA-G* / LNA-A(SEQ ID NO.181);

[0662] (14)LNA-G* / LNA-A* / LNA-G* / dA* / dT* / d(5m)C* / dT* / dT* / dG* / dG* / dT* / LNA-G* / LNA-A* / LNA-A(SEQ ID NO.182);

[0663] (15)LNA-G* / LNA-A* / dG* / dA* / dT* / d(5m)C* / dT* / dT* / dG* / dG* / LNA-T* / LNA-G* / LNA-A(SEQ ID NO.183);

[0664] (16)LNA-G* / LNA-A* / dG* / dA* / dT* / d(5m)C* / dT* / dT* / dG* / dG* / LNA-T* / LNA-G(SEQ ID NO.184);

[0665] (17)LNA-T* / LNA-G* / dA* / dA* / dG* / dA* / dT* / dG* / dG* / dA* / LNA-G* / LNA-G(SEQ ID NO.185);

[0666] (18)LNA-T* / LNA-T* / dG* / dA* / dA* / dG* / dA* / dT* / dG* / dG* / LNA-A* / LNA-G* / LNA-G(SEQ ID NO.186);

[0667] (19)LNA-T* / LNA-T* / dG* / dA* / dA* / dG* / dA* / dT* / dG* / dG* / LNA-A* / LNA-G(SEQ ID NO.187);

[0668] (20)LNA-G* / LNA-T* / LNA-T* / dG* / dA* / dA* / dG* / dA* / dT* / dG* / dG* / LNA-A* / LNA-G* / LNA-G(SEQ ID NO.188);

[0669] (21)LNA-G* / LNA-T* / dT* / dG* / dA* / dA* / dG* / dA* / dT* / dG* / LNA-G* / LNA-A* / LNA-G(SEQ ID NO.189);

[0670] (22)LNA-G* / LNA-T* / dT* / dG* / dA* / dA* / dG* / dA* / dT* / dG* / LNA-G* / LNA-A(SEQ ID NO.190);

[0671] (23)LNA-T* / LNA-G* / LNA-T* / dT* / dG* / dA* / dA* / dG* / dA* / dT* / dG* / dG* / LNA-A* / LNA-G* / LNA-G(SEQ ID NO.191);

[0672] (24)LNA-T* / LNA-G* / LNA-T* / dT* / dG* / dA* / dA* / dG* / dA* / dT* / dG* / LNA-G* / LNA-A* / LNA-G(SEQ ID NO.192);

[0673] (25)LNA-T* / LNA-G* / dT* / dT* / dG* / dA* / dA* / dG* / dA* / dT* / LNA-G* / LNA-G* / LNA-A(SEQ ID NO.193);

[0674] (26)LNA-T* / LNA-G* / dT* / dT* / dG* / dA* / dA* / dG* / dA* / dT* / LNA-G* / LNA-G(SEQ ID NO.194);

[0675] (27)LNA-(5m)C* / LNA-T* / LNA-G* / dT* / dT* / dG* / dA* / dA* / dG* / dA* / dT* / dG* / dG* / LNA-A* / LNA-G* / LNA-G(SEQ ID NO.195);

[0676] (28)LNA-(5m)C* / LNA-T* / LNA-G* / dT* / dT* / dG* / dA* / dA* / dG* / dA* / dT* / dG* / LNA-G* / LNA-A* / LNA-G(SEQ ID NO.196);

[0677] (29)LNA-(5m)C* / LNA-T* / LNA-G* / dT* / dT* / dG* / dA* / dA* / dG* / dA* / dT* / LNA-G* / LNA-G* / LNA-A(SEQ ID NO.197);

[0678] (30)LNA-(5m)C* / LNA-T* / dG* / dT* / dT* / dG* / dA* / dA* / dG* / dA* / LNA-T* / LNA-G* / LNA-G(SEQ ID NO.198);

[0679] (31)LNA-(5m)C* / LNA-T* / dG* / dT* / dT* / dG* / dA* / dA* / dG* / dA* / LNA-T* / LNA-G(SEQ ID NO.199);

[0680] (32)LNA-G* / LNA-(5m)C* / LNA-T* / dG* / dT* / dT* / dG* / dA* / dA* / dG* / dA* / dT* / dG* / LNA-G* / LNA-A* / LNA-G(SEQ ID NO.200);

[0681] (33)LNA-G* / LNA-(5m)C* / LNA-T* / dG* / dT* / dT* / dG* / dA* / dA* / dG* / dA* / dT* / LNA-G* / LNA-G* / LNA-A(SEQ ID NO.201);

[0682] (34)LNA-G* / LNA-(5m)C* / LNA-T* / dG* / dT* / dT* / dG* / dA* / dA* / dG* / dA* / LNA-T* / LNA-G* / LNA-G(SEQ ID NO.202);

[0683] (35)LNA-G* / LNA-(5m)C* / dT* / dG* / dT* / dT* / dG* / dA* / dA* / dG* / LNA-A* / LNA-T* / LNA-G(SEQ ID NO.203);

[0684] (36)LNA-G* / LNA-(5m)C* / dT* / dG* / dT* / dT* / dG* / dA* / dA* / dG* / LNA-A* / LNA-T(SEQ ID NO.204);

[0685] (37)LNA-G* / LNA-T* / LNA-(5m)C* / d(5m)C* / dA* / dT* / dG* / dG* / dT* / dG* / dA* / dA* / LNA-G* / LNA-A* / LNA-G(SEQ ID NO.205);

[0686] (38)LNA-G* / LNA-T* / LNA-(5m)C* / d(5m)C* / dA* / dT* / dG* / dG* / dT* / dG* / dA* / LNA-A* / LNA-G* / LNA-A(SEQ ID NO.206);

[0687] (39)LNA-G* / LNA-T* / d(5m)C* / d(5m)C* / dA* / dT* / dG* / dG* / dT* / dG* / LNA-A* / LNA-A* / LNA-G(SEQ ID NO.207);

[0688] (40)LNA-G* / LNA-T* / d(5m)C* / d(5m)C* / dA* / dT* / dG* / dG* / dT* / dG* / LNA-A* / LNA-A(SEQ ID NO.208);

[0689] (41)LNA-T* / LNA-G* / LNA-T* / d(5m)C* / d(5m)C* / dA* / dT* / dG* / dG* / dT* / dG* / dA* / dA* / LNA-G* / LNA-A* / LNA-G(SEQ ID NO.209);

[0690] (42)LNA-T* / LNA-G* / LNA-T* / d(5m)C* / d(5m)C* / dA* / dT* / dG* / dG* / dT* / dG* / dA* / LNA-A* / LNA-G* / LNA-A(SEQ ID NO.210);

[0691] (43)LNA-T* / LNA-G* / LNA-T* / d(5m)C* / d(5m)C* / dA* / dT* / dG* / dG* / dT* / dG* / LNA-A* / LNA-A* / LNA-G(SEQ ID NO.211);

[0692] (44)LNA-T* / LNA-G* / dT* / d(5m)C* / d(5m)C* / dA* / dT* / dG* / dG* / dT* / LNA-G* / LNA-A* / LNA-A(SEQ ID NO.212);

[0693] (45)LNA-T* / LNA-G* / dT* / d(5m)C* / d(5m)C* / dA* / dT* / dG* / dG* / dT* / LNA-G* / LNA-A(SEQ ID NO.213);

[0694] (46)LNA-A* / LNA-T* / LNA-G* / dT* / d(5m)C* / d(5m)C* / dA* / dT* / dG* / dG* / dT* / dG* / dA* / LNA-A* / LNA-G* / LNA-A(SEQ ID NO.214);

[0695] (47)LNA-A* / LNA-T* / LNA-G* / dT* / d(5m)C* / d(5m)C* / dA* / dT* / dG* / dG* / dT* / dG* / LNA-A* / LNA-A* / LNA-G(SEQ ID NO.215);

[0696] (48)LNA-A* / LNA-T* / LNA-G* / dT* / d(5m)C* / d(5m)C* / dA* / dT* / dG* / dG* / dT* / LNA-G* / LNA-A* / LNA-A(SEQ ID NO.216);

[0697] (49)LNA-A* / LNA-T* / dG* / dT* / d(5m)C* / d(5m)C* / dA* / dT* / dG* / dG* / LNA-T* / LNA-G* / LNA-A(SEQ ID NO.217);

[0698] (50)LNA-A* / LNA-T* / dG* / dT* / d(5m)C* / d(5m)C* / dA* / dT* / dG* / dG* / LNA-T* / LNA-G(SEQ ID NO.218);

[0699] (51)LNA-G* / LNA-A* / LNA-T* / dG* / dT* / d(5m)C* / d(5m)C* / dA* / dT* / dG* / dG* / dT* / dG* / LNA-A* / LNA-A* / LNA-G(SEQ ID NO.219);

[0700] (52)LNA-G* / LNA-A* / LNA-T* / dG* / dT* / d(5m)C* / d(5m)C* / dA* / dT* / dG* / dG* / dT* / LNA-G* / LNA-A* / LNA-A(SEQ ID NO.220);

[0701] (53)LNA-G* / LNA-A* / LNA-T* / dG* / dT* / d(5m)C* / d(5m)C* / dA* / dT* / dG* / dG* / LNA-T* / LNA-G* / LNA-A(SEQ ID NO.221);

[0702] (54)LNA-G* / LNA-A* / dT* / dG* / dT* / d(5m)C* / d(5m)C* / dA* / dT* / dG* / LNA-G* / LNA-T* / LNA-G(SEQ ID NO.222);

[0703] (55)LNA-G* / LNA-A* / dT* / dG* / dT* / d(5m)C* / d(5m)C* / dA* / dT* / dG* / LNA-G* / LNA-T(SEQ ID NO.223);

[0704] (56)LNA-A* / LNA-G* / LNA-A* / dT* / dG* / dT* / d(5m)C* / d(5m)C* / dA* / dT* / dG* / dG* / dT* / LNA-G* / LNA-A* / LNA-A(SEQ ID NO.224);

[0705] (57)LNA-A* / LNA-G* / LNA-A* / dT* / dG* / dT* / d(5m)C* / d(5m)C* / dA* / dT* / dG* / dG* / LNA-T* / LNA-G* / LNA-A(SEQ ID NO.225);

[0706] (58)LNA-A* / LNA-G* / LNA-A* / dT* / dG* / dT* / d(5m)C* / d(5m)C* / dA* / dT* / dG* / LNA-G* / LNA-T* / LNA-G(SEQ ID NO.226);

[0707] (59)LNA-A* / LNA-G* / dA* / dT* / dG* / dT* / d(5m)C* / d(5m)C* / dA* / dT* / LNA-G* / LNA-G* / LNA-T(SEQ ID NO.227);

[0708] (60)LNA-A* / LNA-G* / dA* / dT* / dG* / dT* / d(5m)C* / d(5m)C* / dA* / dT* / LNA-G* / LNA-G(SEQ ID NO.228);

[0709] (61)LNA-T* / LNA-A* / LNA-G* / dA* / dT* / dG* / dT* / d(5m)C* / d(5m)C* / dA* / dT* / dG* / dG* / LNA-T* / LNA-G* / LNA-A(SEQ ID NO.229);

[0710] (62)LNA-T* / LNA-A* / LNA-G* / dA* / dT* / dG* / dT* / d(5m)C* / d(5m)C* / dA* / dT* / dG* / LNA-G* / LNA-T* / LNA-G(SEQ ID NO.230);

[0711] (63)LNA-T* / LNA-A* / LNA-G* / dA* / dT* / dG* / dT* / d(5m)C* / d(5m)C* / dA* / dT* / LNA-G* / LNA-G* / LNA-T(SEQ ID NO.231);

[0712] (64)LNA-T* / LNA-A* / dG* / dA* / dT* / dG* / dT* / d(5m)C* / d(5m)C* / dA* / LNA-T* / LNA-G* / LNA-G(SEQ ID NO.232);

[0713] (65)LNA-T* / LNA-A* / dG* / dA* / dT* / dG* / dT* / d(5m)C* / d(5m)C* / dA* / LNA-T* / LNA-G(SEQ ID NO.233);

[0714] (66)LNA-G* / LNA-T* / LNA-A* / dG* / dA* / dT* / dG* / dT* / d(5m)C* / d(5m)C* / dA* / dT* / dG* / LNA-G* / LNA-T* / LNA-G(SEQ ID NO.234);

[0715] (67)LNA-G* / LNA-T* / LNA-A* / dG* / dA* / dT* / dG* / dT* / d(5m)C* / d(5m)C* / dA* / dT* / LNA-G* / LNA-G* / LNA-T(SEQ ID NO.235);

[0716] (68)LNA-G* / LNA-T* / LNA-A* / dG* / dA* / dT* / dG* / dT* / d(5m)C* / d(5m)C* / dA* / LNA-T* / LNA-G* / LNA-G(SEQ ID NO.236);

[0717] (69)LNA-G* / LNA-T* / dA* / dG* / dA* / dT* / dG* / dT* / d(5m)C* / d(5m)C* / LNA-A* / LNA-T* / LNA-G(SEQ ID NO.237);

[0718] (70)LNA-G* / LNA-T* / dA* / dG* / dA* / dT* / dG* / dT* / d(5m)C* / d(5m)C* / LNA-A* / LNA-T(SEQ ID NO.238);

[0719] (71)LNA-G* / LNA-T* / dA* / dA* / dT* / d(5m)C* / dG* / dA* / dA* / dG* / LNA-A* / LNA-G(SEQ ID NO.239);

[0720] (72)LNA-T* / LNA-G* / dT* / dA* / dA* / dT* / d(5m)C* / dG* / dA* / dA* / LNA-G* / LNA-A* / LNA-G(SEQ ID NO.240);

[0721] (73)LNA-T* / LNA-G* / dT* / dA* / dA* / dT* / d(5m)C* / dG* / dA* / dA* / LNA-G* / LNA-A(SEQ ID NO.241);

[0722] (74)LNA-A* / LNA-T* / LNA-G* / dT* / dA* / dA* / dT* / d(5m)C* / dG* / dA* / dA* / LNA-G* / LNA-A* / LNA-G(SEQ ID NO.242);

[0723] (75)LNA-A* / LNA-T* / dG* / dT* / dA* / dA* / dT* / d(5m)C* / dG* / dA* / LNA-A* / LNA-G* / LNA-A(SEQ ID NO.243);

[0724] (76)LNA-A* / LNA-T* / dG* / dT* / dA* / dA* / dT* / d(5m)C* / dG* / dA* / LNA-A* / LNA-G(SEQ ID NO.244);

[0725] (77)LNA-G* / LNA-(5m)C* / dG* / dG* / d(5m)C* / dT* / dG* / dA* / dT* / d(5m)C* / LNA-A* / LNA-T(SEQ ID NO.245);

[0726] (78)LNA-T* / LNA-G* / d(5m)C* / dG* / dG* / d(5m)C* / dT* / dG* / dA* / dT* / LNA-(5m)C* / LNA-A* / LNA-T(SEQ ID NO.246);

[0727] (79)LNA-T* / LNA-G* / d(5m)C* / dG* / dG* / d(5m)C* / dT* / dG* / dA* / dT* / LNA-(5m)C* / LNA-A(SEQ ID NO.247);

[0728] (80)LNA-A* / LNA-T* / LNA-G* / d(5m)C* / dG* / dG* / d(5m)C* / dT* / dG* / dA* / dT* / LNA-(5m)C* / LNA-A* / LNA-T(SEQ ID NO.248);

[0729] (81)LNA-A* / LNA-T* / dG* / d(5m)C* / dG* / dG* / d(5m)C* / dT* / dG* / dA* / LNA-T* / LNA-(5m)C* / LNA-A(SEQ ID NO.249);

[0730] (82)LNA-A* / LNA-T* / dG* / d(5m)C* / dG* / dG* / d(5m)C* / dT* / dG* / dA* / LNA-T* / LNA-(5m)C(SEQ ID NO.250);

[0731] (83)LNA-A* / LNA-A* / LNA-T* / dG* / d(5m)C* / dG* / dG* / d(5m)C* / dT* / dG* / dA* / dT* / LNA-(5m)C* / LNA-A* / LNA-T(SEQ ID NO.251);

[0732] (84)LNA-A* / LNA-A* / LNA-T* / dG* / d(5m)C* / dG* / dG* / d(5m)C* / dT* / dG* / dA* / LNA-T* / LNA-(5m)C* / LNA-A(SEQ ID NO.252);

[0733] (85)LNA-A* / LNA-A* / dT* / dG* / d(5m)C* / dG* / dG* / d(5m)C* / dT* / dG* / LNA-A* / LNA-T* / LNA-(5m)C(SEQ ID NO.253);

[0734] (86)LNA-A* / LNA-A* / dT* / dG* / d(5m)C* / dG* / dG* / d(5m)C* / dT* / dG* / LNA-A* / LNA-T(SEQ ID NO.254);

[0735] (87)LNA-G* / LNA-A* / LNA-A* / dT* / dG* / d(5m)C* / dG* / dG* / d(5m)C* / dT* / dG* / dA* / dT* / LNA-(5m)C* / LNA-A* / LNA-T(SEQ ID NO.255);

[0736] (88)LNA-G* / LNA-A* / LNA-A* / dT* / dG* / d(5m)C* / dG* / dG* / d(5m)C* / dT* / dG* / dA* / LNA-T* / LNA-(5m)C* / LNA-A(SEQ ID NO.256);

[0737] (89)LNA-G* / LNA-A* / LNA-A* / dT* / dG* / d(5m)C* / dG* / dG* / d(5m)C* / dT* / dG* / LNA-A* / LNA-T* / LNA-(5m)C(SEQ ID NO.257);

[0738] (90)LNA-G* / LNA-A* / dA* / dT* / dG* / d(5m)C* / dG* / dG* / d(5m)C* / dT* / LNA-G* / LNA-A* / LNA-T(SEQ ID NO.258);

[0739] (91)LNA-G* / LNA-A* / dA* / dT* / dG* / d(5m)C* / dG* / dG* / d(5m)C* / dT* / LNA-G* / LNA-A(SEQ ID NO.259);

[0740] (92)LNA-A* / LNA-G* / LNA-A* / dA* / dT* / dG* / d(5m)C* / dG* / dG* / d(5m)C* / dT* / dG* / dA* / LNA-T* / LNA-(5m)C* / LNA-A(SEQ ID NO.260);

[0741] (93)LNA-A* / LNA-G* / LNA-A* / dA* / dT* / dG* / d(5m)C* / dG* / dG* / d(5m)C* / dT* / dG* / LNA-A* / LNA-T* / LNA-(5m)C(SEQ ID NO.261);

[0742] (94)LNA-A* / LNA-G* / LNA-A* / dA* / dT* / dG* / d(5m)C* / dG* / dG* / d(5m)C* / dT* / LNA-G* / LNA-A* / LNA-T(SEQ ID NO.262);

[0743] (95)LNA-A* / LNA-G* / dA* / dA* / dT* / dG* / d(5m)C* / dG* / dG* / d(5m)C* / LNA-T* / LNA-G* / LNA-A(SEQ ID NO.263);

[0744] (96)LNA-A* / LNA-G* / dA* / dA* / dT* / dG* / d(5m)C* / dG* / dG* / d(5m)C* / LNA-T* / LNA-G(SEQ ID NO.264);

[0745] (97)LNA-(5m)C* / LNA-A* / LNA-G* / dA* / dA* / dT* / dG* / d(5m)C* / dG* / dG* / d(5m)C* / dT* / dG* / LNA-A* / LNA-T* / LNA-(5m)C(SEQ ID NO.265);

[0746] (98)LNA-(5m)C* / LNA-A* / LNA-G* / dA* / dA* / dT* / dG* / d(5m)C* / dG* / dG* / d(5m)C* / dT* / LNA-G* / LNA-A* / LNA-T(SEQ ID NO.266);

[0747] (99)LNA-(5m)C* / LNA-A* / LNA-G* / dA* / dA* / dT* / dG* / d(5m)C* / dG* / dG* / d(5m)C* / LNA-T* / LNA-G* / LNA-A(SEQ ID NO.267);

[0748] (100)LNA-(5m)C* / LNA-A* / dG* / dA* / dA* / dT* / dG* / d(5m)C* / dG* / dG* / LNA-(5m)C* / LNA-T* / LNA-G(SEQ ID NO.268);

[0749] (101)LNA-(5m)C* / LNA-A* / dG* / dA* / dA* / dT* / dG* / d(5m)C* / dG* / dG* / LNA-(5m)C* / LNA-T(SEQ ID NO.269);

[0750] (102)LNA-A* / LNA-(5m)C* / LNA-A* / dG* / dA* / dA* / dT* / dG* / d(5m)C* / dG* / dG* / d(5m)C* / dT* / LNA-G* / LNA-A* / LNA-T(SEQ ID NO.270);

[0751] (103)LNA-A* / LNA-(5m)C* / LNA-A* / dG* / dA* / dA* / dT* / dG* / d(5m)C* / dG* / dG* / d(5m)C* / LNA-T* / LNA-G* / LNA-A(SEQ ID NO.271);

[0752] (104)LNA-A* / LNA-(5m)C* / dA* / dG* / dA* / dA* / dT* / dG* / d(5m)C* / dG* / LNA-G* / LNA-(5m)C* / LNA-T(SEQ ID NO.272);

[0753] (105)LNA-A* / LNA-(5m)C* / dA* / dG* / dA* / dA* / dT* / dG* / d(5m)C* / dG* / LNA-G* / LNA-(5m)C(SEQ ID NO.273);

[0754] (106)LNA-T* / LNA-A* / LNA-(5m)C* / dA* / dG* / dA* / dA* / dT* / dG* / d(5m)C* / dG* / dG* / d(5m)C* / LNA-T* / LNA-G* / LNA-A(SEQ ID NO.274);

[0755] (107)LNA-T* / LNA-A* / LNA-(5m)C* / dA* / dG* / dA* / dA* / dT* / dG* / d(5m)C* / dG* / dG* / LNA-(5m)C* / LNA-T* / LNA-G(SEQID NO.275);

[0756] (108)LNA-T* / LNA-A* / LNA-(5m)C* / dA* / dG* / dA* / dA* / dT* / dG* / d(5m)C* / dG* / LNA-G* / LNA-(5m)C* / LNA-T(SEQ ID NO.276);

[0757] (109)LNA-A* / LNA-(5m)C* / LNA-A* / dG* / dA* / dA* / dT* / dG* / d(5m)C* / dG* / dG* / LNA-(5m)C* / LNA-T* / LNA-G(SEQ ID NO.277);

[0758] (110)LNA-T* / LNA-A* / d(5m)C* / dA* / dG* / dA* / dA* / dT* / dG* / d(5m)C* / LNA-G* / LNA-G* / LNA-(5m)C(SEQ ID NO.278);

[0759] (111)LNA-T* / LNA-A* / d(5m)C* / dA* / dG* / dA* / dA* / dT* / dG* / d(5m)C* / LNA-G* / LNA-G(SEQ ID NO.279);

[0760] (112)LNA-G* / LNA-T* / LNA-A* / d(5m)C* / dA* / dG* / dA* / dA* / dT* / dG* / d(5m)C* / dG* / dG* / LNA-(5m)C* / LNA-T* / LNA-G(SEQ ID NO.280);

[0761] (113)LNA-G* / LNA-T* / LNA-A* / d(5m)C* / dA* / dG* / dA* / dA* / dT* / dG* / d(5m)C* / dG* / LNA-G* / LNA-(5m)C* / LNA-T(SEQ ID NO.281);

[0762] (114)LNA-G* / LNA-T* / LNA-A* / d(5m)C* / dA* / dG* / dA* / dA* / dT* / dG* / d(5m)C* / LNA-G* / LNA-G* / LNA-(5m)C(SEQ ID NO.282);

[0763] (115)LNA-G* / LNA-T* / dA* / d(5m)C* / dA* / dG* / dA* / dA* / dT* / dG* / LNA-(5m)C* / LNA-G* / LNA-G(SEQ ID NO.283);

[0764] (116)LNA-G* / LNA-T* / dA* / d(5m)C* / dA* / dG* / dA* / dA* / dT* / dG* / LNA-(5m)C* / LNA-G(SEQ ID NO.284);

[0765] (117)LNA-G* / LNA-G* / d(5m)C* / d(5m)C* / dA* / dG* / d(5m)C* / dA* / dT* / dG* / LNA-A* / LNA-(5m)C(SEQ ID NO.285);

[0766] (118)LNA-G* / LNA-A* / LNA-T* / dG* / dT* / dA* / dA* / dT* / d(5m)C* / dG* / dA* / dA* / LNA-G* / LNA-A* / LNA-G(SEQ ID NO.286);

[0767] (119)LNA-G* / LNA-A* / LNA-T* / dG* / dT* / dA* / dA* / dT* / d(5m)C* / dG* / dA* / LNA-A* / LNA-G* / LNA-A(SEQ ID NO.287);

[0768] (120)LNA-G* / LNA-A* / dT* / dG* / dT* / dA* / dA* / dT* / d(5m)C* / dG* / LNA-A* / LNA-A* / LNA-G(SEQ ID NO.288);

[0769] (121)LNA-G* / LNA-A* / dT* / dG* / dT* / dA* / dA* / dT* / d(5m)C* / dG* / LNA-A* / LNA-A(SEQ ID NO.289);

[0770] (122)LNA-G* / LNA-G* / LNA-A* / dT* / dG* / dT* / dA* / dA* / dT* / d(5m)C* / dG* / dA* / dA* / LNA-G* / LNA-A* / LNA-G(SEQ ID NO.290);

[0771] (123)LNA-G* / LNA-G* / LNA-A* / dT* / dG* / dT* / dA* / dA* / dT* / d(5m)C* / dG* / dA* / LNA-A* / LNA-G* / LNA-A(SEQ ID NO.291);

[0772] (124)LNA-G* / LNA-G* / LNA-A* / dT* / dG* / dT* / dA* / dA* / dT* / d(5m)C* / dG* / LNA-A* / LNA-A* / LNA-G(SEQ ID NO.292);

[0773] (125)LNA-G* / LNA-G* / dA* / dT* / dG* / dT* / dA* / dA* / dT* / d(5m)C* / LNA-G* / LNA-A* / LNA-A(SEQ ID NO.293);

[0774] (126)LNA-G* / LNA-G* / dA* / dT* / dG* / dT* / dA* / dA* / dT* / d(5m)C* / LNA-G* / LNA-A(SEQ ID NO.294);

[0775] (127)LNA-T* / LNA-G* / LNA-G* / dA* / dT* / dG* / dT* / dA* / dA* / dT* / d(5m)C* / dG* / dA* / LNA-A* / LNA-G* / LNA-A(SEQ ID NO.295);

[0776] (128)LNA-T* / LNA-G* / LNA-G* / dA* / dT* / dG* / dT* / dA* / dA* / dT* / d(5m)C* / dG* / LNA-A* / LNA-A* / LNA-G(SEQ ID NO.296);

[0777] (129)LNA-T* / LNA-G* / LNA-G* / dA* / dT* / dG* / dT* / dA* / dA* / dT* / d(5m)C* / LNA-G* / LNA-A* / LNA-A(SEQ ID NO.297);

[0778] (130)LNA-T* / LNA-G* / dG* / dA* / dT* / dG* / dT* / dA* / dA* / dT* / LNA-(5m)C* / LNA-G* / LNA-A(SEQ ID NO.298);

[0779] (131)LNA-T* / LNA-G* / dG* / dA* / dT* / dG* / dT* / dA* / dA* / dT* / LNA-(5m)C* / LNA-G(SEQ ID NO.299);

[0780] (132)LNA-(5m)C* / LNA-T* / LNA-G* / dG* / dA* / dT* / dG* / dT* / dA* / dA* / dT* / d(5m)C* / dG* / LNA-A* / LNA-A* / LNA-G(SEQ ID NO.300);

[0781] (133)LNA-(5m)C* / LNA-T* / LNA-G* / dG* / dA* / dT* / dG* / dT* / dA* / dA* / dT* / d(5m)C* / LNA-G* / LNA-A* / LNA-A(SEQ ID NO.301);

[0782] (134)LNA-(5m)C* / LNA-T* / LNA-G* / dG* / dA* / dT* / dG* / dT* / dA* / dA* / dT* / LNA-(5m)C* / LNA-G* / LNA-A(SEQ ID NO.302);

[0783] (135)LNA-(5m)C* / LNA-T* / dG* / dG* / dA* / dT* / dG* / dT* / dA* / dA* / LNA-T* / LNA-(5m)C* / LNA-G(SEQ ID NO.303);

[0784] (136)LNA-(5m)C* / LNA-T* / dG* / dG* / dA* / dT* / dG* / dT* / dA* / dA* / LNA-T* / LNA-(5m)C(SEQ ID NO.304);

[0785] (137)LNA-A* / LNA-A* / dA* / dG* / dT* / dG* / dG* / d(5m)C* / d(5m)C* / dA* / LNA-(5m)C* / LNA-T(SEQ ID NO.305);

[0786] (138)LNA-(5m)C* / LNA-A* / dA* / dA* / dG* / dT* / dG* / dG* / d(5m)C* / d(5m)C* / LNA-A* / LNA-(5m)C* / LNA-T(SEQ ID NO.306);

[0787] (139)LNA-(5m)C* / LNA-A* / dA* / dA* / dG* / dT* / dG* / dG* / d(5m)C* / d(5m)C* / LNA-A* / LNA-(5m)C(SEQ ID NO.307);

[0788] (140)LNA-A* / LNA-(5m)C* / LNA-A* / dA* / dA* / dG* / dT* / dG* / dG* / d(5m)C* / d(5m)C* / LNA-A* / LNA-(5m)C* / LNA-T(SEQ ID NO.308);

[0789] (141)LNA-A* / LNA-(5m)C* / dA* / dA* / dA* / dG* / dT* / dG* / dG* / d(5m)C* / LNA-(5m)C* / LNA-A* / LNA-(5m)C(SEQ ID NO.309);

[0790] (142)LNA-A* / LNA-(5m)C* / dA* / dA* / dA* / dG* / dT* / dG* / dG* / d(5m)C* / LNA-(5m)C* / LNA-A(SEQ ID NO.310);

[0791] (143)LNA-(5m)C* / LNA-A* / LNA-(5m)C* / dA* / dA* / dA* / dG* / dT* / dG* / dG* / d(5m)C* / d(5m)C* / LNA-A* / LNA-(5m)C* / LNA-T(SEQ ID NO.311);

[0792] (144)LNA-(5m)C* / LNA-A* / LNA-(5m)C* / dA* / dA* / dA* / dG* / dT* / dG* / dG* / d(5m)C* / LNA-(5m)C* / LNA-A* / LNA-(5m)C(SEQ ID NO.312);

[0793] (145)LNA-(5m)C* / LNA-A* / d(5m)C* / dA* / dA* / dA* / dG* / dT* / dG* / dG* / LNA-(5m)C* / LNA-(5m)C* / LNA-A(SEQ ID NO.313);

[0794] (146)LNA-(5m)C* / LNA-A* / d(5m)C* / dA* / dA* / dA* / dG* / dT* / dG* / dG* / LNA-(5m)C* / LNA-(5m)C(SEQ ID NO.314);

[0795] (147)LNA-(5m)C* / LNA-(5m)C* / LNA-A* / d(5m)C* / dA* / dA* / dA* / dG* / dT* / dG* / dG* / d(5m)C* / d(5m)C* / LNA-A* / LNA-(5m)C* / LNA-T(SEQ ID NO.315);

[0796] (148)LNA-(5m)C* / LNA-(5m)C* / LNA-A* / d(5m)C* / dA* / dA* / dA* / dG* / dT* / dG* / dG* / d(5m)C* / LNA-(5m)C* / LNA-A* / LNA-(5m)C(SEQ ID NO.316);

[0797] (149)LNA-(5m)C* / LNA-(5m)C* / LNA-A* / d(5m)C* / dA* / dA* / dA* / dG* / dT* / dG* / dG* / LNA-(5m)C* / LNA-(5m)C* / LNA-A(SEQ ID NO.317);

[0798] (150)LNA-(5m)C* / LNA-(5m)C* / dA* / d(5m)C* / dA* / dA* / dA* / dG* / dT* / dG* / LNA-G* / LNA-(5m)C* / LNA-(5m)C(SEQ ID NO.318);

[0799] (151)LNA-(5m)C* / LNA-(5m)C* / dA* / d(5m)C* / dA* / dA* / dA* / dG* / dT* / dG* / LNA-G* / LNA-(5m)C(SEQ ID NO.319);

[0800] (152)LNA-(5m)C* / LNA-(5m)C* / LNA-(5m)C* / dA* / d(5m)C* / dA* / dA* / dA* / dG* / dT* / dG* / dG* / d(5m)C* / LNA-(5m)C* / LNA-A* / LNA-(5m)C(SEQ ID NO.320);

[0801] (153)LNA-(5m)C* / LNA-(5m)C* / LNA-(5m)C* / dA* / d(5m)C* / dA* / dA* / dA* / dG* / dT* / dG* / dG* / LNA-(5m)C* / LNA-(5m)C* / LNA-A(SEQ ID NO.321);

[0802] (154)LNA-(5m)C* / LNA-(5m)C* / LNA-(5m)C* / dA* / d(5m)C* / dA* / dA* / dA* / dG* / dT* / dG* / LNA-G* / LNA-(5m)C* / LNA-(5m)C(SEQ ID NO.322);

[0803] (155)LNA-(5m)C* / LNA-(5m)C* / d(5m)C* / dA* / d(5m)C* / dA* / dA* / dA* / dG* / dT* / LNA-G* / LNA-G* / LNA-(5m)C(SEQ ID NO.323);

[0804] (156)LNA-(5m)C* / LNA-(5m)C* / d(5m)C* / dA* / d(5m)C* / dA* / dA* / dA* / dG* / dT* / LNA-G* / LNA-G(SEQ ID NO.324);

[0805] (157)LNA-(5m)C* / LNA-(5m)C* / dG* / dT* / dG* / dT* / dA* / dA* / dA* / dT* / LNA-(5m)C* / LNA-A(SEQ ID NO.325);

[0806] (158)LNA-G* / LNA-(5m)C* / dA* / d(5m)C* / d(5m)C* / dA* / dG* / dT* / dA* / d(5m)C* / LNA-(5m)C* / LNA-A(SEQ ID NO.326);

[0807] (159)LNA-T* / LNA-G* / d(5m)C* / dA* / d(5m)C* / d(5m)C* / dA* / dG* / dT* / dA* / LNA-(5m)C* / LNA-(5m)C* / LNA-A(SEQ ID NO.327);

[0808] (160)LNA-T* / LNA-G* / d(5m)C* / dA* / d(5m)C* / d(5m)C* / dA* / dG* / dT* / dA* / LNA-(5m)C* / LNA-(5m)C(SEQ ID NO.328);

[0809] (161)LNA-G* / LNA-(5m)C* / dA* / dG* / d(5m)C* / dG* / d(5m)C* / dT* / dG* / d(5m)C* / LNA-A* / LNA-(5m)C(SEQ ID NO.329);

[0810] (162)LNA-G* / LNA-G* / d(5m)C* / dA* / dG* / d(5m)C* / dG* / d(5m)C* / dT* / dG* / LNA-(5m)C* / LNA-A* / LNA-(5m)C(SEQ ID NO.330);

[0811] (163)LNA-G* / LNA-G* / d(5m)C* / dA* / dG* / d(5m)C* / dG* / d(5m)C* / dT* / dG* / LNA-(5m)C* / LNA-A(SEQ ID NO.331);

[0812] (164)LNA-A* / LNA-G* / LNA-G* / d(5m)C* / dA* / dG* / d(5m)C* / dG* / d(5m)C* / dT* / dG* / LNA-(5m)C* / LNA-A* / LNA-(5m)C(SEQ ID NO.332);

[0813] (165)LNA-A* / LNA-G* / dG* / d(5m)C* / dA* / dG* / d(5m)C* / dG* / d(5m)C* / dT* / LNA-G* / LNA-(5m)C* / LNA-A(SEQ ID NO. 333); or

[0814] (166)LNA-A* / LNA-G* / dG* / d(5m)C* / dA* / dG* / d(5m)C* / dG* / d(5m)C* / dT* / LNA-G* / LNA-(5m)C (SEQ ID NO. 334);

[0815] (167)LNA-A* / LNA-G* / LNA-A* / dA* / dT* / dG* / d(5m)C* / dG* / dG* / d(5m)C* / dT* / dG* / dA* / LNA-T / # / LNA-(5m)C / # / LNA-A (SEQ ID NO. 341);

[0816] In this context, * represents a thiophosphate bond between nucleotides, # represents a methanesulfonylphosphatidyl ester linkage, and 5m indicates that the 5th carbon in cytosine is methylated.

[0817] In some embodiments, the antisense oligonucleotide is selected from any of the following combinations of modifications:

[0818] (1)LNA-(5m)C* / LNA-A* / dT* / dG* / dG* / dT* / dG* / dA* / dA* / dG* / LNA-A* / LNA-G (SEQ ID NO. 169);

[0819] (2)LNA-(5m)C* / LNA-(5m)C* / dA* / dT* / dG* / dG* / dT* / dG* / dA* / dA* / LNA-G* / LNA-A* / LNA-G (SEQ ID NO. 170);

[0820] (3)LNA-(5m)C* / LNA-(5m)C* / dA* / dT* / dG* / dG* / dT* / dG* / dA* / dA* / LNA-G* / LNA-A (SEQ ID NO. 171);

[0821] (4)LNA-T* / LNA-(5m)C* / LNA-(5m)C* / dA* / dT* / dG* / dG* / dT* / dG* / dA* / dA* / LNA-G* / LNA-A* / LNA-G (SEQ ID NO. 172);

[0822] (5)LNA-T* / LNA-(5m)C* / d(5m)C* / dA* / dT* / dG* / dG* / dT* / dG* / dA* / LNA-A* / LNA-G* / LNA-A(SEQ ID NO.173);

[0823] (6)LNA-T* / LNA-(5m)C* / d(5m)C* / dA* / dT* / dG* / dG* / dT* / dG* / dA* / LNA-A* / LNA-G(SEQ ID NO.174);

[0824] (7)LNA-(5m)C* / LNA-(5m)C* / dT* / dG* / d(5m)C* / d(5m)C* / dA* / dG* / dG* / dA* / LNA-A* / LNA-G(SEQ ID NO.175);

[0825] (8)LNA-A* / LNA-G* / dA* / dT* / d(5m)C* / dT* / dT* / dG* / dG* / dT* / LNA-G* / LNA-A* / LNA-A(SEQ ID NO.180);

[0826] (9)LNA-A* / LNA-G* / dA* / dT* / d(5m)C* / dT* / dT* / dG* / dG* / dT* / LNA-G* / LNA-A(SEQ ID NO.181);

[0827] (10)LNA-(5m)C* / LNA-T* / LNA-G* / dT* / dT* / dG* / dA* / dA* / dG* / dA* / dT* / dG* / LNA-G* / LNA-A* / LNA-G(SEQ ID NO.196);

[0828] (11)LNA-(5m)C* / LNA-T* / LNA-G* / dT* / dT* / dG* / dA* / dA* / dG* / dA* / dT* / LNA-G* / LNA-G* / LNA-A(SEQ ID NO.197);

[0829] (12)LNA-(5m)C* / LNA-T* / dG* / dT* / dT* / dG* / dA* / dA* / dG* / dA* / LNA-T* / LNA-G* / LNA-G(SEQ ID NO.198);

[0830] (13)LNA-G* / LNA-(5m)C* / LNA-T* / dG* / dT* / dT* / dG* / dA* / dA* / dG* / dA* / dT* / dG* / LNA-G* / LNA-A* / LNA-G(SEQ ID NO.200);

[0831] (14)LNA-G* / LNA-(5m)C* / LNA-T* / dG* / dT* / dT* / dG* / dA* / dA* / dG* / dA* / dT* / LNA-G* / LNA-G* / LNA-A(SEQ ID NO.201);

[0832] (15)LNA-G* / LNA-(5m)C* / LNA-T* / dG* / dT* / dT* / dG* / dA* / dA* / dG* / dA* / LNA-T* / LNA-G* / LNA-G(SEQ ID NO.202);

[0833] (16)LNA-G* / LNA-A* / LNA-T* / dG* / dT* / d(5m)C* / d(5m)C* / dA* / dT* / dG* / dG* / dT* / dG* / LNA-A* / LNA-A* / LNA-G(SEQ ID NO.219);

[0834] (17)LNA-G* / LNA-A* / LNA-T* / dG* / dT* / d(5m)C* / d(5m)C* / dA* / dT* / dG* / dG* / dT* / LNA-G* / LNA-A* / LNA-A(SEQ ID NO.220);

[0835] (18)LNA-G* / LNA-A* / LNA-T* / dG* / dT* / d(5m)C* / d(5m)C* / dA* / dT* / dG* / dG* / LNA-T* / LNA-G* / LNA-A(SEQ ID NO.221);

[0836] (19)LNA-G* / LNA-A* / dT* / dG* / dT* / d(5m)C* / d(5m)C* / dA* / dT* / dG* / LNA-G* / LNA-T* / LNA-G(SEQ ID NO.222);

[0837] (20)LNA-G* / LNA-A* / dT* / dG* / dT* / d(5m)C* / d(5m)C* / dA* / dT* / dG* / LNA-G* / LNA-T(SEQ ID NO.223);

[0838] (21)LNA-A* / LNA-G* / LNA-A* / dT* / dG* / dT* / d(5m)C* / d(5m)C* / dA* / dT* / dG* / dG* / dT* / LNA-G* / LNA-A* / LNA-A(SEQ ID NO.224);

[0839] (22)LNA-A* / LNA-G* / LNA-A* / dT* / dG* / dT* / d(5m)C* / d(5m)C* / dA* / dT* / dG* / dG* / LNA-T* / LNA-G* / LNA-A(SEQ ID NO.225);

[0840] (23)LNA-A* / LNA-G* / LNA-A* / dT* / dG* / dT* / d(5m)C* / d(5m)C* / dA* / dT* / dG* / LNA-G* / LNA-T* / LNA-G(SEQ ID NO.226);

[0841] (24)LNA-A* / LNA-G* / dA* / dT* / dG* / dT* / d(5m)C* / d(5m)C* / dA* / dT* / LNA-G* / LNA-G* / LNA-T(SEQ ID NO.227);

[0842] (25)LNA-A* / LNA-G* / dA* / dT* / dG* / dT* / d(5m)C* / d(5m)C* / dA* / dT* / LNA-G* / LNA-G(SEQ ID NO.228);

[0843] (26)LNA-G* / LNA-T* / LNA-A* / dG* / dA* / dT* / dG* / dT* / d(5m)C* / d(5m)C* / dA* / dT* / dG* / LNA-G* / LNA-T* / LNA-G(SEQ ID NO.234);

[0844] (27)LNA-G* / LNA-T* / LNA-A* / dG* / dA* / dT* / dG* / dT* / d(5m)C* / d(5m)C* / dA* / dT* / LNA-G* / LNA-G* / LNA-T(SEQ ID NO.235);

[0845] (28)LNA-G* / LNA-T* / LNA-A* / dG* / dA* / dT* / dG* / dT* / d(5m)C* / d(5m)C* / dA* / LNA-T* / LNA-G* / LNA-G(SEQ ID NO.236);

[0846] (29)LNA-G* / LNA-T* / dA* / dG* / dA* / dT* / dG* / dT* / d(5m)C* / d(5m)C* / LNA-A* / LNA-T* / LNA-G(SEQ ID NO.237);

[0847] (30)LNA-G* / LNA-T* / dA* / dG* / dA* / dT* / dG* / dT* / d(5m)C* / d(5m)C* / LNA-A* / LNA-T(SEQ ID NO.238);

[0848] (31)LNA-A* / LNA-T* / LNA-G* / dT* / dA* / dA* / dT* / d(5m)C* / dG* / dA* / dA* / LNA-G* / LNA-A* / LNA-G(SEQ ID NO.242);

[0849] (32)LNA-A* / LNA-G* / LNA-A* / dA* / dT* / dG* / d(5m)C* / dG* / dG* / d(5m)C* / dT* / dG* / dA* / LNA-T* / LNA-(5m)C* / LNA-A(SEQ ID NO.260);

[0850] (33)LNA-A* / LNA-G* / LNA-A* / dA* / dT* / dG* / d(5m)C* / dG* / dG* / d(5m)C* / dT* / dG* / LNA-A* / LNA-T* / LNA-(5m)C(SEQ ID NO.261);

[0851] (34)LNA-A* / LNA-G* / LNA-A* / dA* / dT* / dG* / d(5m)C* / dG* / dG* / d(5m)C* / dT* / LNA-G* / LNA-A* / LNA-T(SEQ ID NO.262);

[0852] (35)LNA-A* / LNA-G* / dA* / dA* / dT* / dG* / d(5m)C* / dG* / dG* / d(5m)C* / LNA-T* / LNA-G* / LNA-A(SEQ ID NO.263);

[0853] (36)LNA-A* / LNA-G* / dA* / dA* / dT* / dG* / d(5m)C* / dG* / dG* / d(5m)C* / LNA-T* / LNA-G(SEQ ID NO.264);

[0854] (37)LNA-(5m)C* / LNA-A* / LNA-G* / dA* / dA* / dT* / dG* / d(5m)C* / dG* / dG* / d(5m)C* / dT* / dG* / LNA-A* / LNA-T* / LNA-(5m)C(SEQ ID NO.265);

[0855] (38)LNA-(5m)C* / LNA-A* / dG* / dA* / dA* / dT* / dG* / d(5m)C* / dG* / dG* / LNA-(5m)C* / LNA-T(SEQ ID NO.269);

[0856] (39)LNA-T* / LNA-A* / LNA-(5m)C* / dA* / dG* / dA* / dA* / dT* / dG* / d(5m)C* / dG* / dG* / d(5m)C* / LNA-T* / LNA-G* / LNA-A(SEQ ID NO.274);

[0857] (40)LNA-A* / LNA-(5m)C* / LNA-A* / dG* / dA* / dA* / dT* / dG* / d(5m)C* / dG* / dG* / LNA-(5m)C* / LNA-T* / LNA-G(SEQ ID NO.277);

[0858] (41)LNA-T* / LNA-A* / d(5m)C* / dA* / dG* / dA* / dA* / dT* / dG* / d(5m)C* / LNA-G* / LNA-G* / LNA-(5m)C(SEQ ID NO.278);

[0859] (42)LNA-T* / LNA-A* / d(5m)C* / dA* / dG* / dA* / dA* / dT* / dG* / d(5m)C* / LNA-G* / LNA-G(SEQ ID NO.279);

[0860] (43)LNA-G* / LNA-T* / dA* / d(5m)C* / dA* / dG* / dA* / dA* / dT* / dG* / LNA-(5m)C* / LNA-G(SEQ ID NO.284);

[0861] (44)LNA-G* / LNA-A* / LNA-T* / dG* / dT* / dA* / dA* / dT* / d(5m)C* / dG* / dA* / dA* / LNA-G* / LNA-A* / LNA-G(SEQ ID NO.286);

[0862] (45)LNA-G* / LNA-A* / LNA-T* / dG* / dT* / dA* / dA* / dT* / d(5m)C* / dG* / dA* / LNA-A* / LNA-G* / LNA-A(SEQ ID NO.287);

[0863] (46)LNA-G* / LNA-G* / LNA-A* / dT* / dG* / dT* / dA* / dA* / dT* / d(5m)C* / dG* / dA* / dA* / LNA-G* / LNA-A* / LNA-G(SEQ ID NO.290);

[0864] (47)LNA-G* / LNA-G* / LNA-A* / dT* / dG* / dT* / dA* / dA* / dT* / d(5m)C* / dG* / dA* / LNA-A* / LNA-G* / LNA-A(SEQ ID NO.291);

[0865] (48)LNA-G* / LNA-G* / LNA-A* / dT* / dG* / dT* / dA* / dA* / dT* / d(5m)C* / dG* / LNA-A* / LNA-A* / LNA-G(SEQ ID NO.292);

[0866] (49)LNA-G* / LNA-G* / dA* / dT* / dG* / dT* / dA* / dA* / dT* / d(5m)C* / LNA-G* / LNA-A* / LNA-A(SEQ ID NO.293);

[0867] (50)LNA-T* / LNA-G* / LNA-G* / dA* / dT* / dG* / dT* / dA* / dA* / dT* / d(5m)C* / dG* / dA* / LNA-A* / LNA-G* / LNA-A(SEQ ID NO.295);

[0868] (51)LNA-T* / LNA-G* / LNA-G* / dA* / dT* / dG* / dT* / dA* / dA* / dT* / d(5m)C* / dG* / LNA-A* / LNA-A* / LNA-G(SEQ ID NO.296);

[0869] (52)LNA-T* / LNA-G* / LNA-G* / dA* / dT* / dG* / dT* / dA* / dA* / dT* / d(5m)C* / LNA-G* / LNA-A* / LNA-A(SEQ ID NO.297);

[0870] (53)LNA-(5m)C* / LNA-(5m)C* / dG* / dT* / dG* / dT* / dA* / dA* / dA* / dT* / LNA-(5m)C* / LNA-A (SEQ ID NO. 325); or

[0871] (54)LNA-G* / LNA-(5m)C* / dA* / d(5m)C* / d(5m)C* / dA* / dG* / dT* / dA* / d(5m)C* / LNA-(5m)C* / LNA-A (SEQ ID NO. 326);

[0872] In this context, * represents a phosphate thioester bond between nucleotides, and 5m indicates that the 5th carbon in the pentose cytosine is methylated.

[0873] In some embodiments, the antisense oligonucleotide is selected from any of the following combinations of modifications:

[0874] (1)LNA-(5m)C* / LNA-A* / dT* / dG* / dG* / dT* / dG* / dA* / dA* / dG* / LNA-A* / LNA-G (SEQ ID NO. 169);

[0875] (2)LNA-A* / LNA-G* / dA* / dT* / d(5m)C* / dT* / dT* / dG* / dG* / dT* / LNA-G* / LNA-A* / LNA-A (SEQ ID NO. 180);

[0876] (3)LNA-A* / LNA-G* / dA* / dT* / d(5m)C* / dT* / dT* / dG* / dG* / dT* / LNA-G* / LNA-A (SEQ ID NO. 181);

[0877] (4)LNA-G* / LNA-A* / LNA-T* / dG* / dT* / d(5m)C* / d(5m)C* / dA* / dT* / dG* / dG* / dT* / dG* / LNA-A* / LNA-A* / LNA-G (SEQ ID NO. 219);

[0878] (5)LNA-G* / LNA-A* / LNA-T* / dG* / dT* / d(5m)C* / d(5m)C* / dA* / dT* / dG* / dG* / LNA-T* / LNA-G* / LNA-A (SEQ ID NO. 221);

[0879] (6)LNA-G* / LNA-A* / dT* / dG* / dT* / d(5m)C* / d(5m)C* / dA* / dT* / dG* / LNA-G* / LNA-T* / LNA-G(SEQ ID NO.222);

[0880] (7)LNA-A* / LNA-G* / LNA-A* / dT* / dG* / dT* / d(5m)C* / d(5m)C* / dA* / dT* / dG* / dG* / dT* / LNA-G* / LNA-A* / LNA-A(SEQ ID NO.224);

[0881] (8)LNA-A* / LNA-G* / LNA-A* / dT* / dG* / dT* / d(5m)C* / d(5m)C* / dA* / dT* / dG* / LNA-G* / LNA-T* / LNA-G(SEQ ID NO.226);

[0882] (9)LNA-A* / LNA-G* / dA* / dT* / dG* / dT* / d(5m)C* / d(5m)C* / dA* / dT* / LNA-G* / LNA-G* / LNA-T(SEQ ID NO.227);

[0883] (10)LNA-A* / LNA-G* / dA* / dT* / dG* / dT* / d(5m)C* / d(5m)C* / dA* / dT* / LNA-G* / LNA-G(SEQ ID NO.228);

[0884] (11)LNA-G* / LNA-T* / LNA-A* / dG* / dA* / dT* / dG* / dT* / d(5m)C* / d(5m)C* / dA* / dT* / dG* / LNA-G* / LNA-T* / LNA-G(SEQ ID NO.234);

[0885] (12)LNA-G* / LNA-T* / LNA-A* / dG* / dA* / dT* / dG* / dT* / d(5m)C* / d(5m)C* / dA* / dT* / LNA-G* / LNA-G* / LNA-T(SEQ ID NO.235);

[0886] (13)LNA-G* / LNA-T* / LNA-A* / dG* / dA* / dT* / dG* / dT* / d(5m)C* / d(5m)C* / dA* / LNA-T* / LNA-G* / LNA-G(SEQ ID NO.236);

[0887] (14)LNA-G* / LNA-T* / dA* / dG* / dA* / dT* / dG* / dT* / d(5m)C* / d(5m)C* / LNA-A* / LNA-T* / LNA-G(SEQ ID NO.237);

[0888] (15)LNA-A* / LNA-T* / LNA-G* / dT* / dA* / dA* / dT* / d(5m)C* / dG* / dA* / dA* / LNA-G* / LNA-A* / LNA-G(SEQ ID NO.242);

[0889] (16)LNA-T* / LNA-A* / LNA-(5m)C* / dA* / dG* / dA* / dA* / dT* / dG* / d(5m)C* / dG* / dG* / d(5m)C* / LNA-T* / LNA-G* / LNA-A(SEQ ID NO.274);

[0890] (17)LNA-A* / LNA-(5m)C* / LNA-A* / dG* / dA* / dA* / dT* / dG* / d(5m)C* / dG* / dG* / LNA-(5m)C* / LNA-T* / LNA-G(SEQ ID NO.277);

[0891] (18)LNA-T* / LNA-A* / d(5m)C* / dA* / dG* / dA* / dA* / dT* / dG* / d(5m)C* / LNA-G* / LNA-G* / LNA-(5m)C(SEQ ID NO.278);

[0892] (19)LNA-T* / LNA-A* / d(5m)C* / dA* / dG* / dA* / dA* / dT* / dG* / d(5m)C* / LNA-G* / LNA-G(SEQ ID NO.279);

[0893] (20)LNA-G* / LNA-T* / dA* / d(5m)C* / dA* / dG* / dA* / dA* / dT* / dG* / LNA-(5m)C* / LNA-G(SEQ ID NO.284);

[0894] (21)LNA-G* / LNA-A* / LNA-T* / dG* / dT* / dA* / dA* / dT* / d(5m)C* / dG* / dA* / dA* / LNA-G* / LNA-A* / LNA-G(SEQ ID NO.286);

[0895] (22)LNA-G* / LNA-A* / LNA-T* / dG* / dT* / dA* / dA* / dT* / d(5m)C* / dG* / dA* / LNA-A* / LNA-G* / LNA-A (SEQ ID NO. 287);

[0896] (23)LNA-G* / LNA-G* / LNA-A* / dT* / dG* / dT* / dA* / dA* / dT* / d(5m)C* / dG* / dA* / dA* / LNA-G* / LNA-A* / LNA-G (SEQ ID NO. 290);

[0897] (24)LNA-G* / LNA-G* / LNA-A* / dT* / dG* / dT* / dA* / dA* / dT* / d(5m)C* / dG* / dA* / LNA-A* / LNA-G* / LNA-A (SEQ ID NO. 291);

[0898] (25)LNA-G* / LNA-G* / LNA-A* / dT* / dG* / dT* / dA* / dA* / dT* / d(5m)C* / dG* / LNA-A* / LNA-A* / LNA-G (SEQ ID NO. 292);

[0899] (26)LNA-G* / LNA-G* / dA* / dT* / dG* / dT* / dA* / dA* / dT* / d(5m)C* / LNA-G* / LNA-A* / LNA-A (SEQ ID NO. 293);

[0900] (27)LNA-T* / LNA-G* / LNA-G* / dA* / dT* / dG* / dT* / dA* / dA* / dT* / d(5m)C* / dG* / dA* / LNA-A* / LNA-G* / LNA-A (SEQ ID NO. 295); or

[0901] (28)LNA-T* / LNA-G* / LNA-G* / dA* / dT* / dG* / dT* / dA* / dA* / dT* / d(5m)C* / dG* / LNA-A* / LNA-A* / LNA-G (SEQ ID NO. 296);

[0902] In this context, * represents a phosphate thioester bond between nucleotides, and 5m indicates that the 5th carbon in cytosine is methylated.

[0903] In some embodiments, the antisense oligonucleotide is selected from any of the following combinations of modifications:

[0904] (1)LNA-T* / LNA-G* / dT* / d(5m)C* / d(5m)C* / dA* / dT* / dG* / dG* / dT* / LNA-G* / LNA-A(SEQ ID NO.213); or

[0905] (2) LNA-G* / LNA-T* / dA* / dG* / dA* / dT* / dG* / dT* / d(5m)C* / d(5m)C* / LNA-A* / LNA-T (SEQ ID NO.238); where * represents a phosphate thioester bond between nucleotides, and 5m represents the methylation modification of the 5th carbon in cytosine.

[0906] In some embodiments, the modified nucleotide further comprises one or more nucleotide modifications selected from the group consisting of: 2'-deoxynucleotides, 2',3'-seco nucleotide mimics, unlocked nucleic acid nucleotides (UNA), glycol nucleic acid nucleotides (GNA), bicyclic nucleic acids (BNA), 2'-F-arabinonucleotides, 2'-methoxyethyl nucleotides, abase-free nucleotides, ribitol, reverse nucleotides, reverse abase-free nucleotides (Invab), reverse 2'-OMe nucleotides, reverse 2'-deoxynucleotides, 2'-amino-modified nucleotides, 2'-alkyl-modified nucleotides, morpholinonucleotides, 3'-OMe nucleotides, phosphate ester-modified nucleotides, terminal nucleotides linked to cholesterol derivatives or dodecanoic acid bis(decylamide) groups, 2'-amino-modified nucleotides, aminophosphates, or non-natural bases containing nucleotides.

[0907] In some embodiments, the antisense oligonucleotide contains at least one modified nucleotide inter-bond.

[0908] In some embodiments, the modified nucleotide inter-bonds include thiophosphate bonds and / or methanesulfonylphosphatidyl linkages.

[0909] In some embodiments, the modified nucleotide inter-bonds include phosphate thioester bonds.

[0910] In some embodiments, the modified nucleotide inter-bonds include methanesulfonylphosphatidyl ester linkages.

[0911] In some embodiments, the internucleotide bonds of the modified nucleotides are phosphate thioester bonds.

[0912] In some embodiments, the internucleotide bonds of the modified nucleotides are phosphate thioester bonds.

[0913] In some embodiments, the modified nucleotide inter-bonds simultaneously include at least one thiophosphate bond and at least one methanesulfonylphosphatidyl linkage.

[0914] In some embodiments, the antisense oligonucleotide may optionally also include one or more nucleotides conjugated to one or more target ligands.

[0915] In some implementations, the targeting ligand is conjugated to the 5' end of the antisense oligonucleotide.

[0916] In some implementations, the targeting ligand comprises a protein, a small molecule compound, a carbohydrate, or a lipid.

[0917] In some embodiments, the protein is selected from natural proteins, synthetic polyamino acids, peptides, and antibodies.

[0918] In some embodiments, the natural protein is selected from human serum albumin, low-density lipoprotein, or globulin.

[0919] In some embodiments, the synthetic polyamino acid is selected from polylysine, poly-L-aspartic acid, poly-L-glutamic acid, styrene-maleic anhydride copolymer, poly(L-lactic acid-co-ethylene glycol) copolymer, diethylene ether-maleic anhydride copolymer, N-(2-hydroxypropyl)methacrylamide copolymer, polyethylene glycol, polyvinyl alcohol, polyurethane, poly(2-ethylacrylic acid), N-isopropylacrylamide polymer, or polyphosphoric acid.

[0920] In some embodiments, the carbohydrate is selected from dextran, pullulan, chitin, chitosan, inulin, cyclodextrin, amino sugars, or hyaluronic acid.

[0921] In some embodiments, the lipid is selected from fatty acids, sterols, or phospholipids.

[0922] In some embodiments, the fatty acid is selected from capric acid, caprylic acid, lauric acid, palmitic acid, myristic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, arachidonic acid, or eicosenoic acid.

[0923] In some embodiments, the sterol is selected from cholesterol, cholesterol group, cholesterol alcohol, stigmasterol, cholesterol acid, or ergosterol.

[0924] In some embodiments, the phospholipid is selected from di-hexadecyl-racemic glycerol or triethylamine 1,2-di-O-hexadecyl-racemic glycerol-3-hydrophosphonate.

[0925] In some implementations, the targeting ligand comprises an amino sugar.

[0926] In some embodiments, the targeting ligand comprises an N-acetylgalactosamine (GalNAc) moiety.

[0927] In some implementations, the GalNac portion is a monovalent GalNAc portion, a divalent GalNAc portion, a trivalent GalNAc portion, or a tetravalent GalNAc portion.

[0928] In some implementations, the targeting ligand has the following structure:

[0929] On the other hand, this disclosure provides a composition comprising the aforementioned antisense oligonucleotide or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier.

[0930] In some embodiments, the composition further comprises one or more additional therapeutic components.

[0931] In some embodiments, the therapeutic component is selected from dipeptidyl peptidase-4 (DPP-4) inhibitors, insulin, insulin analogs, biguanides, sulfonylureas, thiazolidinediones (TZDs), α-glucosidase inhibitors, or glucagon-like peptide-1 (GLP-1) receptor agonists, angiotensin-converting enzyme (ACE) inhibitors, endothelin receptor antagonists (ERA), angiotensin II receptor blockers (ARBs), mineralocorticoid receptor (MR) antagonists, and aldosterone synthase (AS) inhibitors.

[0932] In some embodiments, the DPP-4 inhibitor is selected from sitagliptin, vildagliptin, saxagliptin, linagliptin, alogliptin, tenegliptin, anagliptin, trelagliptin, and omaligliptin.

[0933] In some embodiments, the α-glucosidase inhibitor is selected from acarbose, voglibose, and miglitol.

[0934] In some embodiments, the GLP-1 receptor agonist is selected from semaglutide, liraglutide, exenatide, dulaglutide, and tirzepatide.

[0935] In some embodiments, the ACE inhibitor is selected from benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, and trundolapril.

[0936] In some implementations, the ERA is selected from zibotentan, atrasertan, avosentan, and sparsertan.

[0937] In some implementations, the ARB is selected from irbesartan, losartan, olmesartan, and valsartan.

[0938] In some embodiments, the MR antagonist is selected from spironolactone, eplerenone, finerenone, esaxerenone, apararenone, balcinerone, and occedurenone.

[0939] In some implementations, the AS inhibitor is selected from Baxdrostat, Vicadrostat, and Lorundrostat.

[0940] In some embodiments, the composition is packaged in a box, container, packaging, dispenser, pre-filled syringe, or vial.

[0941] In some embodiments, the composition is formulated for administration via ocular, vaginal, rectal, nasal, transdermal, subcutaneous, intravenous, intra-arterial, intralymphatic, intrabronchial, intrapleural, intraperitoneal, cerebrospinal, or intramuscular injection, or for administration to the lungs, intrathecal, or intracardiac.

[0942] On the other hand, this disclosure provides a cell that contains the aforementioned antisense oligonucleotides.

[0943] On the other hand, this disclosure provides a method for inhibiting SGLT2 and / or SGLT1 gene expression in vitro, the method comprising the following steps:

[0944] Contact the cells with an effective amount of the aforementioned antisense oligonucleotide and / or the aforementioned composition.

[0945] On the other hand, this disclosure provides a kit containing the aforementioned antisense oligonucleotides and / or the aforementioned compositions.

[0946] On the other hand, this disclosure provides the use of the aforementioned antisense oligonucleotide and / or the aforementioned composition in the preparation of a medicament for the prevention and / or treatment of diseases.

[0947] In some implementations, the disease is an sglt1 and / or sglt2 related disease.

[0948] In some implementations, the disease is type 1 diabetes, type 2 diabetes, diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, delayed wound healing, insulin resistance, hyperglycemia, hyperinsulinemia, chronic kidney disease, heart failure with preserved ejection fraction, heart failure with reduced ejection fraction, elevated blood levels of fatty acids or glycerol, hyperlipidemia, dyslipidemia, obesity, hypertriglyceridemia, syndrome X, diabetic complications or atherosclerosis, hypertension, hyperuricemia, or cardiovascular disease.

[0949] On the other hand, this disclosure provides the use of the aforementioned antisense oligonucleotides and / or the aforementioned compositions for the prevention and / or treatment of diseases.

[0950] In some implementations, the disease is an sglt1 and / or sglt2 related disease.

[0951] In some implementations, the disease is type 1 diabetes, type 2 diabetes, diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, delayed wound healing, insulin resistance, hyperglycemia, hyperinsulinemia, chronic kidney disease, heart failure with preserved ejection fraction, heart failure with reduced ejection fraction, elevated blood levels of fatty acids or glycerol, hyperlipidemia, dyslipidemia, obesity, hypertriglyceridemia, syndrome X, diabetic complications or atherosclerosis, hypertension, hyperuricemia, or cardiovascular disease.

[0952] On the other hand, this disclosure provides a method for preventing and / or treating a disease, comprising administering an effective amount of the aforementioned antisense oligonucleotide and / or the aforementioned composition to a subject in need.

[0953] In some implementations, the disease is an sglt1 and / or sglt2 related disease.

[0954] In some implementations, the disease is type 1 diabetes, type 2 diabetes, diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, delayed wound healing, insulin resistance, hyperglycemia, hyperinsulinemia, chronic kidney disease, heart failure with preserved ejection fraction, heart failure with reduced ejection fraction, elevated blood levels of fatty acids or glycerol, hyperlipidemia, dyslipidemia, obesity, hypertriglyceridemia, syndrome X, diabetic complications or atherosclerosis, hypertension, hyperuricemia, or cardiovascular disease.

[0955] On the other hand, this disclosure provides pharmaceutical compositions for the prevention and / or treatment of diseases, wherein the pharmaceutical compositions comprise the aforementioned antisense oligonucleotides and / or the aforementioned compositions.

[0956] In some implementations, the disease is an sglt1 and / or sglt2 related disease.

[0957] In some implementations, the disease is type 1 diabetes, type 2 diabetes, diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, delayed wound healing, insulin resistance, hyperglycemia, hyperinsulinemia, chronic kidney disease, heart failure with preserved ejection fraction, heart failure with reduced ejection fraction, elevated blood levels of fatty acids or glycerol, hyperlipidemia, dyslipidemia, obesity, hypertriglyceridemia, syndrome X, diabetic complications or atherosclerosis, hypertension, hyperuricemia, or cardiovascular disease.

[0958] For the purpose of clarity and concise description, the features are described herein as part of some identical or separate embodiments; however, it will be understood that the scope of this disclosure may include some embodiments having a combination of all or some of the features described.

[0959] The present disclosure will now be described in more detail with reference to specific embodiments. However, the embodiments are for illustrative purposes only and are not intended to limit the scope of the present disclosure.

[0960] Example

[0961] The known starting materials disclosed herein can be synthesized using methods known in the art.

[0962] Example 1: Design and Synthesis of Dual-Targeted ASO

[0963] ASOs were designed using human SGLT1 (GENBANK search number: NM000343.4, SEQ ID NO:167) and SGLT2 (GENBANK search number: NM003041.4, SEQ ID NO:168) as target genes, totaling 166 sequences. All sequences were modified with LNA. The naked sequence information and modification information are detailed in Table 1.

[0964] As shown in Table 1, the columns labeled "Gapmer Modification Patterns" represent the modification patterns of the corresponding ASOs. Each ASO consists of three parts: a 5' wing, a spacer segment, and a 3' wing. The first number represents the number of monomers in the 5' wing, the second in the spacer segment, and the third in the 3' wing. The spacer segment contains deoxyribonucleotides, and each nucleotide in each wing segment contains a 2'-modified sugar. Specific 2'-modified sugars are also indicated in the "Gapmer Modification Patterns" column. For example, the modification pattern "2-8-2" for ASO-01 refers to a 2-8-2 LNA gapmer modification pattern, where an 8-ribonucleotide spacer segment is flanked by a 2-nucleotide wing segment, where the nucleotides in the wing segment are 2'-LNA nucleotides. The internucleotide bond is a phosphate thioester.

[0965] Furthermore, the columns labeled "ASO S1 Region" represent the target sites of the corresponding ASO in SGLT1, and the columns labeled "ASO S2 Region" represent the target sites of the corresponding ASO in SGLT2. The columns labeled "Sequence" represent the raw sequence information, and the columns labeled "Modified Sequence" represent the sequence information after modification of the raw sequence. The spacer segments in the modified sequences are DNA sequences.

[0966] Table 1. Dual-target sequence information

[0967] Example 2: In vitro dual-luciferase reporter gene activity inhibition effect test of dual-targeted ASO

[0968] Construct psiCHECK-sglt1 and psiCHECK-sglt2 plasmids. Seed Hepa1-6 cells (ATCC, cat.CRL-1830) at a density of 20,000 cells / well in 96-well plates, with a volume of 90 μL per well. Add 0.3 μL of transfection reagent per well, and treat with ASO at concentrations of 100 nM and 10 nM (or 1 nM). Mix 5 μL of lipo2000 (Thermo Fisher Scientific, cat.L300015) dilution buffer with 5 μL of ASO and plasmid dilution buffer at a 1:1 ratio. Incubate at room temperature for 5 min. Then, add 10 μL of the transfection complex to the cells, gently mix, and incubate in a cell culture incubator for 24 h. The Luciferase Assay System (Vazyme, cat.DD1205) was used for detection. An ASO1-LNA group was included as a control in each 96-well plate.

[0969] The experimental results are shown in Table 2. Among them, 55 sequences showed that the inhibitory effect on SGLT2 was comparable to or better than that of ASO1-LNA, and the inhibition of SGLT1 was greater than 50%.

[0970] Table 2. Screening results of the in vitro dual-luciferase system

[0971] Example 3: Test of the inhibitory effect of dual-target ASO on target genes at the in vitro cellular level

[0972] SGLT2 was detected using HK-2 cells (ATCC, cat.CRL-2190), and SGLT1 was detected using Caco-2 cells (ATCC, cat.HTB-37).

[0973] When the cells in the culture dish have swelled to 80%-90% confluence, digest the cells using 1×10⁻⁶ water. 5 Cells were seeded at a density of 500 μL per well in a 24-well plate and cultured for 24 h in a 5% CO2, 37°C cell culture incubator.

[0974] Discard the old culture medium in the 24-well plate, add 450 μL of FBS-free (containing antibiotics) DMEM medium to each well, and dilute the transfection reagent lipo2000 (Thermo Fisher Scientific, cat. L300015) at 0.75 μL / well with ASO at concentrations of 500 nM and 50 nM, respectively, with 25 μL of Opti-MEM to dilute the transfection reagent and ASO stock solution (20 μM).

[0975] Mix the transfection reagent dilution and ASO dilution at a 1:1 ratio, incubate at room temperature for 5 min, add 50 μL of transfection complex to each well, and then place the 24-well plate in an incubator for 24 h.

[0976] Discard the cell culture supernatant, wash the cells once with 500 μL PBS, and add 500 μL of lysis buffer RL from the RNA extraction kit (Vazyme, cat.RC112-01) to extract total RNA according to the kit instructions.

[0977] Reverse transcription of RNA was performed according to the kit instructions (Vazyme, cat.R333);

[0978] Primers were designed for SGLT1, SGLT2, and GADPH as shown in Table 3 below.

[0979] Table 3. Primer Information

[0980] qPCR was performed according to the kit instructions (Thermo Fisher Scientific, cat.4312704), and the expression of sglt1 and sglt2 was calculated using ΔΔCT. The results are shown in Table 4.

[0981] Table 4 shows that the 28 ASO sequences exhibited better inhibition of SGLT2 than ASO1-LNA, and also showed greater than 50% inhibition of SGLT1.

[0982] Table 4. In vitro qPCR results

[0983] Example 4A: Efficacy test of ASO1 with different modifications in db / db mice

[0984] The positive control in this disclosure is sequence number ASO1 (ISIS ID: 388626), with the sequence from 5' to 3' being GGCATGAGCTTC, and its corresponding modification mode being 2-8-2MOE. It is an ASO product targeting SGLT2 disclosed in the prior art, specifically referred to EP patent: EP2023940B1 and Chinese patent CN103554205A.

[0985] To verify that LNA or cEt-modified ASO1 molecules are more effective than 2'MOE-modified ASO1, we used the ASO1 sequence and replaced the MOE modification in the wing region with LNA (ASO1-LNA) or cEt (ASO1-cEt). In the classic db / db diabetic mouse model, mice were subcutaneously administered four times at 0, 7, 14, and 21 days with different solvent groups (PBS), ASO1, ASO1-LNA, and ASO1-cEt), at a concentration of 1 μmol / kg each time, and blood glucose levels were monitored weekly. After the last administration, the mice were continuously fed to observe the duration of efficacy in each group and evaluate the hypoglycemic effect of different modified ASO1 molecules.

[0986] Male db / db mice were purchased from Chengdu Yaokang Biotechnology Co., Ltd. Mice were housed at a room temperature of 20–25℃, relative humidity of 40%–70%, with alternating light and dark cycles of 12 hours. After a week of acclimatization, mice were subcutaneously administered 1 μmol / kg once a week for a total of four times. The day of administration was designated as day 0. Blood glucose levels were monitored two days after each administration and weekly after drug withdrawal. After a 4-hour fast, 60–80 μL of blood was collected via orbital sampling, centrifuged at 3000×g at 4℃ for 15 min, and the supernatant was collected. Blood glucose levels were measured using a Beckman automated biochemical analyzer (DxC 700AU). The results are shown in Figure 1. All three modifications—MOE, LNA, and cEt—significantly reduced blood glucose. At 16 and 23 days post-administration, the hypoglycemic effects of ASO1-LNA and ASO1-cEt were similar, and both were significantly superior to the ASO1 group. Forty-four days after administration, blood glucose levels in the ASO1 group had returned to those in the solvent group, indicating that the duration of its efficacy did not exceed three weeks. In contrast, the hypoglycemic effects of ASO1-LNA and ASO1-cEt persisted until day 58, remaining significantly superior to the ASO1 group. This demonstrates that, building upon the therapeutic effect of ASO1, LNA or cEt modification significantly enhances both efficacy and duration of action.

[0987] Example 4B: Activity assay of MsPA-modified ASO in C57BL / N mice

[0988] To investigate the effect of the MsPA-modified dual-targeting sequence ASO-92 on the activity of mice, C57BL / 6N mice were administered a single subcutaneous injection of ASO-92 and ASO-92-04. Specific sequence information and modifications are shown in Table 1, where * represents a PS bond and # represents a MsPA bond. The dose was 0.3 μmol / kg. Seven days after administration, mice were euthanized, and kidneys were collected for RT-qPCR to detect SLGT2 expression. SLGT2 expression is shown in Table 5. The same method was used to verify the inhibitory effect of the MsPA-modified ASO on SGLT1. The results showed that the MsPA-modified and PS-modified dual-targeting ASOs had similar inhibitory effects on SGLT1 and SGLT2; replacing the PS bond with the MsPA bond did not affect the activity of ASO-92.

[0989] Table 5. Inhibitory effect of ASO on mSGLT2

[0990] Example 5: Detection of ASO1-LNA distribution in mouse tissues

[0991] To explore the targeting ability and tissue distribution of LNA-modified ASO1 in mice, C57BL / 6N mice were administered a single subcutaneous injection of ASO1-LNA at a dose of 1 μmol / kg. Three days after administration, the mice were euthanized, and the heart, liver, spleen, lungs, kidneys, small intestine, brain, gastrocnemius muscle, lymph nodes, injection site skin, and testes were harvested. LC-MS was used to analyze the exposure of ASO1-LNA in each tissue. Figure 2 shows that after systemic administration, LNA-modified ASO1 was mainly distributed in the kidneys, with a small amount distributed at the injection site, lymph nodes, and liver, and almost undetectable in the lungs, brain, and small intestine. Therefore, compared with existing SGLT2 small molecule inhibitors, LNA-modified ASO1 has better kidney targeting and can avoid SGLT1 expressed in the small intestine, thus avoiding potential safety issues.

[0992] Example 6: Test of the inhibitory effect of dual-targeting ASO on hSGLT2 in SGLT2 humanized mice (C57BL / 6J-hSGLT2)

[0993] Since some dual-targeting sequences are not identical to mouse SGLT2 but are homologous to human SGLT2, we used CRISPR / Cas9 technology to replace the human SLC5A2 transcript NM003041.4 with the mouse SLC5A2 transcript via homologous recombination, constructing a humanized SGLT2 mouse (C57BL / 6J-hSGLT2) that expresses human SGLT2 but not mouse SGLT2. We examined the inhibitory effect of dual-targeting ASO on hSGLT2 in C57BL / 6J-hSGLT2 mice. Mice were housed at room temperature of 20–25°C, relative humidity of 40%–70%, with 12-hour light-dark cycles, and were acclimatized for one week before being randomly divided into groups of four. Male mice were administered a single subcutaneous dose of 0.3 μmol / kg at 8 weeks of age. Three days after administration, the mice were euthanized with CO2, and kidneys were collected. Target gene expression was detected by RT-qPCR, following the methods described in the previous examples. The qPCR results were normalized to the PBS group, and the results are shown in Table 6 below. The results show that ASO-45 and ASO-70 significantly enhanced the KD effect on SGLT2 compared to ASO1-LNA.

[0994] Table 6. Inhibitory effect of ASO on hSGLT2

[0995] Example 7: Test of the inhibitory effect of dual-targeted ASO on mSGLT1 in C57BL / 6J mice

[0996] Male C57BL / 6J mice were purchased from Vital River Laboratory Animal Technology Co., Ltd. The housing conditions were controlled at room temperature of 20–25℃, relative humidity of 40%–70%, and alternating light and dark cycles of 12 hours. Feed was provided by Jiangsu Xietong Bioengineering Co., Ltd., feed production license: Su Si Zheng (2019) 01008. Drinking water was autoclaved tap water. Animals had free access to food and water. Cages and other equipment used for animal housing were autoclaved before use. Mice were acclimatized for one week, and at 8 weeks of age, they were randomly divided into groups of 5 mice each, and administered a single subcutaneous dose of 3 μmol / kg. Three days after administration, the mice were euthanized with CO2, and kidneys were collected. Target gene expression was detected by RT-qPCR, following the method described in the previous example. qPCR results were normalized to the PBS group, and the results are shown in Table 7 below. The results showed that ASO-50, ASO-70, and ASO-136 inhibited mSGLT1.

[0997] Table 7. Inhibitory effect of ASO on mSGLT1

[0998] Example 8: Efficacy test of dual-targeted ASO in SGLT2 humanized mice

[0999] To test the hypoglycemic effect of dual-targeted ASO in mice, we induced diabetes in female hSGLT2 mice using streptozotocin (STZ). All mice were intraperitoneally injected with 50 mg / kg STZ for 5 consecutive days, with a 6-hour fast before administration. To prevent STZ-induced hypoglycemia from affecting mouse health, 0.4 g / mL glucose solution (2 g / kg) was injected intraperitoneally 2 hours after each administration. One week after the last STZ administration, tail blood glucose levels were measured using a Roche Accu-chek handheld glucometer. Successful modeling was defined as a random blood glucose level exceeding 16.7 mmol / L for 3 consecutive days. Mice whose blood glucose levels did not meet the target were re-injected with 50 mg / kg STZ. The modeling success rate was over 90% after approximately one week. Mice were divided into groups of 4 based on their fasting blood glucose levels. They were treated subcutaneously twice a week at a dose of 1 μmol / kg for 2 weeks. The first ASO administration was designated as day 0. Two days after each administration, the mice were fasted for 6 hours before blood glucose was measured. The results are shown in Figure 3 and Table 8. The blood glucose levels of ASO-45 and ASO-70 were close to those of wild-type mice, and their blood glucose-lowering effect was better than that of ASO1-LNA.

[1000] Table 8. Hypoglycemic effect of dual-targeted ASO in SGLT2 humanized mice

[1001] Example 9: Efficacy evaluation of dual-targeting ASO in non-human primates

[1002] To evaluate the efficacy of dual-targeting ASO-70 and ASO1-LNA in non-human primates, we subcutaneously injected ASO1-LNA and ASO-70 into cynomolgus monkeys and monitored their 24-hour urinary glucose excretion.

[1003] The cynomolgus monkeys weighed 3–4 kg and were between 3 and 5 years old. All animals had free access to non-human primate food twice daily and free access to water. The monkeys were acclimatized for 2 weeks before the first administration. Then, based on blood and urine biochemistry, the monkeys were randomly divided into two groups of 3 monkeys each. Day 0 was defined as the day of the first administration. Animals in the ASO1-LNA and ASO-70 groups were administered 3 μmol / kg of ASO1-LNA and ASO-70 compounds on Day 0 and Day 14, respectively. Urine was collected from the animals over 24 hours during Day-2–Day-1, Day 27–Day 28, and Day 39–Day 40, and the urine volume was recorded. After urine collection, 2 mL of urine was centrifuged at 4°C and 3200g for 15 minutes. The supernatant was collected, and the urine glucose concentration was measured. The 24-hour urinary glucose excretion was calculated as: urine glucose concentration × 24-hour urine volume. The results are shown in Table 9. ASO1-LNA showed the highest urinary glucose excretion on Day 27–Day 28 after administration, followed by a decrease on Day 39–Day 40. ASO-70 showed the highest 24-hour urinary glucose excretion on Day 39–Day 40 after administration, and the maximum 24-hour urinary glucose excretion in the ASO-70 group was six times that of the ASO1-LNA group. Therefore, the dual-targeting sequence ASO-70 group significantly promoted urinary glucose excretion in non-human primates for a significantly longer duration than the ASO1-LNA group.

[1004] Table 9. Effects of dual-targeted ASO-70 on urinary glucose excretion in cynomolgus monkeys

[1005] The technical features of the above embodiments can be combined in any way. For the sake of brevity, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[1006] The embodiments described above are merely illustrative of several implementations of this disclosure, and while the descriptions are specific and detailed, they should not be construed as limiting the scope of the invention patent. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of this disclosure, and these all fall within the protection scope of this disclosure. Therefore, the protection scope of this patent should be determined by the appended claims.

Claims

An antisense oligonucleotide that dually targets SGLT2 and SGLT1, wherein the antisense oligonucleotide is 10-18 nucleotides in length, wherein... The antisense oligonucleotide is at least partially complementary to a segment of nucleotides in the respective transcribed mRNAs of SGLT2 and SGLT1, and reduces the amount of the corresponding mRNA or the expression level of the corresponding protein of SGLT2 and SGLT1. According to claim 1, the antisense oligonucleotide, wherein, The antisense oligonucleotide comprises at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, or at least 16 consecutive nucleotide sequences that differ from the nucleotide sequences shown in any of SEQ ID NO:1-166 by no more than 4, 3, 2, or 1 nucleotides. According to claim 1 or 2, the antisense oligonucleotide, wherein, The transcribed mRNA sequence of SGLT1 is shown in SEQ ID NO:

167. According to claim 1 or 2, the antisense oligonucleotide, wherein, The transcribed mRNA sequence of SGLT2 is shown in SEQ ID NO:

168. According to any one of claims 1-4, the antisense oligonucleotide, wherein, The antisense oligonucleotide is complementary to a portion or part of the nucleobase fragment 1 in the sequence shown in SEQ ID NO:167, and the nucleobase fragment 1 complementary to the antisense oligonucleotide is selected from the following regions or fragments thereof: (1) Segment 1231-1244 of SEQ ID NO:167; (2) Segment 195-206 of SEQ ID NO:167; (3) Segment 1136-1148 of SEQ ID NO:167; (4) Segment 484-497 of SEQ ID NO:167; (5) Segment 1205-1221 of SEQ ID NO:167; (6) Segment 1231-1251 of SEQ ID NO:167; (7) Segment 1375-1388 of SEQ ID NO:167; (8) Segment 1018-1038 of SEQ ID NO:167; (9) Segment 1174-1185 of SEQ ID NO:167; (10) Segment 1375-1392 of SEQ ID NO:167; (11) Segment 262-278 of SEQ ID NO:167; (12) Segment 620-631 of SEQ ID NO:167; (13) Segment 886-898 of SEQ ID NO:167; or (14) Segment 913-926 of SEQ ID NO:

167. According to any one of claims 1-4, the antisense oligonucleotide, wherein, The antisense oligonucleotide is complementary to a portion or part of the nucleobase fragment 2 in the sequence shown in SEQ ID NO:168, and the nucleobase fragment 2 complementary to the antisense oligonucleotide is selected from the following regions or fragments thereof: (1) Segment 1224-1237 of SEQ ID NO:168; (2) Segment 179-190 of SEQ ID NO:168; (3) Segment 1129-1141 of SEQ ID NO:168; (4) Segment 468-481 of SEQ ID NO:168; (5) Segment 1198-1214 of SEQ ID NO:168; (6) Segment 1224-1244 of SEQ ID NO:168; (7) Segment 1368-1381 of SEQ ID NO:168; (8) Segment 1011-1031 of SEQ ID NO:168; (9) Segment 1167-1178 of SEQ ID NO:168; (10) Segment 1368-1385 of SEQ ID NO:168; (11) Segment 246-262 of SEQ ID NO:168; (12) Segment 571-582 of SEQ ID NO:168; (13) Segment 879-891 of SEQ ID NO:168; or (14) Segment 906-919 of SEQ ID NO:

168. According to any one of claims 1-6, the antisense oligonucleotide, wherein, The antisense oligonucleotide is complementary to an equal-length portion or part of the sequence of nucleobase fragment 1 in the sequence shown in SEQ ID NO:167, and is also complementary to an equal-length portion or part of the sequence of nucleobase fragment 2 in the sequence shown in SEQ ID NO:

168. The nucleobase fragments 1 and 2 complementary to the antisense oligonucleotide are selected from any of the following combinations: (1) Nucleobase fragment 1 is the 1231-1242 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1224-1235 segment of SEQ ID NO:168; (2) Nucleobase fragment 1 is the 1231-1243 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1224-1236 segment of SEQ ID NO:168; (3) Nucleobase fragment 1 is the 1232-1243 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1225-1236 segment of SEQ ID NO:168; (4) Nucleobase fragment 1 is the 1231-1244 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1224-1237 segment of SEQ ID NO:168; (5) Nucleobase fragment 1 is the 1232-1244 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1225-1237 segment of SEQ ID NO:168; (6) Nucleobase fragment 1 is the 1233-1244 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1226-1237 segment of SEQ ID NO:168; (7) Nucleobase fragment 1 is the 195-206 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 179-190 segment of SEQ ID NO:168; (8) Nucleobase fragment 1 is the 1136-1147 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1129-1140 segment of SEQ ID NO:168; (9) Nucleobase fragment 1 is segment 1136-1148 of SEQ ID NO:167; Nucleobase fragment 2 is segment 1129-1141 of SEQ ID NO:168; (10) Nucleobase fragment 1 is segment 1137-1148 of SEQ ID NO:167; Nucleobase fragment 2 is segment 1130-1141 of SEQ ID NO:168; (11) Nucleobase fragment 1 is the 484-495 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 468-479 segment of SEQ ID NO:168; (12) Nucleobase fragment 1 is the 484-496 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 468-480 segment of SEQ ID NO:168; (13) Nucleobase fragment 1 is the 485-496 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 469-480 segment of SEQ ID NO:168; (14) Nucleobase fragment 1 is the 484-497 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 468-481 segment of SEQ ID NO:168; (15) Nucleobase fragment 1 is the 485-497 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 469-481 segment of SEQ ID NO:168; (16) Nucleobase fragment 1 is segment 486-497 of SEQ ID NO:167; Nucleobase fragment 2 is segment 470-481 of SEQ ID NO:168; (17) Nucleobase fragment 1 is the 1205-1216 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1198-1209 segment of SEQ ID NO:168; (18) Nucleobase fragment 1 is the 1205-1217 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1198-1210 segment of SEQ ID NO:168; (19) Nucleobase fragment 1 is the 1206-1217 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1199-1210 segment of SEQ ID NO:168; (20) Nucleobase fragment 1 is the 1205-1218 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1198-1211 segment of SEQ ID NO:168; (21) Nucleobase fragment 1 is the 1206-1218 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1199-1211 segment of SEQ ID NO:168; (22) Nucleobase fragment 1 is the 1207-1218 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1200-1211 segment of SEQ ID NO:168; (23) Nucleobase fragment 1 is the 1205-1219 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1198-1212 segment of SEQ ID NO:168; (24) Nucleobase fragment 1 is the 1206-1219 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1199-1212 segment of SEQ ID NO:168; (25) Nucleobase fragment 1 is the 1207-1219 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1200-1212 segment of SEQ ID NO:168; (26) Nucleobase fragment 1 is the 1208-1219 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1201-1212 segment of SEQ ID NO:168; (27) Nucleobase fragment 1 is the 1205-1220 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1198-1213 segment of SEQ ID NO:168; (28) Nucleobase fragment 1 is the 1206-1220 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1199-1213 segment of SEQ ID NO:168; (29) Nucleobase fragment 1 is the 1207-1220 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1200-1213 segment of SEQ ID NO:168; (30) Nucleobase fragment 1 is the 1208-1220 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1201-1213 segment of SEQ ID NO:168; (31) Nucleobase fragment 1 is the 1209-1220 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1202-1213 segment of SEQ ID NO:168; (32) Nucleobase fragment 1 is the 1206-1221 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1199-1214 segment of SEQ ID NO:168; (33) Nucleobase fragment 1 is the 1207-1221 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1200-1214 segment of SEQ ID NO:168; (34) Nucleobase fragment 1 is the 1208-1221 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1201-1214 segment of SEQ ID NO:168; (35) Nucleobase fragment 1 is the 1209-1221 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1202-1214 segment of SEQ ID NO:168; (36) Nucleobase fragment 1 is the 1210-1221 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1203-1214 segment of SEQ ID NO:168; (37) Nucleobase fragment 1 is the 1231-1245 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1224-1238 segment of SEQ ID NO:168; (38) Nucleobase fragment 1 is the 1232-1245 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1225-1238 segment of SEQ ID NO:168; (39) Nucleobase fragment 1 is the 1233-1245 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1226-1238 segment of SEQ ID NO:168; (40) Nucleobase fragment 1 is the 1234-1245 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1227-1238 segment of SEQ ID NO:168; (41) Nucleobase fragment 1 is the 1231-1246 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1224-1239 segment of SEQ ID NO:168; (42) Nucleobase fragment 1 is the 1232-1246 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1225-1239 segment of SEQ ID NO:168; (43) Nucleobase fragment 1 is the 1233-1246 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1226-1239 segment of SEQ ID NO:168; (44) Nucleobase fragment 1 is the 1234-1246 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1227-1239 segment of SEQ ID NO:168; (45) Nucleobase fragment 1 is the 1235-1246 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1228-1239 segment of SEQ ID NO:168; (46) Nucleobase fragment 1 is the 1232-1247 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1225-1240 segment of SEQ ID NO:168; (47) Nucleobase fragment 1 is the 1233-1247 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1226-1240 segment of SEQ ID NO:168; (48) Nucleobase fragment 1 is the 1234-1247 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1227-1240 segment of SEQ ID NO:168; (49) Nucleobase fragment 1 is the 1235-1247 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1228-1240 segment of SEQ ID NO:168; (50) Nucleobase fragment 1 is the 1236-1247 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1229-1240 segment of SEQ ID NO:168; (51) Nucleobase fragment 1 is segment 1233-1248 of SEQ ID NO:167; Nucleobase fragment 2 is segment 1226-1241 of SEQ ID NO:168; (52) Nucleobase fragment 1 is segment 1234-1248 of SEQ ID NO:167; Nucleobase fragment 2 is segment 1227-1241 of SEQ ID NO:168; (53) Nucleobase fragment 1 is the 1235-1248 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1228-1241 segment of SEQ ID NO:168; (54) Nucleobase fragment 1 is segment 1236-1248 of SEQ ID NO:167; Nucleobase fragment 2 is segment 1229-1241 of SEQ ID NO:168; (55) Nucleobase fragment 1 is segment 1237-1248 of SEQ ID NO:167; Nucleobase fragment 2 is segment 1230-1241 of SEQ ID NO:168; (56) Nucleobase fragment 1 is the 1234-1249 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1227-1242 segment of SEQ ID NO:168; (57) Nucleobase fragment 1 is the 1235-1249 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1228-1242 segment of SEQ ID NO:168; (58) Nucleobase fragment 1 is the 1236-1249 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1229-1242 segment of SEQ ID NO:168; (59) Nucleobase fragment 1 is segment 1237-1249 of SEQ ID NO:167; Nucleobase fragment 2 is segment 1230-1242 of SEQ ID NO:168; (60) Nucleobase fragment 1 is segment 1238-1249 of SEQ ID NO:167; Nucleobase fragment 2 is segment 1231-1242 of SEQ ID NO:168; (61) Nucleobase fragment 1 is the 1235-1250 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1228-1243 segment of SEQ ID NO:168; (62) Nucleobase fragment 1 is the 1236-1250 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1229-1243 segment of SEQ ID NO:168; (63) Nucleobase fragment 1 is the 1237-1250 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1230-1243 segment of SEQ ID NO:168; (64) Nucleobase fragment 1 is the 1238-1250 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1231-1243 segment of SEQ ID NO:168; (65) Nucleobase fragment 1 is the 1239-1250 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1232-1243 segment of SEQ ID NO:168; (66) Nucleobase fragment 1 is the 1236-1251 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1229-1244 segment of SEQ ID NO:168; (67) Nucleobase fragment 1 is the 1237-1251 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1230-1244 segment of SEQ ID NO:168; (68) Nucleobase fragment 1 is the 1238-1251 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1231-1244 segment of SEQ ID NO:168; (69) Nucleobase fragment 1 is the 1239-1251 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1232-1244 segment of SEQ ID NO:168; (70) Nucleobase fragment 1 is the 1240-1251 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1233-1244 segment of SEQ ID NO:168; (71) Nucleobase fragment 1 is the 1375-1386 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1368-1379 segment of SEQ ID NO:168; (72) Nucleobase fragment 1 is the 1375-1387 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1368-1380 segment of SEQ ID NO:168; (73) Nucleobase fragment 1 is the 1376-1387 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1369-1380 segment of SEQ ID NO:168; (74) Nucleobase fragment 1 is the 1375-1388 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1368-1381 segment of SEQ ID NO:168; (75) Nucleobase fragment 1 is the 1376-1388 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1369-1381 segment of SEQ ID NO:168; (76) Nucleobase fragment 1 is the 1377-1388 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1370-1381 segment of SEQ ID NO:168; (77) Nucleobase fragment 1 is segment 1018-1029 of SEQ ID NO:167; Nucleobase fragment 2 is segment 1011-1022 of SEQ ID NO:168; (78) Nucleobase fragment 1 is the 1018-1030 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1011-1023 segment of SEQ ID NO:168; (79) Nucleobase fragment 1 is the 1019-1030 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1012-1023 segment of SEQ ID NO:168; (80) Nucleobase fragment 1 is the 1018-1031 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1011-1024 segment of SEQ ID NO:168; (81) Nucleobase fragment 1 is the 1019-1031 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1012-1024 segment of SEQ ID NO:168; (82) Nucleobase fragment 1 is the 1020-1031 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1013-1024 segment of SEQ ID NO:168; (83) Nucleobase fragment 1 is the 1018-1032 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1011-1025 segment of SEQ ID NO:168; (84) Nucleobase fragment 1 is the 1019-1032 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1012-1025 segment of SEQ ID NO:168; (85) Nucleobase fragment 1 is the 1020-1032 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1013-1025 segment of SEQ ID NO:168; (86) Nucleobase fragment 1 is segment 1021-1032 of SEQ ID NO:167; Nucleobase fragment 2 is segment 1014-1025 of SEQ ID NO:168; (87) Nucleobase fragment 1 is the 1018-1033 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1011-1026 segment of SEQ ID NO:168; (88) Nucleobase fragment 1 is the 1019-1033 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1012-1026 segment of SEQ ID NO:168; (89) Nucleobase fragment 1 is the 1020-1033 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1013-1026 segment of SEQ ID NO:168; (90) Nucleobase fragment 1 is the 1021-1033 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1014-1026 segment of SEQ ID NO:168; (91) Nucleobase fragment 1 is the 1022-1033 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1015-1026 segment of SEQ ID NO:168; (92) Nucleobase fragment 1 is the 1019-1034 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1012-1027 segment of SEQ ID NO:168; (93) Nucleobase fragment 1 is the 1020-1034 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1013-1027 segment of SEQ ID NO:168; (94) Nucleobase fragment 1 is segment 1021-1034 of SEQ ID NO:167; Nucleobase fragment 2 is segment 1014-1027 of SEQ ID NO:168; (95) Nucleobase fragment 1 is the 1022-1034 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1015-1027 segment of SEQ ID NO:168; (96) Nucleobase fragment 1 is the 1023-1034 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1016-1027 segment of SEQ ID NO:168; (97) Nucleobase fragment 1 is the 1020-1035 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1013-1028 segment of SEQ ID NO:168; (98) Nucleobase fragment 1 is the 1021-1035 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1014-1028 segment of SEQ ID NO:168; (99) Nucleobase fragment 1 is the 1022-1035 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1015-1028 segment of SEQ ID NO:168; (100) Nucleobase fragment 1 is the 1023-1035 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1016-1028 segment of SEQ ID NO:168; (101) Nucleobase fragment 1 is the 1024-1035 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1017-1028 segment of SEQ ID NO:168; (102) Nucleobase fragment 1 is the 1021-1036 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1014-1029 segment of SEQ ID NO:168; (103) Nucleobase fragment 1 is the 1022-1036 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1015-1029 segment of SEQ ID NO:168; (104) Nucleobase fragment 1 is the 1024-1036 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1017-1029 segment of SEQ ID NO:168; (105) Nucleobase fragment 1 is the 1023-1036 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1016-1029 segment of SEQ ID NO:168; (106) Nucleobase fragment 1 is the 1025-1036 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1018-1029 segment of SEQ ID NO:168; (107) Nucleobase fragment 1 is the 1022-1037 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1015-1030 segment of SEQ ID NO:168; (108) Nucleobase fragment 1 is the 1023-1037 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1016-1030 segment of SEQ ID NO:168; (109) Nucleobase fragment 1 is the 1024-1037 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1017-1030 segment of SEQ ID NO:168; (110) Nucleobase fragment 1 is the 1025-1037 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1018-1030 segment of SEQ ID NO:168; (111) Nucleobase fragment 1 is the 1026-1037 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1019-1030 segment of SEQ ID NO:168; (112) Nucleobase fragment 1 is the 1023-1038 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1016-1031 segment of SEQ ID NO:168; (113) Nucleobase fragment 1 is segment 1024-1038 of SEQ ID NO:167; Nucleobase fragment 2 is segment 1017-1031 of SEQ ID NO:168; (114) Nucleobase fragment 1 is the 1025-1038 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1018-1031 segment of SEQ ID NO:168; (115) Nucleobase fragment 1 is the 1026-1038 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1019-1031 segment of SEQ ID NO:168; (116) Nucleobase fragment 1 is the 1027-1038 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1020-1031 segment of SEQ ID NO:168; (117) Nucleobase fragment 1 is the 1174-1185 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1167-1178 segment of SEQ ID NO:168; (118) Nucleobase fragment 1 is the 1375-1389 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1368-1382 segment of SEQ ID NO:168; (119) Nucleobase fragment 1 is the 1376-1389 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1369-1382 segment of SEQ ID NO:168; (120) Nucleobase fragment 1 is the 1377-1389 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1370-1382 segment of SEQ ID NO:168; (121) Nucleobase fragment 1 is the 1378-1389 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1371-1382 segment of SEQ ID NO:168; (122) Nucleobase fragment 1 is the 1375-1390 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1368-1383 segment of SEQ ID NO:168; (123) Nucleobase fragment 1 is the 1376-1390 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1369-1383 segment of SEQ ID NO:168; (124) Nucleobase fragment 1 is the 1377-1390 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1370-1383 segment of SEQ ID NO:168; (125) Nucleobase fragment 1 is the 1378-1390 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1371-1383 segment of SEQ ID NO:168; (126) Nucleobase fragment 1 is the 1379-1390 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1372-1383 segment of SEQ ID NO:168; (127) Nucleobase fragment 1 is the 1376-1391 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1369-1384 segment of SEQ ID NO:168; (128) Nucleobase fragment 1 is the 1377-1391 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1370-1384 segment of SEQ ID NO:168; (129) Nucleobase fragment 1 is the 1378-1391 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1371-1384 segment of SEQ ID NO:168; (130) Nucleobase fragment 1 is the 1379-1391 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1372-1384 segment of SEQ ID NO:168; (131) Nucleobase fragment 1 is the 1380-1391 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1373-1384 segment of SEQ ID NO:168; (132) Nucleobase fragment 1 is the 1377-1392 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1370-1385 segment of SEQ ID NO:168; (133) Nucleobase fragment 1 is the 1378-1392 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1371-1385 segment of SEQ ID NO:168; (134) Nucleobase fragment 1 is the 1379-1392 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1372-1385 segment of SEQ ID NO:168; (135) Nucleobase fragment 1 is the 1380-1392 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 1373-1385 segment of SEQ ID NO:168; (136) Nucleobase fragment 1 is segment 1381-1392 of SEQ ID NO:167; Nucleobase fragment 2 is segment 1374-1385 of SEQ ID NO:168; (137) Nucleobase fragment 1 is segment 262-273 of SEQ ID NO:167; Nucleobase fragment 2 is segment 246-257 of SEQ ID NO:168; (138) Nucleobase fragment 1 is segment 262-274 of SEQ ID NO:167; Nucleobase fragment 2 is segment 246-258 of SEQ ID NO:168; (139) Nucleobase fragment 1 is segment 263-274 of SEQ ID NO:167; Nucleobase fragment 2 is segment 247-258 of SEQ ID NO:168; (140) Nucleobase fragment 1 is the 262-275 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 246-259 segment of SEQ ID NO:168; (141) Nucleobase fragment 1 is segment 263-275 of SEQ ID NO:167; Nucleobase fragment 2 is segment 247-259 of SEQ ID NO:168; (142) Nucleobase fragment 1 is the 264-275 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 248-259 segment of SEQ ID NO:168; (143) Nucleobase fragment 1 is the 262-276 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 246-260 segment of SEQ ID NO:168; (144) Nucleobase fragment 1 is the 263-276 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 247-260 segment of SEQ ID NO:168; (145) Nucleobase fragment 1 is the 264-276 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 248-260 segment of SEQ ID NO:168; (146) Nucleobase fragment 1 is the 265-276 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 249-260 segment of SEQ ID NO:168; (147) Nucleobase fragment 1 is the 262-277 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 246-261 segment of SEQ ID NO:168; (148) Nucleobase fragment 1 is the 263-277 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 247-261 segment of SEQ ID NO:168; (149) Nucleobase fragment 1 is the 264-277 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 248-261 segment of SEQ ID NO:168; (150) Nucleobase fragment 1 is the 265-277 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 249-261 segment of SEQ ID NO:168; (151) Nucleobase fragment 1 is the 266-277 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 250-261 segment of SEQ ID NO:168; (152) Nucleobase fragment 1 is segment 263-278 of SEQ ID NO:167; Nucleobase fragment 2 is segment 247-262 of SEQ ID NO:168; (153) Nucleobase fragment 1 is segment 264-278 of SEQ ID NO:167; Nucleobase fragment 2 is segment 248-262 of SEQ ID NO:168; (154) Nucleobase fragment 1 is segment 265-278 of SEQ ID NO:167; Nucleobase fragment 2 is segment 249-262 of SEQ ID NO:168; (155) Nucleobase fragment 1 is segment 266-278 of SEQ ID NO:167; Nucleobase fragment 2 is segment 250-262 of SEQ ID NO:168; (156) Nucleobase fragment 1 is segment 267-278 of SEQ ID NO:167; Nucleobase fragment 2 is segment 251-262 of SEQ ID NO:168; (157) Nucleobase fragment 1 is segment 620-631 of SEQ ID NO:167; Nucleobase fragment 2 is segment 571-582 of SEQ ID NO:168; (158) Nucleobase fragment 1 is the 886-897 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 879-890 segment of SEQ ID NO:168; (159) Nucleobase fragment 1 is the 886-898 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 879-891 segment of SEQ ID NO:168; (160) Nucleobase fragment 1 is the 887-898 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 880-891 segment of SEQ ID NO:168; (161) Nucleobase fragment 1 is the 913-924 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 906-917 segment of SEQ ID NO:168; (162) Nucleobase fragment 1 is the 913-925 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 906-918 segment of SEQ ID NO:168; (163) Nucleobase fragment 1 is the 914-925 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 907-918 segment of SEQ ID NO:168; (164) Nucleobase fragment 1 is the 913-926 segment of SEQ ID NO:167; Nucleobase fragment 2 is the 906-919 segment of SEQ ID NO:168; (165) Nucleobase fragment 1 is region 914-926 of SEQ ID NO:167; nucleobase fragment 2 is region 907-919 of SEQ ID NO:168; or (166) Nucleobase fragment 1 is segment 915-926 of SEQ ID NO:167; nucleobase fragment 2 is segment 908-919 of SEQ ID NO:

168. According to any one of claims 1-7, the antisense oligonucleotide, wherein, The antisense oligonucleotide is 10-16 nucleotides in length. According to any one of claims 1-8, the antisense oligonucleotide, wherein, The antisense oligonucleotide comprises: A spacer segment consisting of 8-10 consecutive deoxynucleotides; The 5' wing region consists of 1-3 consecutive nucleotides; and A 3' wing region consisting of 1-3 consecutive nucleotides; The spacer segment is located between the 5' wing region and the 3' wing region, and the 5' wing region and the 3' wing region contain modified nucleotides; Preferably, each nucleotide in the 5' wing region and the 3' wing region is a modified nucleotide; Preferably, the spacer segment contains modified nucleotides. According to claim 9, the antisense oligonucleotide, wherein, The modified nucleotides are base-modified nucleotides, sugar-modified nucleotides, and / or phosphate backbone-modified nucleotides. According to claim 10, the antisense oligonucleotide, wherein, The modified nucleotide is a sugar-modified nucleotide; Preferably, the sugar-modified nucleotide contains a cyclopropyl group located at the 5' carbon of the sugar; Preferably, the sugar-modified nucleotide contains a bridge between the 4'-carbon and the 2'-carbon of the sugar, and the sugar-modified nucleotide is a 4'-2'-bridged bicyclic nucleotide. According to claim 11, the antisense oligonucleotide, wherein, The sugar-modified nucleotide contains a 2' substituent other than H or OH, the 2' substituent being independently selected from substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, or halogen. According to claim 12, the antisense oligonucleotide, wherein, The bridge independently comprises one or two to four linking groups, which are independently selected from -R-[C(R1)(R2)] n -R'-、-[C(R1)(R2)] n -R-R'-、-R-R'-[C(R1)(R2)] n -, -RC(R1)=C(R2)-R'-, -R-R'-C(R1)=C(R2)-, -C(R1)=C(R2)-R-R'-, -C(R1)=N-; R and R' are each independently selected from single bonds, -N(R3)-, -O-, -S-, -Se-, -Si(R4)(R5)-, -C(=O)-, -C(=S)-, -C(=NR3)-; Preferably, the linking group is independently selected from -[C(R1)(R2)] n -、-[C(R1)(R2)] n -O-、-[C(R1)(R2)] n -N(R3)-、-[C(R1)(R2)] n -N(R3)-O-、-[C(R1)(R2)] n -ON(R3)-、-[C(R1)(R2)] n -S-, -C(R1)=C(R2)-, -C(R1)=N-; in, n is 1, 2, 3 or 4; Each R1, R2, R4, R5 is independently selected from H, protecting group, hydroxyl group, substituted or unsubstituted C1-C. 12 Alkyl, substituted or unsubstituted C2-C 12 alkenyl, substituted or unsubstituted C2-C 12 Alkyne, substituted or unsubstituted C5-C 20 Aryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heteroaryl, substituted or unsubstituted C5-C7 alicyclic group, halogen, OJ1, NJ1J2, SJ1, N3, COOJ1, acyl (C(=O)-H or C(=O)-J1), substituted acyl, CN, sulfonyl (S(=O)2-J1) or sulfonyloxy (S(=O)-J1), or R1 and R2 linked together to form C3-C6 cycloalkyl or heterocyclic alkyl; R3 is selected from H, protecting group, hydroxyl group, substituted or unsubstituted C1-C. 12 Alkyl, substituted or unsubstituted C2-C 12 alkenyl, substituted or unsubstituted C2-C 12 Alkyne, substituted or unsubstituted C5-C 20 Aryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heteroaryl, substituted or unsubstituted C5-C7 alicyclic group, halogen, OJ1, NJ1J2, SJ1, N3, COOJ1, acyl (C(=O)-H or C(=O)-J1), substituted acyl, CN, sulfonyl (S(=O)2-J1), sulfonyloxy (S(=O)-J1) or -C(=NH)-NH2; Each J1 and J2 is independently H, substituted or unsubstituted C1-C. 12 Alkyl, substituted or unsubstituted C2-C 12 alkenyl, substituted or unsubstituted C2-C 12 Alkyne, substituted or unsubstituted C5-C 20 Aryl, substituted or unsubstituted acyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted C1-C 12 Aminoalkyl or protecting group. According to claim 13, the antisense oligonucleotide, wherein, The bridge is independently 4'-CH2-2', 4'-(CH2)2-2', 4'-CH2-O-2', 4'-CH(CH3)-O-2', 4'-C(C3H5)-O-2', 4'-CH2-ON(R3)-2', 4'-CH2-N(R3)-O-2', 4'-CH2-N(R3)-2', 4'-CH(R1)-NH-2', 4'-CH(R1)-N(R3)-2', 4'-CH2-S-2', 4'-CH(CH3)-S-2', 4'-CH2-R4-2', or 4'-C(=O)-N(R3)-2', wherein each R1, R2, R3 is independently a protecting group or a C1-C3 alkyl group. According to claim 13, the antisense oligonucleotide, wherein, The bridge is independently 4'-C(C3H6)-O-2' or 4'-C(C2H4)-O-2', wherein each R1, R2, R3 is independently a protecting group or a C1-C3 alkyl group. According to any one of claims 1-15, the antisense oligonucleotide, wherein, The sugar-modified nucleotides are LNA, cET, ENA, 2'-fluorine-modified nucleotides, 2'-O-methyl-modified nucleotides, and combinations thereof; Preferably, the sugar-modified nucleotide is an LNA nucleotide selected from the following structures: Wherein, the definitions of R1, R2, and R are as described in claim 14; preferably, R is selected from O, S, or N-R3, and the definitions of R1, R2, and R3 are as described in claim 14; Preferably, the sugar-modified nucleotide is an LNA nucleotide selected from the following structures: R3 is defined as described in claim 14. The antisense oligonucleotide according to any one of claims 1-16, wherein, The modified nucleotide is a phosphate backbone modified nucleotide, and the phosphate backbone includes phosphate backbone modification of the spacer segment and / or phosphate backbone modification of the wing region. Preferably, the phosphate backbone modification includes 5'-phosphate mimicry modification; Preferably, the 5'-phosphate ester mimic is selected from 5'-oxymethylphosphonate, 5'-vinylphosphonic acid, 5'-vinylphosphonate-2'-N-acetyl or 5'-malonylphosphonate. The antisense oligonucleotide according to any one of claims 1-17 has a modification pattern selected from 2-8-2, 2-8-3, 3-8-3, 3-9-3, 3-10-3, wherein the first number represents the number of nucleotides in the 5' wing region, the second number represents the number of deoxynucleotides in the spacer region, and the third number represents the number of nucleotides in the 3' wing region. The antisense nucleotide sequence according to any one of claims 1-18, wherein, The antisense nucleotide sequence is selected from any of the following modified sequences: (1) It has the nucleotide sequence shown in SEQ ID NO:1 and the modification pattern shown in 2-8-2; (2) It has the nucleotide sequence shown in SEQ ID NO:2 and the modification pattern shown in 2-8-3; (3) It has a nucleotide sequence as shown in SEQ ID NO:3 and a modification pattern as shown in 2-8-2; (4) Having a nucleotide sequence as shown in SEQ ID NO:4 and a modification pattern as shown in 3-8-3; (5) Having a nucleotide sequence as shown in SEQ ID NO:5 and a modification pattern as shown in 2-8-3; (6) Having a nucleotide sequence as shown in SEQ ID NO:6 and a modification pattern as shown in 2-8-2; (7) Having a nucleotide sequence as shown in SEQ ID NO:7 and a modification pattern as shown in 2-8-2; (8) Having a nucleotide sequence as shown in SEQ ID NO:8 and a modification pattern as shown in 2-8-2; (9) Having a nucleotide sequence as shown in SEQ ID NO:9 and a modification pattern as shown in 2-8-3; (10) Having a nucleotide sequence as shown in SEQ ID NO:10 and a modification pattern as shown in 2-8-2; (11) Having a nucleotide sequence as shown in SEQ ID NO:11 and a modification pattern as shown in 2-8-2; (12) Having a nucleotide sequence as shown in SEQ ID NO:12 and a modification pattern as shown in 2-8-3; (13) Having a nucleotide sequence as shown in SEQ ID NO:13 and a modification pattern as shown in 2-8-2; (14) Having a nucleotide sequence as shown in SEQ ID NO:14 and a modification pattern as shown in 3-8-3; (15) Having a nucleotide sequence as shown in SEQ ID NO:15 and a modification pattern as shown in 2-8-3; (16) Having a nucleotide sequence as shown in SEQ ID NO:16 and a modification pattern as shown in 2-8-2; (17) Having a nucleotide sequence as shown in SEQ ID NO:17 and a modification pattern as shown in 2-8-2; (18) Having a nucleotide sequence as shown in SEQ ID NO:18 and a modification pattern as shown in 2-8-3; (19) Having a nucleotide sequence as shown in SEQ ID NO:19 and a modification pattern as shown in 2-8-2; (20) Having a nucleotide sequence as shown in SEQ ID NO:20 and a modification pattern as shown in 3-8-3; (21) Having a nucleotide sequence as shown in SEQ ID NO:21 and a modification pattern as shown in 2-8-3; (22) Having a nucleotide sequence as shown in SEQ ID NO:22 and a modification pattern as shown in 2-8-2; (23) Having a nucleotide sequence as shown in SEQ ID NO:23 and a modification pattern as shown in 3-9-3; (24) Having a nucleotide sequence as shown in SEQ ID NO:24 and a modification pattern as shown in 3-8-3; (25) Having a nucleotide sequence as shown in SEQ ID NO:25 and a modification pattern as shown in 2-8-3; (26) Having a nucleotide sequence as shown in SEQ ID NO:26 and a modification pattern as shown in 2-8-2; (27) Having a nucleotide sequence as shown in SEQ ID NO:27 and a modification pattern as shown in 3-10-3; (28) Having a nucleotide sequence as shown in SEQ ID NO:28 and a modification pattern as shown in 3-9-3; (29) Having a nucleotide sequence as shown in SEQ ID NO:29 and a modification pattern as shown in 3-8-3; (30) Having a nucleotide sequence as shown in SEQ ID NO:30 and a modification pattern as shown in 2-8-3; (31) Having a nucleotide sequence as shown in SEQ ID NO:31 and a modification pattern as shown in 2-8-2; (32) Having a nucleotide sequence as shown in SEQ ID NO:32 and a modification pattern as shown in 3-10-3; (33) Having a nucleotide sequence as shown in SEQ ID NO:33 and a modification pattern as shown in 3-9-3; (34) Having a nucleotide sequence as shown in SEQ ID NO:34 and a modification pattern as shown in 3-8-3; (35) Having a nucleotide sequence as shown in SEQ ID NO:35 and a modification pattern as shown in 2-8-3; (36) Having a nucleotide sequence as shown in SEQ ID NO:36 and a modification pattern as shown in 2-8-2; (37) Having a nucleotide sequence as shown in SEQ ID NO:37 and a modification pattern as shown in 3-9-3; (38) Having a nucleotide sequence as shown in SEQ ID NO:38 and a modification pattern as shown in 3-8-3; (39) Having a nucleotide sequence as shown in SEQ ID NO:39 and a modification pattern as shown in 2-8-3; (40) Having a nucleotide sequence as shown in SEQ ID NO:40 and a modification pattern as shown in 2-8-2; (41) Having a nucleotide sequence as shown in SEQ ID NO:41 and a modification pattern as shown in 3-10-3; (42) Having a nucleotide sequence as shown in SEQ ID NO:42 and a modification pattern as shown in 3-9-3; (43) Having a nucleotide sequence as shown in SEQ ID NO:43 and a modification pattern as shown in 3-8-3; (44) Having a nucleotide sequence as shown in SEQ ID NO:44 and a modification pattern as shown in 2-8-3; (45) Having a nucleotide sequence as shown in SEQ ID NO:45 and a modification pattern as shown in 2-8-2; (46) Having a nucleotide sequence as shown in SEQ ID NO:46 and a modification pattern as shown in 3-10-3; (47) Having a nucleotide sequence as shown in SEQ ID NO:47 and a modification pattern as shown in 3-9-3; (48) Having a nucleotide sequence as shown in SEQ ID NO:48 and a modification pattern as shown in 3-8-3; (49) Having a nucleotide sequence as shown in SEQ ID NO:49 and a modification pattern as shown in 2-8-3; (50) Having a nucleotide sequence as shown in SEQ ID NO:50 and a modification pattern as shown in 2-8-2; (51) Having a nucleotide sequence as shown in SEQ ID NO:51 and a modification pattern as shown in 3-10-3; (52) Having a nucleotide sequence as shown in SEQ ID NO:52 and a modification pattern as shown in 3-9-3; (53) Having a nucleotide sequence as shown in SEQ ID NO:53 and a modification pattern as shown in 3-8-3; (54) Having a nucleotide sequence as shown in SEQ ID NO:54 and a modification pattern as shown in 2-8-3; (55) Having a nucleotide sequence as shown in SEQ ID NO:55 and a modification pattern as shown in 2-8-2; (56) Having a nucleotide sequence as shown in SEQ ID NO:56 and a modification pattern as shown in 3-10-3; (57) Having a nucleotide sequence as shown in SEQ ID NO:57 and a modification pattern as shown in 3-9-3; (58) Having a nucleotide sequence as shown in SEQ ID NO:58 and a modification pattern as shown in 3-8-3; (59) Having a nucleotide sequence as shown in SEQ ID NO:59 and a modification pattern as shown in 2-8-3; (60) Having a nucleotide sequence as shown in SEQ ID NO:60 and a modification pattern as shown in 2-8-2; (61) Having a nucleotide sequence as shown in SEQ ID NO:61 and a modification pattern as shown in 3-10-3; (62) Having a nucleotide sequence as shown in SEQ ID NO:62 and a modification pattern as shown in 3-9-3; (63) Having a nucleotide sequence as shown in SEQ ID NO:63 and a modification pattern as shown in 3-8-3; (64) Having a nucleotide sequence as shown in SEQ ID NO:64 and a modification pattern as shown in 2-8-3; (65) Having a nucleotide sequence as shown in SEQ ID NO:65 and a modification pattern as shown in 2-8-2; (66) Having a nucleotide sequence as shown in SEQ ID NO:66 and a modification pattern as shown in 3-10-3; (67) Having a nucleotide sequence as shown in SEQ ID NO:67 and a modification pattern as shown in 3-9-3; (68) Having a nucleotide sequence as shown in SEQ ID NO:68 and a modification pattern as shown in 3-8-3; (69) Having a nucleotide sequence as shown in SEQ ID NO:69 and a modification pattern as shown in 2-8-3; (70) Having a nucleotide sequence as shown in SEQ ID NO:70 and a modification pattern as shown in 2-8-2; (71) Having a nucleotide sequence as shown in SEQ ID NO:71 and a modification pattern as shown in 2-8-2; (72) Having a nucleotide sequence as shown in SEQ ID NO:72 and a modification pattern as shown in 2-8-3; (73) Having a nucleotide sequence as shown in SEQ ID NO:73 and a modification pattern as shown in 2-8-2; (74) Having a nucleotide sequence as shown in SEQ ID NO:74 and a modification pattern as shown in 3-8-3; (75) Having a nucleotide sequence as shown in SEQ ID NO:75 and a modification pattern as shown in 2-8-3; (76) Having a nucleotide sequence as shown in SEQ ID NO:76 and a modification pattern as shown in 2-8-2; (77) Having a nucleotide sequence as shown in SEQ ID NO:77 and a modification pattern as shown in 2-8-2; (78) Having a nucleotide sequence as shown in SEQ ID NO:78 and a modification pattern as shown in 2-8-3; (79) Having a nucleotide sequence as shown in SEQ ID NO:79 and a modification pattern as shown in 2-8-2; (80) Having a nucleotide sequence as shown in SEQ ID NO:80 and a modification pattern as shown in 3-8-3; (81) Having a nucleotide sequence as shown in SEQ ID NO:81 and a modification pattern as shown in 2-8-3; (82) Having a nucleotide sequence as shown in SEQ ID NO:82 and a modification pattern as shown in 2-8-2; (83) Having a nucleotide sequence as shown in SEQ ID NO:83 and a modification pattern as shown in 3-9-3; (84) Having a nucleotide sequence as shown in SEQ ID NO:84 and a modification pattern as shown in 3-8-3; (85) Having a nucleotide sequence as shown in SEQ ID NO:85 and a modification pattern as shown in 2-8-3; (86) Having a nucleotide sequence as shown in SEQ ID NO:86 and a modification pattern as shown in 2-8-2; (87) Having a nucleotide sequence as shown in SEQ ID NO:87 and a modification pattern as shown in 3-10-3; (88) Having a nucleotide sequence as shown in SEQ ID NO:88 and a modification pattern as shown in 3-9-3; (89) Having a nucleotide sequence as shown in SEQ ID NO:89 and a modification pattern as shown in 3-8-3; (90) Having a nucleotide sequence as shown in SEQ ID NO:90 and a modification pattern as shown in 2-8-3; (91) Having a nucleotide sequence as shown in SEQ ID NO:91 and a modification pattern as shown in 2-8-2; (92) Having a nucleotide sequence as shown in SEQ ID NO:92 and a modification pattern as shown in 3-10-3; (93) Having a nucleotide sequence as shown in SEQ ID NO:93 and a modification pattern as shown in 3-9-3; (94) Having a nucleotide sequence as shown in SEQ ID NO:94 and a modification pattern as shown in 3-8-3; (95) Having a nucleotide sequence as shown in SEQ ID NO:95 and a modification pattern as shown in 2-8-3; (96) Having a nucleotide sequence as shown in SEQ ID NO:96 and a modification pattern as shown in 2-8-2; (97) Having a nucleotide sequence as shown in SEQ ID NO:97 and a modification pattern as shown in 3-10-3; (98) Having a nucleotide sequence as shown in SEQ ID NO:98 and a modification pattern as shown in 3-9-3; (99) has the nucleotide sequence shown in SEQ ID NO:99 and the modification pattern shown in 3-8-3; (100) has the nucleotide sequence shown in SEQ ID NO:100 and the modification pattern shown in 2-8-3; (101) has the nucleotide sequence shown in SEQ ID NO:101 and the modification pattern shown in 2-8-2; (102) Having a nucleotide sequence as shown in SEQ ID NO:102 and a modification pattern as shown in 3-10-3; (103) has the nucleotide sequence shown in SEQ ID NO:103 and the modification pattern shown in 3-9-3; (104) has the nucleotide sequence shown in SEQ ID NO:104 and the modification pattern shown in 3-8-3; (105) has the nucleotide sequence shown in SEQ ID NO:105 and the modification pattern shown in 2-8-3; (106) has the nucleotide sequence shown in SEQ ID NO:106 and the modification pattern shown in 2-8-2; (107) has the nucleotide sequence shown in SEQ ID NO:107 and the modification pattern shown in 3-10-3; (108) has the nucleotide sequence shown in SEQ ID NO:108 and the modification pattern shown in 3-9-3; (109) has the nucleotide sequence shown in SEQ ID NO:109 and the modification pattern shown in 3-8-3; (110) has the nucleotide sequence shown in SEQ ID NO:110 and the modification pattern shown in 2-8-3; (111) has the nucleotide sequence shown in SEQ ID NO:111 and the modification pattern shown in 2-8-2; (112) Having a nucleotide sequence as shown in SEQ ID NO:112 and a modification pattern as shown in 3-10-3; (113) Having a nucleotide sequence as shown in SEQ ID NO:113 and a modification pattern as shown in 3-9-3; (114) Having the nucleotide sequence shown in SEQ ID NO:114 and the modification pattern shown in 3-8-3; (115) has the nucleotide sequence shown in SEQ ID NO:115 and the modification pattern shown in 2-8-3; (116) has the nucleotide sequence shown in SEQ ID NO:116 and the modification pattern shown in 2-8-2; (117) Having the nucleotide sequence shown in SEQ ID NO:117 and the modification pattern shown in 2-8-2; (118) Having the nucleotide sequence shown in SEQ ID NO:118 and the modification pattern shown in 3-9-3; (119) has the nucleotide sequence shown in SEQ ID NO:119 and the modification pattern shown in 3-8-3; (120) has the nucleotide sequence shown in SEQ ID NO:120 and the modification pattern shown in 2-8-3; (121) Having the nucleotide sequence shown in SEQ ID NO:121 and the modification pattern shown in 2-8-2; (122) has the nucleotide sequence shown in SEQ ID NO:122 and the modification pattern shown in 3-10-3; (123) has the nucleotide sequence shown in SEQ ID NO:123 and the modification pattern shown in 3-9-3; (124) has the nucleotide sequence shown in SEQ ID NO:124 and the modification pattern shown in 3-8-3; (125) has the nucleotide sequence shown in SEQ ID NO:125 and the modification pattern shown in 2-8-3; (126) has the nucleotide sequence shown in SEQ ID NO:126 and the modification pattern shown in 2-8-2; (127) Having a nucleotide sequence as shown in SEQ ID NO:127 and a modification pattern as shown in 3-10-3; (128) has the nucleotide sequence shown in SEQ ID NO:128 and the modification pattern shown in 3-9-3; (129) has the nucleotide sequence shown in SEQ ID NO:129 and the modification pattern shown in 3-8-3; (130) has the nucleotide sequence shown in SEQ ID NO:130 and the modification pattern shown in 2-8-3; (131) Having the nucleotide sequence shown in SEQ ID NO:131 and the modification pattern shown in 2-8-2; (132) Having a nucleotide sequence as shown in SEQ ID NO:132 and a modification pattern as shown in 3-10-3; (133) has the nucleotide sequence shown in SEQ ID NO:133 and the modification pattern shown in 3-9-3; (134) has the nucleotide sequence shown in SEQ ID NO:134 and the modification pattern shown in 3-8-3; (135) has the nucleotide sequence shown in SEQ ID NO:135 and the modification pattern shown in 2-8-3; (136) has the nucleotide sequence shown in SEQ ID NO:136 and the modification pattern shown in 2-8-2; (137) has the nucleotide sequence shown in SEQ ID NO:137 and the modification pattern shown in 2-8-2; (138) has the nucleotide sequence shown in SEQ ID NO:138 and the modification pattern shown in 2-8-3; (139) has the nucleotide sequence shown in SEQ ID NO:139 and the modification pattern shown in 2-8-2; (140) has the nucleotide sequence shown in SEQ ID NO:140 and the modification pattern shown in 3-8-3; (141) Having the nucleotide sequence shown in SEQ ID NO:141 and the modification pattern shown in 2-8-3; (142) Having a nucleotide sequence as shown in SEQ ID NO:142 and a modification pattern as shown in 2-8-2; (143) Having the nucleotide sequence shown in SEQ ID NO:143 and the modification pattern shown in 3-9-3; (144) has the nucleotide sequence shown in SEQ ID NO:144 and the modification pattern shown in 3-8-3; (145) has the nucleotide sequence shown in SEQ ID NO:145 and the modification pattern shown in 2-8-3; (146) has the nucleotide sequence shown in SEQ ID NO:146 and the modification pattern shown in 2-8-2; (147) Having a nucleotide sequence as shown in SEQ ID NO:147 and a modification pattern as shown in 3-10-3; (148) Having the nucleotide sequence shown in SEQ ID NO:148 and the modification pattern shown in 3-9-3; (149) has the nucleotide sequence shown in SEQ ID NO:149 and the modification pattern shown in 3-8-3; (150) has the nucleotide sequence shown in SEQ ID NO:150 and the modification pattern shown in 2-8-3; (151) Having a nucleotide sequence as shown in SEQ ID NO:151 and a modification pattern as shown in 2-8-2; (152) Having a nucleotide sequence as shown in SEQ ID NO:152 and a modification pattern as shown in 3-10-3; (153) has the nucleotide sequence shown in SEQ ID NO:153 and the modification pattern shown in 3-9-3; (154) has the nucleotide sequence shown in SEQ ID NO:154 and the modification pattern shown in 3-8-3; (155) has the nucleotide sequence shown in SEQ ID NO:155 and the modification pattern shown in 2-8-3; (156) has the nucleotide sequence shown in SEQ ID NO:156 and the modification pattern shown in 2-8-2; (157) has the nucleotide sequence shown in SEQ ID NO:157 and the modification pattern shown in 2-8-2; (158) has the nucleotide sequence shown in SEQ ID NO:158 and the modification pattern shown in 2-8-2; (159) has the nucleotide sequence shown in SEQ ID NO:159 and the modification pattern shown in 2-8-3; (160) has the nucleotide sequence shown in SEQ ID NO:160 and the modification pattern shown in 2-8-2; (161) Having the nucleotide sequence shown in SEQ ID NO:161 and the modification pattern shown in 2-8-2; (162) has the nucleotide sequence shown in SEQ ID NO:162 and the modification pattern shown in 2-8-3; (163) has the nucleotide sequence shown in SEQ ID NO:163 and the modification pattern shown in 2-8-2; (164) has the nucleotide sequence shown in SEQ ID NO:164 and the modification pattern shown in 3-8-3; (165) Having the nucleotide sequence shown in SEQ ID NO:165 and the modification pattern shown in 2-8-3; or (166) has the nucleotide sequence shown in SEQ ID NO:166 and the modification pattern shown in 2-8-2; In the modified pattern, the first number represents the number of nucleotides in the 5' wing region, the second number represents the number of nucleotides in the spacer region, and the third number represents the number of nucleotides in the 3' wing region. According to claim 19, the antisense oligonucleotide, wherein, The antisense nucleotide sequence is selected from any of the following modified sequences: (1) It has the nucleotide sequence shown in SEQ ID NO:1 and the modification pattern shown in 2-8-2; (2) It has the nucleotide sequence shown in SEQ ID NO:2 and the modification pattern shown in 2-8-3; (3) It has a nucleotide sequence as shown in SEQ ID NO:3 and a modification pattern as shown in 2-8-2; (4) Having a nucleotide sequence as shown in SEQ ID NO:4 and a modification pattern as shown in 3-8-3; (5) Having a nucleotide sequence as shown in SEQ ID NO:5 and a modification pattern as shown in 2-8-3; (6) Having a nucleotide sequence as shown in SEQ ID NO:6 and a modification pattern as shown in 2-8-2; (7) Having a nucleotide sequence as shown in SEQ ID NO:7 and a modification pattern as shown in 2-8-2; (8) Having a nucleotide sequence as shown in SEQ ID NO:12 and a modification pattern as shown in 2-8-3; (9) Having a nucleotide sequence as shown in SEQ ID NO:13 and a modification pattern as shown in 2-8-2; (10) Having a nucleotide sequence as shown in SEQ ID NO:28 and a modification pattern as shown in 3-9-3; (11) Having a nucleotide sequence as shown in SEQ ID NO:29 and a modification pattern as shown in 3-8-3; (12) Having a nucleotide sequence as shown in SEQ ID NO:30 and a modification pattern as shown in 2-8-3; (13) Having a nucleotide sequence as shown in SEQ ID NO:32 and a modification pattern as shown in 3-10-3; (14) Having a nucleotide sequence as shown in SEQ ID NO:33 and a modification pattern as shown in 3-9-3; (15) Having a nucleotide sequence as shown in SEQ ID NO:34 and a modification pattern as shown in 3-8-3; (16) Having a nucleotide sequence as shown in SEQ ID NO:51 and a modification pattern as shown in 3-10-3; (17) Having a nucleotide sequence as shown in SEQ ID NO:52 and a modification pattern as shown in 3-9-3; (18) Having a nucleotide sequence as shown in SEQ ID NO:53 and a modification pattern as shown in 3-8-3; (19) Having a nucleotide sequence as shown in SEQ ID NO:54 and a modification pattern as shown in 2-8-3; (20) Having a nucleotide sequence as shown in SEQ ID NO:55 and a modification pattern as shown in 2-8-2; (21) Having a nucleotide sequence as shown in SEQ ID NO:56 and a modification pattern as shown in 3-10-3; (22) Having a nucleotide sequence as shown in SEQ ID NO:57 and a modification pattern as shown in 3-9-3; (23) Having a nucleotide sequence as shown in SEQ ID NO:58 and a modification pattern as shown in 3-8-3; (24) Having a nucleotide sequence as shown in SEQ ID NO:59 and a modification pattern as shown in 2-8-3; (25) Having a nucleotide sequence as shown in SEQ ID NO:60 and a modification pattern as shown in 2-8-2; (26) Having a nucleotide sequence as shown in SEQ ID NO:66 and a modification pattern as shown in 3-10-3; (27) Having a nucleotide sequence as shown in SEQ ID NO:67 and a modification pattern as shown in 3-9-3; (28) Having a nucleotide sequence as shown in SEQ ID NO:68 and a modification pattern as shown in 3-8-3; (29) Having a nucleotide sequence as shown in SEQ ID NO:69 and a modification pattern as shown in 2-8-3; (30) Having a nucleotide sequence as shown in SEQ ID NO:70 and a modification pattern as shown in 2-8-2; (31) Having a nucleotide sequence as shown in SEQ ID NO:74 and a modification pattern as shown in 3-8-3; (32) Having a nucleotide sequence as shown in SEQ ID NO:92 and a modification pattern as shown in 3-10-3; (33) Having a nucleotide sequence as shown in SEQ ID NO:93 and a modification pattern as shown in 3-9-3; (34) Having a nucleotide sequence as shown in SEQ ID NO:94 and a modification pattern as shown in 3-8-3; (35) Having a nucleotide sequence as shown in SEQ ID NO:95 and a modification pattern as shown in 2-8-3; (36) Having a nucleotide sequence as shown in SEQ ID NO:96 and a modification pattern as shown in 2-8-2; (37) Having a nucleotide sequence as shown in SEQ ID NO:97 and a modification pattern as shown in 3-10-3; (38) Having a nucleotide sequence as shown in SEQ ID NO:101 and a modification pattern as shown in 2-8-2; (39) Having a nucleotide sequence as shown in SEQ ID NO:106 and a modification pattern as shown in 2-8-2; (40) Having a nucleotide sequence as shown in SEQ ID NO:109 and a modification pattern as shown in 3-8-3; (41) Having a nucleotide sequence as shown in SEQ ID NO:110 and a modification pattern as shown in 2-8-3; (42) Having a nucleotide sequence as shown in SEQ ID NO:111 and a modification pattern as shown in 2-8-2; (43) Having a nucleotide sequence as shown in SEQ ID NO:114 and a modification pattern as shown in 3-8-3; (44) Having a nucleotide sequence as shown in SEQ ID NO:116 and a modification pattern as shown in 2-8-2; (45) Having a nucleotide sequence as shown in SEQ ID NO:118 and a modification pattern as shown in 3-9-3; (46) Having a nucleotide sequence as shown in SEQ ID NO:119 and a modification pattern as shown in 3-8-3; (47) Having a nucleotide sequence as shown in SEQ ID NO:122 and a modification pattern as shown in 3-10-3; (48) Having a nucleotide sequence as shown in SEQ ID NO:123 and a modification pattern as shown in 3-9-3; (49) Having a nucleotide sequence as shown in SEQ ID NO:124 and a modification pattern as shown in 3-8-3; (50) Having a nucleotide sequence as shown in SEQ ID NO:125 and a modification pattern as shown in 2-8-3; (51) Having a nucleotide sequence as shown in SEQ ID NO:127 and a modification pattern as shown in 3-10-3; (52) Having a nucleotide sequence as shown in SEQ ID NO:128 and a modification pattern as shown in 3-9-3; (53) Having a nucleotide sequence as shown in SEQ ID NO:129 and a modification pattern as shown in 3-8-3; (54) Having a nucleotide sequence as shown in SEQ ID NO:157 and a modification pattern as shown in 2-8-2; or (55) Having a nucleotide sequence as shown in SEQ ID NO:158 and a modification pattern as shown in 2-8-2; In the modified pattern, the first number represents the number of nucleotides in the 5' wing region, the second number represents the number of nucleotides in the spacer region, and the third number represents the number of nucleotides in the 3' wing region. According to claim 20, the antisense oligonucleotide, wherein, The antisense nucleotide sequence is selected from any of the following modified sequences: (1) It has the nucleotide sequence shown in SEQ ID NO:1 and the modification pattern shown in 2-8-2; (2) It has a nucleotide sequence as shown in SEQ ID NO:12 and a modification pattern as shown in 2-8-3; (3) It has a nucleotide sequence as shown in SEQ ID NO:13 and a modification pattern as shown in 2-8-2; (4) Having a nucleotide sequence as shown in SEQ ID NO:51 and a modification pattern as shown in 3-10-3; (5) Having a nucleotide sequence as shown in SEQ ID NO:53 and a modification pattern as shown in 3-8-3; (6) Having a nucleotide sequence as shown in SEQ ID NO:54 and a modification pattern as shown in 2-8-3; (7) Having a nucleotide sequence as shown in SEQ ID NO:56 and a modification pattern as shown in 3-10-3; (8) Having a nucleotide sequence as shown in SEQ ID NO:58 and a modification pattern as shown in 3-8-3; (9) Having a nucleotide sequence as shown in SEQ ID NO:59 and a modification pattern as shown in 2-8-3; (10) Having a nucleotide sequence as shown in SEQ ID NO:60 and a modification pattern as shown in 2-8-2; (11) Having a nucleotide sequence as shown in SEQ ID NO:66 and a modification pattern as shown in 3-10-3; (12) Having a nucleotide sequence as shown in SEQ ID NO:67 and a modification pattern as shown in 3-9-3; (13) Having a nucleotide sequence as shown in SEQ ID NO:68 and a modification pattern as shown in 3-8-3; (14) Having a nucleotide sequence as shown in SEQ ID NO:69 and a modification pattern as shown in 2-8-3; (15) Having a nucleotide sequence as shown in SEQ ID NO:74 and a modification pattern as shown in 3-8-3; (16) Having a nucleotide sequence as shown in SEQ ID NO:106 and a modification pattern as shown in 2-8-2; (17) Having a nucleotide sequence as shown in SEQ ID NO:109 and a modification pattern as shown in 3-8-3; (18) Having a nucleotide sequence as shown in SEQ ID NO:110 and a modification pattern as shown in 2-8-3; (19) Having a nucleotide sequence as shown in SEQ ID NO:111 and a modification pattern as shown in 2-8-2; (20) Having a nucleotide sequence as shown in SEQ ID NO:116 and a modification pattern as shown in 2-8-2; (21) Having a nucleotide sequence as shown in SEQ ID NO:118 and a modification pattern as shown in 3-9-3; (22) Having a nucleotide sequence as shown in SEQ ID NO:119 and a modification pattern as shown in 3-8-3; (23) Having a nucleotide sequence as shown in SEQ ID NO:122 and a modification pattern as shown in 3-10-3; (24) Having a nucleotide sequence as shown in SEQ ID NO:123 and a modification pattern as shown in 3-9-3; (25) Having a nucleotide sequence as shown in SEQ ID NO:124 and a modification pattern as shown in 3-8-3; (26) Having a nucleotide sequence as shown in SEQ ID NO:125 and a modification pattern as shown in 2-8-3; (27) Having a nucleotide sequence as shown in SEQ ID NO:127 and a modification pattern as shown in 3-10-3; or (28) Having a nucleotide sequence as shown in SEQ ID NO:128 and a modification pattern as shown in 3-9-3; In the modified pattern, the first number represents the number of nucleotides in the 5' wing region, the second number represents the number of nucleotides in the spacer region, and the third number represents the number of nucleotides in the 3' wing region. The antisense oligonucleotide according to any one of claims 1-21, wherein, The nucleotides in the 5' and 3' wings of the modified pattern are LNA nucleotides or cEt nucleotides. The antisense oligonucleotide according to any one of claims 1-22, wherein, The antisense oligonucleotide is selected from any of the following combinations of modifications: (1)LNA-(5m)C* / LNA-A* / dT* / dG* / dG* / dT* / dG* / dA* / dA* / dG* / LNA-A* / LNA-G (SEQ ID NO. 169); (2)LNA-(5m)C* / LNA-(5m)C* / dA* / dT* / dG* / dG* / dT* / dG* / dA* / dA* / LNA-G* / LNA-A* / LNA-G (SEQ ID NO. 170); (3)LNA-(5m)C* / LNA-(5m)C* / dA* / dT* / dG* / dG* / dT* / dG* / dA* / dA* / LNA-G* / LNA-A(SEQ ID NO.171); (4)LNA-T* / LNA-(5m)C* / LNA-(5m)C* / dA* / dT* / dG* / dG* / dT* / dG* / dA* / dA* / LNA-G* / LNA-A* / LNA-G(SEQ ID NO.172); (5)LNA-T* / LNA-(5m)C* / d(5m)C* / dA* / dT* / dG* / dG* / dT* / dG* / dA* / LNA-A* / LNA-G* / LNA-A(SEQ ID NO.173); (6)LNA-T* / LNA-(5m)C* / d(5m)C* / dA* / dT* / dG* / dG* / dT* / dG* / dA* / LNA-A* / LNA-G(SEQ ID NO.174); (7)LNA-(5m)C* / LNA-(5m)C* / dT* / dG* / d(5m)C* / d(5m)C* / dA* / dG* / dG* / dA* / LNA-A* / LNA-G(SEQ ID NO.175); (8)LNA-T* / LNA-G* / dG* / dG* / d(5m)C* / dA* / dT* / dG* / dA* / dG* / LNA-(5m)C* / LNA-T(SEQ ID NO.176); (9)LNA-T* / LNA-T* / dG* / dG* / dG* / d(5m)C* / dA* / dT* / dG* / dA* / LNA-G* / LNA-(5m)C* / LNA-T(SEQ ID NO.177); (10)LNA-T* / LNA-T* / dG* / dG* / dG* / d(5m)C* / dA* / dT* / dG* / dA* / LNA-G* / LNA-(5m)C(SEQ ID NO.178); (11)LNA-G* / LNA-A* / dT* / d(5m)C* / dT* / dT* / dG* / dG* / dT* / dG* / LNA-A* / LNA-A(SEQ ID NO.179); (12)LNA-A* / LNA-G* / dA* / dT* / d(5m)C* / dT* / dT* / dG* / dG* / dT* / LNA-G* / LNA-A* / LNA-A(SEQ ID NO.180); (13)LNA-A* / LNA-G* / dA* / dT* / d(5m)C* / dT* / dT* / dG* / dG* / dT* / LNA-G* / LNA-A(SEQ ID NO.181); (14)LNA-G* / LNA-A* / LNA-G* / dA* / dT* / d(5m)C* / dT* / dT* / dG* / dG* / dT* / LNA-G* / LNA-A* / LNA-A(SEQ ID NO.182); (15)LNA-G* / LNA-A* / dG* / dA* / dT* / d(5m)C* / dT* / dT* / dG* / dG* / LNA-T* / LNA-G* / LNA-A(SEQ ID NO.183); (16)LNA-G* / LNA-A* / dG* / dA* / dT* / d(5m)C* / dT* / dT* / dG* / dG* / LNA-T* / LNA-G(SEQ ID NO.184); (17)LNA-T* / LNA-G* / dA* / dA* / dG* / dA* / dT* / dG* / dG* / dA* / LNA-G* / LNA-G(SEQ ID NO.185); (18)LNA-T* / LNA-T* / dG* / dA* / dA* / dG* / dA* / dT* / dG* / dG* / LNA-A* / LNA-G* / LNA-G(SEQ ID NO.186); (19)LNA-T* / LNA-T* / dG* / dA* / dA* / dG* / dA* / dT* / dG* / dG* / LNA-A* / LNA-G(SEQ ID NO.187); (20)LNA-G* / LNA-T* / LNA-T* / dG* / dA* / dA* / dG* / dA* / dT* / dG* / dG* / LNA-A* / LNA-G* / LNA-G(SEQ ID NO.188); (21)LNA-G* / LNA-T* / dT* / dG* / dA* / dA* / dG* / dA* / dT* / dG* / LNA-G* / LNA-A* / LNA-G(SEQ ID NO.189); (22)LNA-G* / LNA-T* / dT* / dG* / dA* / dA* / dG* / dA* / dT* / dG* / LNA-G* / LNA-A(SEQ ID NO.190); (23)LNA-T* / LNA-G* / LNA-T* / dT* / dG* / dA* / dA* / dG* / dA* / dT* / dG* / dG* / LNA-A* / LNA-G* / LNA-G(SEQ ID NO.191); (24)LNA-T* / LNA-G* / LNA-T* / dT* / dG* / dA* / dA* / dG* / dA* / dT* / dG* / LNA-G* / LNA-A* / LNA-G(SEQ ID NO.192); (25)LNA-T* / LNA-G* / dT* / dT* / dG* / dA* / dA* / dG* / dA* / dT* / LNA-G* / LNA-G* / LNA-A(SEQ ID NO.193); (26)LNA-T* / LNA-G* / dT* / dT* / dG* / dA* / dA* / dG* / dA* / dT* / LNA-G* / LNA-G(SEQ ID NO.194); (27)LNA-(5m)C* / LNA-T* / LNA-G* / dT* / dT* / dG* / dA* / dA* / dG* / dA* / dT* / dG* / dG* / LNA-A* / LNA-G* / LNA-G(SEQ ID NO.195); (28)LNA-(5m)C* / LNA-T* / LNA-G* / dT* / dT* / dG* / dA* / dA* / dG* / dA* / dT* / dG* / LNA-G* / LNA-A* / LNA-G(SEQ ID NO.196); (29)LNA-(5m)C* / LNA-T* / LNA-G* / dT* / dT* / dG* / dA* / dA* / dG* / dA* / dT* / LNA-G* / LNA-G* / LNA-A(SEQ ID NO.197); (30)LNA-(5m)C* / LNA-T* / dG* / dT* / dT* / dG* / dA* / dA* / dG* / dA* / LNA-T* / LNA-G* / LNA-G(SEQ ID NO.198); (31)LNA-(5m)C* / LNA-T* / dG* / dT* / dT* / dG* / dA* / dA* / dG* / dA* / LNA-T* / LNA-G(SEQ ID NO.199); (32)LNA-G* / LNA-(5m)C* / LNA-T* / dG* / dT* / dT* / dG* / dA* / dA* / dG* / dA* / dT* / dG* / LNA-G* / LNA-A* / LNA-G(SEQ ID NO.200); (33)LNA-G* / LNA-(5m)C* / LNA-T* / dG* / dT* / dT* / dG* / dA* / dA* / dG* / dA* / dT* / LNA-G* / LNA-G* / LNA-A(SEQ ID NO.201); (34)LNA-G* / LNA-(5m)C* / LNA-T* / dG* / dT* / dT* / dG* / dA* / dA* / dG* / dA* / LNA-T* / LNA-G* / LNA-G(SEQ ID NO.202); (35)LNA-G* / LNA-(5m)C* / dT* / dG* / dT* / dT* / dG* / dA* / dA* / dG* / LNA-A* / LNA-T* / LNA-G(SEQ ID NO.203); (36)LNA-G* / LNA-(5m)C* / dT* / dG* / dT* / dT* / dG* / dA* / dA* / dG* / LNA-A* / LNA-T(SEQ ID NO.204); (37)LNA-G* / LNA-T* / LNA-(5m)C* / d(5m)C* / dA* / dT* / dG* / dG* / dT* / dG* / dA* / dA* / LNA-G* / LNA-A* / LNA-G(SEQ ID NO.205); (38)LNA-G* / LNA-T* / LNA-(5m)C* / d(5m)C* / dA* / dT* / dG* / dG* / dT* / dG* / dA* / LNA-A* / LNA-G* / LNA-A(SEQ ID NO.206); (39)LNA-G* / LNA-T* / d(5m)C* / d(5m)C* / dA* / dT* / dG* / dG* / dT* / dG* / LNA-A* / LNA-A* / LNA-G(SEQ ID NO.207); (40)LNA-G* / LNA-T* / d(5m)C* / d(5m)C* / dA* / dT* / dG* / dG* / dT* / dG* / LNA-A* / LNA-A(SEQ ID NO.208); (41)LNA-T* / LNA-G* / LNA-T* / d(5m)C* / d(5m)C* / dA* / dT* / dG* / dG* / dT* / dG* / dA* / dA* / LNA-G* / LNA-A* / LNA-G(SEQ ID NO.209); (42)LNA-T* / LNA-G* / LNA-T* / d(5m)C* / d(5m)C* / dA* / dT* / dG* / dG* / dT* / dG* / dA* / LNA-A* / LNA-G* / LNA-A(SEQ ID NO.210); (43)LNA-T* / LNA-G* / LNA-T* / d(5m)C* / d(5m)C* / dA* / dT* / dG* / dG* / dT* / dG* / LNA-A* / LNA-A* / LNA-G(SEQ ID NO.211); (44)LNA-T* / LNA-G* / dT* / d(5m)C* / d(5m)C* / dA* / dT* / dG* / dG* / dT* / LNA-G* / LNA-A* / LNA-A(SEQ ID NO.212); (45)LNA-T* / LNA-G* / dT* / d(5m)C* / d(5m)C* / dA* / dT* / dG* / dG* / dT* / LNA-G* / LNA-A(SEQ ID NO.213); (46)LNA-A* / LNA-T* / LNA-G* / dT* / d(5m)C* / d(5m)C* / dA* / dT* / dG* / dG* / dT* / dG* / dA* / LNA-A* / LNA-G* / LNA-A(SEQ ID NO.214); (47)LNA-A* / LNA-T* / LNA-G* / dT* / d(5m)C* / d(5m)C* / dA* / dT* / dG* / dG* / dT* / dG* / LNA-A* / LNA-A* / LNA-G(SEQ ID NO.215); (48)LNA-A* / LNA-T* / LNA-G* / dT* / d(5m)C* / d(5m)C* / dA* / dT* / dG* / dG* / dT* / LNA-G* / LNA-A* / LNA-A(SEQ ID NO.216); (49)LNA-A* / LNA-T* / dG* / dT* / d(5m)C* / d(5m)C* / dA* / dT* / dG* / dG* / LNA-T* / LNA-G* / LNA-A(SEQ ID NO.217); (50)LNA-A* / LNA-T* / dG* / dT* / d(5m)C* / d(5m)C* / dA* / dT* / dG* / dG* / LNA-T* / LNA-G(SEQ ID NO.218); (51)LNA-G* / LNA-A* / LNA-T* / dG* / dT* / d(5m)C* / d(5m)C* / dA* / dT* / dG* / dG* / dT* / dG* / LNA-A* / LNA-A* / LNA-G(SEQ ID NO.219); (52)LNA-G* / LNA-A* / LNA-T* / dG* / dT* / d(5m)C* / d(5m)C* / dA* / dT* / dG* / dG* / dT* / LNA-G* / LNA-A* / LNA-A(SEQ ID NO.220); (53)LNA-G* / LNA-A* / LNA-T* / dG* / dT* / d(5m)C* / d(5m)C* / dA* / dT* / dG* / dG* / LNA-T* / LNA-G* / LNA-A(SEQ ID NO.221); (54)LNA-G* / LNA-A* / dT* / dG* / dT* / d(5m)C* / d(5m)C* / dA* / dT* / dG* / LNA-G* / LNA-T* / LNA-G(SEQ ID NO.222); (55)LNA-G* / LNA-A* / dT* / dG* / dT* / d(5m)C* / d(5m)C* / dA* / dT* / dG* / LNA-G* / LNA-T(SEQ ID NO.223); (56)LNA-A* / LNA-G* / LNA-A* / dT* / dG* / dT* / d(5m)C* / d(5m)C* / dA* / dT* / dG* / dG* / dT* / LNA-G* / LNA-A* / LNA-A(SEQ ID NO.224); (57)LNA-A* / LNA-G* / LNA-A* / dT* / dG* / dT* / d(5m)C* / d(5m)C* / dA* / dT* / dG* / dG* / LNA-T* / LNA-G* / LNA-A(SEQ ID NO.225); (58)LNA-A* / LNA-G* / LNA-A* / dT* / dG* / dT* / d(5m)C* / d(5m)C* / dA* / dT* / dG* / LNA-G* / LNA-T* / LNA-G(SEQ ID NO.226); (59)LNA-A* / LNA-G* / dA* / dT* / dG* / dT* / d(5m)C* / d(5m)C* / dA* / dT* / LNA-G* / LNA-G* / LNA-T(SEQ ID NO.227); (60)LNA-A* / LNA-G* / dA* / dT* / dG* / dT* / d(5m)C* / d(5m)C* / dA* / dT* / LNA-G* / LNA-G(SEQ ID NO.228); (61)LNA-T* / LNA-A* / LNA-G* / dA* / dT* / dG* / dT* / d(5m)C* / d(5m)C* / dA* / dT* / dG* / dG* / LNA-T* / LNA-G* / LNA-A(SEQ ID NO.229); (62)LNA-T* / LNA-A* / LNA-G* / dA* / dT* / dG* / dT* / d(5m)C* / d(5m)C* / dA* / dT* / dG* / LNA-G* / LNA-T* / LNA-G(SEQ ID NO.230); (63)LNA-T* / LNA-A* / LNA-G* / dA* / dT* / dG* / dT* / d(5m)C* / d(5m)C* / dA* / dT* / LNA-G* / LNA-G* / LNA-T(SEQ ID NO.231); (64)LNA-T* / LNA-A* / dG* / dA* / dT* / dG* / dT* / d(5m)C* / d(5m)C* / dA* / LNA-T* / LNA-G* / LNA-G(SEQ ID NO.232); (65)LNA-T* / LNA-A* / dG* / dA* / dT* / dG* / dT* / d(5m)C* / d(5m)C* / dA* / LNA-T* / LNA-G(SEQ ID NO.233); (66)LNA-G* / LNA-T* / LNA-A* / dG* / dA* / dT* / dG* / dT* / d(5m)C* / d(5m)C* / dA* / dT* / dG* / LNA-G* / LNA-T* / LNA-G(SEQ ID NO.234); (67)LNA-G* / LNA-T* / LNA-A* / dG* / dA* / dT* / dG* / dT* / d(5m)C* / d(5m)C* / dA* / dT* / LNA-G* / LNA-G* / LNA-T(SEQ ID NO.235); (68)LNA-G* / LNA-T* / LNA-A* / dG* / dA* / dT* / dG* / dT* / d(5m)C* / d(5m)C* / dA* / LNA-T* / LNA-G* / LNA-G(SEQ ID NO.236); (69)LNA-G* / LNA-T* / dA* / dG* / dA* / dT* / dG* / dT* / d(5m)C* / d(5m)C* / LNA-A* / LNA-T* / LNA-G(SEQ ID NO.237); (70)LNA-G* / LNA-T* / dA* / dG* / dA* / dT* / dG* / dT* / d(5m)C* / d(5m)C* / LNA-A* / LNA-T(SEQ ID NO.238); (71)LNA-G* / LNA-T* / dA* / dA* / dT* / d(5m)C* / dG* / dA* / dA* / dG* / LNA-A* / LNA-G(SEQ ID NO.239); (72)LNA-T* / LNA-G* / dT* / dA* / dA* / dT* / d(5m)C* / dG* / dA* / dA* / LNA-G* / LNA-A* / LNA-G(SEQ ID NO.240); (73)LNA-T* / LNA-G* / dT* / dA* / dA* / dT* / d(5m)C* / dG* / dA* / dA* / LNA-G* / LNA-A(SEQ ID NO.241); (74)LNA-A* / LNA-T* / LNA-G* / dT* / dA* / dA* / dT* / d(5m)C* / dG* / dA* / dA* / LNA-G* / LNA-A* / LNA-G(SEQ ID NO.242); (75)LNA-A* / LNA-T* / dG* / dT* / dA* / dA* / dT* / d(5m)C* / dG* / dA* / LNA-A* / LNA-G* / LNA-A(SEQ ID NO.243); (76)LNA-A* / LNA-T* / dG* / dT* / dA* / dA* / dT* / d(5m)C* / dG* / dA* / LNA-A* / LNA-G(SEQ ID NO.244); (77)LNA-G* / LNA-(5m)C* / dG* / dG* / d(5m)C* / dT* / dG* / dA* / dT* / d(5m)C* / LNA-A* / LNA-T(SEQ ID NO.245); (78)LNA-T* / LNA-G* / d(5m)C* / dG* / dG* / d(5m)C* / dT* / dG* / dA* / dT* / LNA-(5m)C* / LNA-A* / LNA-T(SEQ ID NO.246); (79)LNA-T* / LNA-G* / d(5m)C* / dG* / dG* / d(5m)C* / dT* / dG* / dA* / dT* / LNA-(5m)C* / LNA-A(SEQ ID NO.247); (80)LNA-A* / LNA-T* / LNA-G* / d(5m)C* / dG* / dG* / d(5m)C* / dT* / dG* / dA* / dT* / LNA-(5m)C* / LNA-A* / LNA-T(SEQ ID NO.248); (81)LNA-A* / LNA-T* / dG* / d(5m)C* / dG* / dG* / d(5m)C* / dT* / dG* / dA* / LNA-T* / LNA-(5m)C* / LNA-A(SEQ ID NO.249); (82)LNA-A* / LNA-T* / dG* / d(5m)C* / dG* / dG* / d(5m)C* / dT* / dG* / dA* / LNA-T* / LNA-(5m)C(SEQ ID NO.250); (83)LNA-A* / LNA-A* / LNA-T* / dG* / d(5m)C* / dG* / dG* / d(5m)C* / dT* / dG* / dA* / dT* / LNA-(5m)C* / LNA-A* / LNA-T(SEQ ID NO.251); (84)LNA-A* / LNA-A* / LNA-T* / dG* / d(5m)C* / dG* / dG* / d(5m)C* / dT* / dG* / dA* / LNA-T* / LNA-(5m)C* / LNA-A(SEQ ID NO.252); (85)LNA-A* / LNA-A* / dT* / dG* / d(5m)C* / dG* / dG* / d(5m)C* / dT* / dG* / LNA-A* / LNA-T* / LNA-(5m)C(SEQ ID NO.253); (86)LNA-A* / LNA-A* / dT* / dG* / d(5m)C* / dG* / dG* / d(5m)C* / dT* / dG* / LNA-A* / LNA-T(SEQ ID NO.254); (87)LNA-G* / LNA-A* / LNA-A* / dT* / dG* / d(5m)C* / dG* / dG* / d(5m)C* / dT* / dG* / dA* / dT* / LNA-(5m)C* / LNA-A* / LNA-T(SEQ ID NO.255); (88)LNA-G* / LNA-A* / LNA-A* / dT* / dG* / d(5m)C* / dG* / dG* / d(5m)C* / dT* / dG* / dA* / LNA-T* / LNA-(5m)C* / LNA-A(SEQ ID NO.256); (89)LNA-G* / LNA-A* / LNA-A* / dT* / dG* / d(5m)C* / dG* / dG* / d(5m)C* / dT* / dG* / LNA-A* / LNA-T* / LNA-(5m)C(SEQ ID NO.257); (90)LNA-G* / LNA-A* / dA* / dT* / dG* / d(5m)C* / dG* / dG* / d(5m)C* / dT* / LNA-G* / LNA-A* / LNA-T(SEQ ID NO.258); (91)LNA-G* / LNA-A* / dA* / dT* / dG* / d(5m)C* / dG* / dG* / d(5m)C* / dT* / LNA-G* / LNA-A(SEQ ID NO.259); (92)LNA-A* / LNA-G* / LNA-A* / dA* / dT* / dG* / d(5m)C* / dG* / dG* / d(5m)C* / dT* / dG* / dA* / LNA-T* / LNA-(5m)C* / LNA-A(SEQ ID NO.260); (93)LNA-A* / LNA-G* / LNA-A* / dA* / dT* / dG* / d(5m)C* / dG* / dG* / d(5m)C* / dT* / dG* / LNA-A* / LNA-T* / LNA-(5m)C(SEQ ID NO.261); (94)LNA-A* / LNA-G* / LNA-A* / dA* / dT* / dG* / d(5m)C* / dG* / dG* / d(5m)C* / dT* / LNA-G* / LNA-A* / LNA-T(SEQ ID NO.262); (95)LNA-A* / LNA-G* / dA* / dA* / dT* / dG* / d(5m)C* / dG* / dG* / d(5m)C* / LNA-T* / LNA-G* / LNA-A(SEQ ID NO.263); (96)LNA-A* / LNA-G* / dA* / dA* / dT* / dG* / d(5m)C* / dG* / dG* / d(5m)C* / LNA-T* / LNA-G(SEQ ID NO.264); (97)LNA-(5m)C* / LNA-A* / LNA-G* / dA* / dA* / dT* / dG* / d(5m)C* / dG* / dG* / d(5m)C* / dT* / dG* / LNA-A* / LNA-T* / LNA-(5m)C(SEQ ID NO.265); (98)LNA-(5m)C* / LNA-A* / LNA-G* / dA* / dA* / dT* / dG* / d(5m)C* / dG* / dG* / d(5m)C* / dT* / LNA-G* / LNA-A* / LNA-T(SEQ ID NO.266); (99)LNA-(5m)C* / LNA-A* / LNA-G* / dA* / dA* / dT* / dG* / d(5m)C* / dG* / dG* / d(5m)C* / LNA-T* / LNA-G* / LNA-A(SEQ ID NO.267); (100)LNA-(5m)C* / LNA-A* / dG* / dA* / dA* / dT* / dG* / d(5m)C* / dG* / dG* / LNA-(5m)C* / LNA-T* / LNA-G(SEQ ID NO.268); (101)LNA-(5m)C* / LNA-A* / dG* / dA* / dA* / dT* / dG* / d(5m)C* / dG* / dG* / LNA-(5m)C* / LNA-T(SEQ ID NO.269); (102)LNA-A* / LNA-(5m)C* / LNA-A* / dG* / dA* / dA* / dT* / dG* / d(5m)C* / dG* / dG* / d(5m)C* / dT* / LNA-G* / LNA-A* / LNA-T(SEQ ID NO.270); (103)LNA-A* / LNA-(5m)C* / LNA-A* / dG* / dA* / dA* / dT* / dG* / d(5m)C* / dG* / dG* / d(5m)C* / LNA-T* / LNA-G* / LNA-A(SEQ ID NO.271); (104)LNA-A* / LNA-(5m)C* / dA* / dG* / dA* / dA* / dT* / dG* / d(5m)C* / dG* / LNA-G* / LNA-(5m)C* / LNA-T(SEQ ID NO.272); (105)LNA-A* / LNA-(5m)C* / dA* / dG* / dA* / dA* / dT* / dG* / d(5m)C* / dG* / LNA-G* / LNA-(5m)C(SEQ ID NO.273); (106)LNA-T* / LNA-A* / LNA-(5m)C* / dA* / dG* / dA* / dA* / dT* / dG* / d(5m)C* / dG* / dG* / d(5m)C* / LNA-T* / LNA-G* / LNA-A(SEQ ID NO.274); (107)LNA-T* / LNA-A* / LNA-(5m)C* / dA* / dG* / dA* / dA* / dT* / dG* / d(5m)C* / dG* / dG* / LNA-(5m)C* / LNA-T* / LNA-G(SEQ ID NO.275); (108)LNA-T* / LNA-A* / LNA-(5m)C* / dA* / dG* / dA* / dA* / dT* / dG* / d(5m)C* / dG* / LNA-G* / LNA-(5m)C* / LNA-T(SEQ ID NO.276); (109)LNA-A* / LNA-(5m)C* / LNA-A* / dG* / dA* / dA* / dT* / dG* / d(5m)C* / dG* / dG* / LNA-(5m)C* / LNA-T* / LNA-G(SEQ ID NO.277); (110)LNA-T* / LNA-A* / d(5m)C* / dA* / dG* / dA* / dA* / dT* / dG* / d(5m)C* / LNA-G* / LNA-G* / LNA-(5m)C(SEQ ID NO.278); (111)LNA-T* / LNA-A* / d(5m)C* / dA* / dG* / dA* / dA* / dT* / dG* / d(5m)C* / LNA-G* / LNA-G(SEQ ID NO.279); (112)LNA-G* / LNA-T* / LNA-A* / d(5m)C* / dA* / dG* / dA* / dA* / dT* / dG* / d(5m)C* / dG* / dG* / LNA-(5m)C* / LNA-T* / LNA-G(SEQ ID NO.280); (113)LNA-G* / LNA-T* / LNA-A* / d(5m)C* / dA* / dG* / dA* / dA* / dT* / dG* / d(5m)C* / dG* / LNA-G* / LNA-(5m)C* / LNA-T(SEQ ID NO.281); (114)LNA-G* / LNA-T* / LNA-A* / d(5m)C* / dA* / dG* / dA* / dA* / dT* / dG* / d(5m)C* / LNA-G* / LNA-G* / LNA-(5m)C(SEQ ID NO.282); (115)LNA-G* / LNA-T* / dA* / d(5m)C* / dA* / dG* / dA* / dA* / dT* / dG* / LNA-(5m)C* / LNA-G* / LNA-G(SEQ ID NO.283); (116)LNA-G* / LNA-T* / dA* / d(5m)C* / dA* / dG* / dA* / dA* / dT* / dG* / LNA-(5m)C* / LNA-G(SEQ ID NO.284); (117)LNA-G* / LNA-G* / d(5m)C* / d(5m)C* / dA* / dG* / d(5m)C* / dA* / dT* / dG* / LNA-A* / LNA-(5m)C(SEQ ID NO.285); (118)LNA-G* / LNA-A* / LNA-T* / dG* / dT* / dA* / dA* / dT* / d(5m)C* / dG* / dA* / dA* / LNA-G* / LNA-A* / LNA-G(SEQ ID NO.286); (119)LNA-G* / LNA-A* / LNA-T* / dG* / dT* / dA* / dA* / dT* / d(5m)C* / dG* / dA* / LNA-A* / LNA-G* / LNA-A(SEQ ID NO.287); (120)LNA-G* / LNA-A* / dT* / dG* / dT* / dA* / dA* / dT* / d(5m)C* / dG* / LNA-A* / LNA-A* / LNA-G(SEQ ID NO.288); (121)LNA-G* / LNA-A* / dT* / dG* / dT* / dA* / dA* / dT* / d(5m)C* / dG* / LNA-A* / LNA-A(SEQ ID NO.289); (122)LNA-G* / LNA-G* / LNA-A* / dT* / dG* / dT* / dA* / dA* / dT* / d(5m)C* / dG* / dA* / dA* / LNA-G* / LNA-A* / LNA-G(SEQ ID NO.290); (123)LNA-G* / LNA-G* / LNA-A* / dT* / dG* / dT* / dA* / dA* / dT* / d(5m)C* / dG* / dA* / LNA-A* / LNA-G* / LNA-A(SEQ ID NO.291); (124)LNA-G* / LNA-G* / LNA-A* / dT* / dG* / dT* / dA* / dA* / dT* / d(5m)C* / dG* / LNA-A* / LNA-A* / LNA-G(SEQ ID NO.292); (125)LNA-G* / LNA-G* / dA* / dT* / dG* / dT* / dA* / dA* / dT* / d(5m)C* / LNA-G* / LNA-A* / LNA-A(SEQ ID NO.293); (126)LNA-G* / LNA-G* / dA* / dT* / dG* / dT* / dA* / dA* / dT* / d(5m)C* / LNA-G* / LNA-A(SEQ ID NO.294); (127)LNA-T* / LNA-G* / LNA-G* / dA* / dT* / dG* / dT* / dA* / dA* / dT* / d(5m)C* / dG* / dA* / LNA-A* / LNA-G* / LNA-A(SEQ ID NO.295); (128)LNA-T* / LNA-G* / LNA-G* / dA* / dT* / dG* / dT* / dA* / dA* / dT* / d(5m)C* / dG* / LNA-A* / LNA-A* / LNA-G(SEQ ID NO.296); (129)LNA-T* / LNA-G* / LNA-G* / dA* / dT* / dG* / dT* / dA* / dA* / dT* / d(5m)C* / LNA-G* / LNA-A* / LNA-A(SEQ ID NO.297); (130)LNA-T* / LNA-G* / dG* / dA* / dT* / dG* / dT* / dA* / dA* / dT* / LNA-(5m)C* / LNA-G* / LNA-A(SEQ ID NO.298); (131)LNA-T* / LNA-G* / dG* / dA* / dT* / dG* / dT* / dA* / dA* / dT* / LNA-(5m)C* / LNA-G(SEQ ID NO.299); (132)LNA-(5m)C* / LNA-T* / LNA-G* / dG* / dA* / dT* / dG* / dT* / dA* / dA* / dT* / d(5m)C* / dG* / LNA-A* / LNA-A* / LNA-G(SEQ ID NO.300); (133)LNA-(5m)C* / LNA-T* / LNA-G* / dG* / dA* / dT* / dG* / dT* / dA* / dA* / dT* / d(5m)C* / LNA-G* / LNA-A* / LNA-A(SEQ ID NO.301); (134)LNA-(5m)C* / LNA-T* / LNA-G* / dG* / dA* / dT* / dG* / dT* / dA* / dA* / dT* / LNA-(5m)C* / LNA-G* / LNA-A(SEQ ID NO.302); (135)LNA-(5m)C* / LNA-T* / dG* / dG* / dA* / dT* / dG* / dT* / dA* / dA* / LNA-T* / LNA-(5m)C* / LNA-G(SEQ ID NO.303); (136)LNA-(5m)C* / LNA-T* / dG* / dG* / dA* / dT* / dG* / dT* / dA* / dA* / LNA-T* / LNA-(5m)C(SEQ ID NO.304); (137)LNA-A* / LNA-A* / dA* / dG* / dT* / dG* / dG* / d(5m)C* / d(5m)C* / dA* / LNA-(5m)C* / LNA-T(SEQ ID NO.305); (138)LNA-(5m)C* / LNA-A* / dA* / dA* / dG* / dT* / dG* / dG* / d(5m)C* / d(5m)C* / LNA-A* / LNA-(5m)C* / LNA-T(SEQ ID NO.306); (139)LNA-(5m)C* / LNA-A* / dA* / dA* / dG* / dT* / dG* / dG* / d(5m)C* / d(5m)C* / LNA-A* / LNA-(5m)C(SEQ ID NO.307); (140)LNA-A* / LNA-(5m)C* / LNA-A* / dA* / dA* / dG* / dT* / dG* / dG* / d(5m)C* / d(5m)C* / LNA-A* / LNA-(5m)C* / LNA-T(SEQ ID NO.308); (141)LNA-A* / LNA-(5m)C* / dA* / dA* / dA* / dG* / dT* / dG* / dG* / d(5m)C* / LNA-(5m)C* / LNA-A* / LNA-(5m)C(SEQ ID NO.309); (142)LNA-A* / LNA-(5m)C* / dA* / dA* / dA* / dG* / dT* / dG* / dG* / d(5m)C* / LNA-(5m)C* / LNA-A(SEQ ID NO.310); (143)LNA-(5m)C* / LNA-A* / LNA-(5m)C* / dA* / dA* / dA* / dG* / dT* / dG* / dG* / d(5m)C* / d(5m)C* / LNA-A* / LNA-(5m)C* / LNA-T(SEQ ID NO.311); (144)LNA-(5m)C* / LNA-A* / LNA-(5m)C* / dA* / dA* / dA* / dG* / dT* / dG* / dG* / d(5m)C* / LNA-(5m)C* / LNA-A* / LNA-(5m)C(SEQ ID NO.312); (145)LNA-(5m)C* / LNA-A* / d(5m)C* / dA* / dA* / dA* / dG* / dT* / dG* / dG* / LNA-(5m)C* / LNA-(5m)C* / LNA-A(SEQ ID NO.313); (146)LNA-(5m)C* / LNA-A* / d(5m)C* / dA* / dA* / dA* / dG* / dT* / dG* / dG* / LNA-(5m)C* / LNA-(5m)C(SEQ ID NO.314); (147)LNA-(5m)C* / LNA-(5m)C* / LNA-A* / d(5m)C* / dA* / dA* / dA* / dG* / dT* / dG* / dG* / d(5m)C* / d(5m)C* / LNA-A* / LNA-(5m)C* / LNA-T(SEQ ID NO.315); (148)LNA-(5m)C* / LNA-(5m)C* / LNA-A* / d(5m)C* / dA* / dA* / dA* / dG* / dT* / dG* / dG* / d(5m)C* / LNA-(5m)C* / LNA-A* / LNA-(5m)C(SEQ ID NO.316); (149)LNA-(5m)C* / LNA-(5m)C* / LNA-A* / d(5m)C* / dA* / dA* / dA* / dG* / dT* / dG* / dG* / LNA-(5m)C* / LNA-(5m)C* / LNA-A(SEQ ID NO.317); (150)LNA-(5m)C* / LNA-(5m)C* / dA* / d(5m)C* / dA* / dA* / dA* / dG* / dT* / dG* / LNA-G* / LNA-(5m)C* / LNA-(5m)C(SEQ ID NO.318); (151)LNA-(5m)C* / LNA-(5m)C* / dA* / d(5m)C* / dA* / dA* / dA* / dG* / dT* / dG* / LNA-G* / LNA-(5m)C(SEQ ID NO.319); (152)LNA-(5m)C* / LNA-(5m)C* / LNA-(5m)C* / dA* / d(5m)C* / dA* / dA* / dA* / dG* / dT* / dG* / dG* / d(5m)C* / LNA-(5m)C* / LNA-A* / LNA-(5m)C(SEQ ID NO.320); (153)LNA-(5m)C* / LNA-(5m)C* / LNA-(5m)C* / dA* / d(5m)C* / dA* / dA* / dA* / dG* / dT* / dG* / dG* / LNA-(5m)C* / LNA-(5m)C* / LNA-A(SEQ ID NO.321); (154)LNA-(5m)C* / LNA-(5m)C* / LNA-(5m)C* / dA* / d(5m)C* / dA* / dA* / dA* / dG* / dT* / dG* / LNA-G* / LNA-(5m)C* / LNA-(5m)C(SEQ ID NO.322); (155)LNA-(5m)C* / LNA-(5m)C* / d(5m)C* / dA* / d(5m)C* / dA* / dA* / dA* / dG* / dT* / LNA-G* / LNA-G* / LNA-(5m)C(SEQ ID NO.323); (156)LNA-(5m)C* / LNA-(5m)C* / d(5m)C* / dA* / d(5m)C* / dA* / dA* / dA* / dG* / dT* / LNA-G* / LNA-G(SEQ ID NO.324); (157)LNA-(5m)C* / LNA-(5m)C* / dG* / dT* / dG* / dT* / dA* / dA* / dA* / dT* / LNA-(5m)C* / LNA-A(SEQ ID NO.325); (158)LNA-G* / LNA-(5m)C* / dA* / d(5m)C* / d(5m)C* / dA* / dG* / dT* / dA* / d(5m)C* / LNA-(5m)C* / LNA-A(SEQ ID NO.326); (159)LNA-T* / LNA-G* / d(5m)C* / dA* / d(5m)C* / d(5m)C* / dA* / dG* / dT* / dA* / LNA-(5m)C* / LNA-(5m)C* / LNA-A(SEQ ID NO.327); (160)LNA-T* / LNA-G* / d(5m)C* / dA* / d(5m)C* / d(5m)C* / dA* / dG* / dT* / dA* / LNA-(5m)C* / LNA-(5m)C (SEQ ID NO. 328); (161)LNA-G* / LNA-(5m)C* / dA* / dG* / d(5m)C* / dG* / d(5m)C* / dT* / dG* / d(5m)C* / LNA-A* / LNA-(5m)C (SEQ ID NO. 329); (162)LNA-G* / LNA-G* / d(5m)C* / dA* / dG* / d(5m)C* / dG* / d(5m)C* / dT* / dG* / LNA-(5m)C* / LNA-A* / LNA-(5m)C (SEQ ID NO. 330); (163)LNA-G* / LNA-G* / d(5m)C* / dA* / dG* / d(5m)C* / dG* / d(5m)C* / dT* / dG* / LNA-(5m)C* / LNA-A (SEQ ID NO. 331); (164)LNA-A* / LNA-G* / LNA-G* / d(5m)C* / dA* / dG* / d(5m)C* / dG* / d(5m)C* / dT* / dG* / LNA-(5m)C* / LNA-A* / LNA-(5m)C (SEQ ID NO. 332); (165)LNA-A* / LNA-G* / dG* / d(5m)C* / dA* / dG* / d(5m)C* / dG* / d(5m)C* / dT* / LNA-G* / LNA-(5m)C* / LNA-A(SEQ ID NO. 333); or (166)LNA-A* / LNA-G* / dG* / d(5m)C* / dA* / dG* / d(5m)C* / dG* / d(5m)C* / dT* / LNA-G* / LNA-(5m)C (SEQ ID NO. 334); (167)LNA-A* / LNA-G* / LNA-A* / dA* / dT* / dG* / d(5m)C* / dG* / dG* / d(5m)C* / dT* / dG* / dA* / LNA-T / # / LNA-(5m)C / # / LNA-A(SEQ ID NO.341); where * represents a thiophosphate bond between nucleotides, # represents a methanesulfonylphosphatidyl ester linkage, and 5m represents methylation modification of the 5th carbon in cytosine. According to claim 23, the antisense oligonucleotide, wherein, The antisense oligonucleotide is selected from any of the following combinations of modifications: (1)LNA-(5m)C* / LNA-A* / dT* / dG* / dG* / dT* / dG* / dA* / dA* / dG* / LNA-A* / LNA-G (SEQ ID NO. 169); (2)LNA-(5m)C* / LNA-(5m)C* / dA* / dT* / dG* / dG* / dT* / dG* / dA* / dA* / LNA-G* / LNA-A* / LNA-G(SEQ ID NO.170); (3)LNA-(5m)C* / LNA-(5m)C* / dA* / dT* / dG* / dG* / dT* / dG* / dA* / dA* / LNA-G* / LNA-A(SEQ ID NO.171); (4)LNA-T* / LNA-(5m)C* / LNA-(5m)C* / dA* / dT* / dG* / dG* / dT* / dG* / dA* / dA* / LNA-G* / LNA-A* / LNA-G(SEQ ID NO.172); (5)LNA-T* / LNA-(5m)C* / d(5m)C* / dA* / dT* / dG* / dG* / dT* / dG* / dA* / LNA-A* / LNA-G* / LNA-A(SEQ ID NO.173); (6)LNA-T* / LNA-(5m)C* / d(5m)C* / dA* / dT* / dG* / dG* / dT* / dG* / dA* / LNA-A* / LNA-G(SEQ ID NO.174); (7)LNA-(5m)C* / LNA-(5m)C* / dT* / dG* / d(5m)C* / d(5m)C* / dA* / dG* / dG* / dA* / LNA-A* / LNA-G(SEQ ID NO.175); (8)LNA-A* / LNA-G* / dA* / dT* / d(5m)C* / dT* / dT* / dG* / dG* / dT* / LNA-G* / LNA-A* / LNA-A(SEQ ID NO.180); (9)LNA-A* / LNA-G* / dA* / dT* / d(5m)C* / dT* / dT* / dG* / dG* / dT* / LNA-G* / LNA-A(SEQ ID NO.181); (10)LNA-(5m)C* / LNA-T* / LNA-G* / dT* / dT* / dG* / dA* / dA* / dG* / dA* / dT* / dG* / LNA-G* / LNA-A* / LNA-G(SEQ ID NO.196); (11)LNA-(5m)C* / LNA-T* / LNA-G* / dT* / dT* / dG* / dA* / dA* / dG* / dA* / dT* / LNA-G* / LNA-G* / LNA-A(SEQ ID NO.197); (12)LNA-(5m)C* / LNA-T* / dG* / dT* / dT* / dG* / dA* / dA* / dG* / dA* / LNA-T* / LNA-G* / LNA-G(SEQ ID NO.198); (13)LNA-G* / LNA-(5m)C* / LNA-T* / dG* / dT* / dT* / dG* / dA* / dA* / dG* / dA* / dT* / dG* / LNA-G* / LNA-A* / LNA-G(SEQ ID NO.200); (14)LNA-G* / LNA-(5m)C* / LNA-T* / dG* / dT* / dT* / dG* / dA* / dA* / dG* / dA* / dT* / LNA-G* / LNA-G* / LNA-A(SEQ ID NO.201); (15)LNA-G* / LNA-(5m)C* / LNA-T* / dG* / dT* / dT* / dG* / dA* / dA* / dG* / dA* / LNA-T* / LNA-G* / LNA-G(SEQ ID NO.202); (16)LNA-G* / LNA-A* / LNA-T* / dG* / dT* / d(5m)C* / d(5m)C* / dA* / dT* / dG* / dG* / dT* / dG* / LNA-A* / LNA-A* / LNA-G(SEQ ID NO.219); (17)LNA-G* / LNA-A* / LNA-T* / dG* / dT* / d(5m)C* / d(5m)C* / dA* / dT* / dG* / dG* / dT* / LNA-G* / LNA-A* / LNA-A(SEQ ID NO.220); (18)LNA-G* / LNA-A* / LNA-T* / dG* / dT* / d(5m)C* / d(5m)C* / dA* / dT* / dG* / dG* / LNA-T* / LNA-G* / LNA-A(SEQ ID NO.221); (19)LNA-G* / LNA-A* / dT* / dG* / dT* / d(5m)C* / d(5m)C* / dA* / dT* / dG* / LNA-G* / LNA-T* / LNA-G(SEQ ID NO.222); (20)LNA-G* / LNA-A* / dT* / dG* / dT* / d(5m)C* / d(5m)C* / dA* / dT* / dG* / LNA-G* / LNA-T(SEQ ID NO.223); (21)LNA-A* / LNA-G* / LNA-A* / dT* / dG* / dT* / d(5m)C* / d(5m)C* / dA* / dT* / dG* / dG* / dT* / LNA-G* / LNA-A* / LNA-A(SEQ ID NO.224); (22)LNA-A* / LNA-G* / LNA-A* / dT* / dG* / dT* / d(5m)C* / d(5m)C* / dA* / dT* / dG* / dG* / LNA-T* / LNA-G* / LNA-A(SEQ ID NO.225); (23)LNA-A* / LNA-G* / LNA-A* / dT* / dG* / dT* / d(5m)C* / d(5m)C* / dA* / dT* / dG* / LNA-G* / LNA-T* / LNA-G(SEQ ID NO.226); (24)LNA-A* / LNA-G* / dA* / dT* / dG* / dT* / d(5m)C* / d(5m)C* / dA* / dT* / LNA-G* / LNA-G* / LNA-T(SEQ ID NO.227); (25)LNA-A* / LNA-G* / dA* / dT* / dG* / dT* / d(5m)C* / d(5m)C* / dA* / dT* / LNA-G* / LNA-G(SEQ ID NO.228); (26)LNA-G* / LNA-T* / LNA-A* / dG* / dA* / dT* / dG* / dT* / d(5m)C* / d(5m)C* / dA* / dT* / dG* / LNA-G* / LNA-T* / LNA-G(SEQ ID NO.234); (27)LNA-G* / LNA-T* / LNA-A* / dG* / dA* / dT* / dG* / dT* / d(5m)C* / d(5m)C* / dA* / dT* / LNA-G* / LNA-G* / LNA-T(SEQ ID NO.235); (28)LNA-G* / LNA-T* / LNA-A* / dG* / dA* / dT* / dG* / dT* / d(5m)C* / d(5m)C* / dA* / LNA-T* / LNA-G* / LNA-G(SEQ ID NO.236); (29)LNA-G* / LNA-T* / dA* / dG* / dA* / dT* / dG* / dT* / d(5m)C* / d(5m)C* / LNA-A* / LNA-T* / LNA-G(SEQ ID NO.237); (30)LNA-G* / LNA-T* / dA* / dG* / dA* / dT* / dG* / dT* / d(5m)C* / d(5m)C* / LNA-A* / LNA-T(SEQ ID NO.238); (31)LNA-A* / LNA-T* / LNA-G* / dT* / dA* / dA* / dT* / d(5m)C* / dG* / dA* / dA* / LNA-G* / LNA-A* / LNA-G(SEQ ID NO.242); (32)LNA-A* / LNA-G* / LNA-A* / dA* / dT* / dG* / d(5m)C* / dG* / dG* / d(5m)C* / dT* / dG* / dA* / LNA-T* / LNA-(5m)C* / LNA-A(SEQ ID NO.260); (33)LNA-A* / LNA-G* / LNA-A* / dA* / dT* / dG* / d(5m)C* / dG* / dG* / d(5m)C* / dT* / dG* / LNA-A* / LNA-T* / LNA-(5m)C(SEQ ID NO.261); (34)LNA-A* / LNA-G* / LNA-A* / dA* / dT* / dG* / d(5m)C* / dG* / dG* / d(5m)C* / dT* / LNA-G* / LNA-A* / LNA-T(SEQ ID NO.262); (35)LNA-A* / LNA-G* / dA* / dA* / dT* / dG* / d(5m)C* / dG* / dG* / d(5m)C* / LNA-T* / LNA-G* / LNA-A(SEQ ID NO.263); (36)LNA-A* / LNA-G* / dA* / dA* / dT* / dG* / d(5m)C* / dG* / dG* / d(5m)C* / LNA-T* / LNA-G(SEQ ID NO.264); (37)LNA-(5m)C* / LNA-A* / LNA-G* / dA* / dA* / dT* / dG* / d(5m)C* / dG* / dG* / d(5m)C* / dT* / dG* / LNA-A* / LNA-T* / LNA-(5m)C(SEQ ID NO.265); (38)LNA-(5m)C* / LNA-A* / dG* / dA* / dA* / dT* / dG* / d(5m)C* / dG* / dG* / LNA-(5m)C* / LNA-T(SEQ ID NO.269); (39)LNA-T* / LNA-A* / LNA-(5m)C* / dA* / dG* / dA* / dA* / dT* / dG* / d(5m)C* / dG* / dG* / d(5m)C* / LNA-T* / LNA-G* / LNA-A(SEQ ID NO.274); (40)LNA-A* / LNA-(5m)C* / LNA-A* / dG* / dA* / dA* / dT* / dG* / d(5m)C* / dG* / dG* / LNA-(5m)C* / LNA-T* / LNA-G(SEQ ID NO.277); (41)LNA-T* / LNA-A* / d(5m)C* / dA* / dG* / dA* / dA* / dT* / dG* / d(5m)C* / LNA-G* / LNA-G* / LNA-(5m)C(SEQ ID NO.278); (42)LNA-T* / LNA-A* / d(5m)C* / dA* / dG* / dA* / dA* / dT* / dG* / d(5m)C* / LNA-G* / LNA-G(SEQ ID NO.279); (43)LNA-G* / LNA-T* / dA* / d(5m)C* / dA* / dG* / dA* / dA* / dT* / dG* / LNA-(5m)C* / LNA-G(SEQ ID NO.284); (44)LNA-G* / LNA-A* / LNA-T* / dG* / dT* / dA* / dA* / dT* / d(5m)C* / dG* / dA* / dA* / LNA-G* / LNA-A* / LNA-G(SEQ ID NO.286); (45)LNA-G* / LNA-A* / LNA-T* / dG* / dT* / dA* / dA* / dT* / d(5m)C* / dG* / dA* / LNA-A* / LNA-G* / LNA-A(SEQ ID NO.287); (46)LNA-G* / LNA-G* / LNA-A* / dT* / dG* / dT* / dA* / dA* / dT* / d(5m)C* / dG* / dA* / dA* / LNA-G* / LNA-A* / LNA-G(SEQ IDNO.290); (47)LNA-G* / LNA-G* / LNA-A* / dT* / dG* / dT* / dA* / dA* / dT* / d(5m)C* / dG* / dA* / LNA-A* / LNA-G* / LNA-A(SEQ ID NO.291); (48)LNA-G* / LNA-G* / LNA-A* / dT* / dG* / dT* / dA* / dA* / dT* / d(5m)C* / dG* / LNA-A* / LNA-A* / LNA-G(SEQ ID NO.292); (49)LNA-G* / LNA-G* / dA* / dT* / dG* / dT* / dA* / dA* / dT* / d(5m)C* / LNA-G* / LNA-A* / LNA-A(SEQ ID NO.293); (50)LNA-T* / LNA-G* / LNA-G* / dA* / dT* / dG* / dT* / dA* / dA* / dT* / d(5m)C* / dG* / dA* / LNA-A* / LNA-G* / LNA-A(SEQ ID NO.295); (51)LNA-T* / LNA-G* / LNA-G* / dA* / dT* / dG* / dT* / dA* / dA* / dT* / d(5m)C* / dG* / LNA-A* / LNA-A* / LNA-G (SEQ ID NO. 296); (52)LNA-T* / LNA-G* / LNA-G* / dA* / dT* / dG* / dT* / dA* / dA* / dT* / d(5m)C* / LNA-G* / LNA-A* / LNA-A (SEQ ID NO. 297); (53)LNA-(5m)C* / LNA-(5m)C* / dG* / dT* / dG* / dT* / dA* / dA* / dA* / dT* / LNA-(5m)C* / LNA-A (SEQ ID NO. 325); or (54)LNA-G* / LNA-(5m)C* / dA* / d(5m)C* / d(5m)C* / dA* / dG* / dT* / dA* / d(5m)C* / LNA-(5m)C* / LNA-A (SEQ ID NO. 326); In this context, * represents a phosphate thioester bond between nucleotides, and 5m indicates that the 5th carbon in cytosine is methylated. According to claim 24, the antisense oligonucleotide, wherein, The antisense oligonucleotide is selected from any of the following combinations of modifications: (1)LNA-(5m)C* / LNA-A* / dT* / dG* / dG* / dT* / dG* / dA* / dA* / dG* / LNA-A* / LNA-G (SEQ ID NO. 169); (2)LNA-A* / LNA-G* / dA* / dT* / d(5m)C* / dT* / dT* / dG* / dG* / dT* / LNA-G* / LNA-A* / LNA-A (SEQ ID NO. 180); (3)LNA-A* / LNA-G* / dA* / dT* / d(5m)C* / dT* / dT* / dG* / dG* / dT* / LNA-G* / LNA-A (SEQ ID NO. 181); (4)LNA-G* / LNA-A* / LNA-T* / dG* / dT* / d(5m)C* / d(5m)C* / dA* / dT* / dG* / dG* / dT* / dG* / LNA-A* / LNA-A* / LNA-G (SEQ ID NO. 219); (5)LNA-G* / LNA-A* / LNA-T* / dG* / dT* / d(5m)C* / d(5m)C* / dA* / dT* / dG* / dG* / LNA-T* / LNA-G* / LNA-A (SEQ ID NO. 221); (6)LNA-G* / LNA-A* / dT* / dG* / dT* / d(5m)C* / d(5m)C* / dA* / dT* / dG* / LNA-G* / LNA-T* / LNA-G (SEQ ID NO. 222); (7)LNA-A* / LNA-G* / LNA-A* / dT* / dG* / dT* / d(5m)C* / d(5m)C* / dA* / dT* / dG* / dG* / dT* / LNA-G* / LNA-A* / LNA-A(SEQ ID NO.224); (8)LNA-A* / LNA-G* / LNA-A* / dT* / dG* / dT* / d(5m)C* / d(5m)C* / dA* / dT* / dG* / LNA-G* / LNA-T* / LNA-G(SEQ ID NO.226); (9)LNA-A* / LNA-G* / dA* / dT* / dG* / dT* / d(5m)C* / d(5m)C* / dA* / dT* / LNA-G* / LNA-G* / LNA-T(SEQ ID NO.227); (10)LNA-A* / LNA-G* / dA* / dT* / dG* / dT* / d(5m)C* / d(5m)C* / dA* / dT* / LNA-G* / LNA-G(SEQ ID NO.228); (11)LNA-G* / LNA-T* / LNA-A* / dG* / dA* / dT* / dG* / dT* / d(5m)C* / d(5m)C* / dA* / dT* / dG* / LNA-G* / LNA-T* / LNA-G(SEQ ID NO.234); (12)LNA-G* / LNA-T* / LNA-A* / dG* / dA* / dT* / dG* / dT* / d(5m)C* / d(5m)C* / dA* / dT* / LNA-G* / LNA-G* / LNA-T(SEQ ID NO.235); (13)LNA-G* / LNA-T* / LNA-A* / dG* / dA* / dT* / dG* / dT* / d(5m)C* / d(5m)C* / dA* / LNA-T* / LNA-G* / LNA-G(SEQ ID NO.236); (14)LNA-G* / LNA-T* / dA* / dG* / dA* / dT* / dG* / dT* / d(5m)C* / d(5m)C* / LNA-A* / LNA-T* / LNA-G(SEQ ID NO.237); (15)LNA-A* / LNA-T* / LNA-G* / dT* / dA* / dA* / dT* / d(5m)C* / dG* / dA* / dA* / LNA-G* / LNA-A* / LNA-G(SEQ ID NO.242); (16)LNA-T* / LNA-A* / LNA-(5m)C* / dA* / dG* / dA* / dA* / dT* / dG* / d(5m)C* / dG* / dG* / d(5m)C* / LNA-T* / LNA-G* / LNA-A(SEQ ID NO.274); (17)LNA-A* / LNA-(5m)C* / LNA-A* / dG* / dA* / dA* / dT* / dG* / d(5m)C* / dG* / dG* / LNA-(5m)C* / LNA-T* / LNA-G(SEQ ID NO.277); (18)LNA-T* / LNA-A* / d(5m)C* / dA* / dG* / dA* / dA* / dT* / dG* / d(5m)C* / LNA-G* / LNA-G* / LNA-(5m)C(SEQ ID NO.278); (19)LNA-T* / LNA-A* / d(5m)C* / dA* / dG* / dA* / dA* / dT* / dG* / d(5m)C* / LNA-G* / LNA-G(SEQ ID NO.279); (20)LNA-G* / LNA-T* / dA* / d(5m)C* / dA* / dG* / dA* / dA* / dT* / dG* / LNA-(5m)C* / LNA-G(SEQ ID NO.284); (21)LNA-G* / LNA-A* / LNA-T* / dG* / dT* / dA* / dA* / dT* / d(5m)C* / dG* / dA* / dA* / LNA-G* / LNA-A* / LNA-G(SEQ ID NO.286); (22)LNA-G* / LNA-A* / LNA-T* / dG* / dT* / dA* / dA* / dT* / d(5m)C* / dG* / dA* / LNA-A* / LNA-G* / LNA-A(SEQ ID NO.287); (23)LNA-G* / LNA-G* / LNA-A* / dT* / dG* / dT* / dA* / dA* / dT* / d(5m)C* / dG* / dA* / dA* / LNA-G* / LNA-A* / LNA-G(SEQ ID NO.290); (24)LNA-G* / LNA-G* / LNA-A* / dT* / dG* / dT* / dA* / dA* / dT* / d(5m)C* / dG* / dA* / LNA-A* / LNA-G* / LNA-A(SEQ ID NO.291); (25)LNA-G* / LNA-G* / LNA-A* / dT* / dG* / dT* / dA* / dA* / dT* / d(5m)C* / dG* / LNA-A* / LNA-A* / LNA-G(SEQ ID NO.292); (26)LNA-G* / LNA-G* / dA* / dT* / dG* / dT* / dA* / dA* / dT* / d(5m)C* / LNA-G* / LNA-A* / LNA-A(SEQ ID NO.293); (27)LNA-T* / LNA-G* / LNA-G* / dA* / dT* / dG* / dT* / dA* / dA* / dT* / d(5m)C* / dG* / dA* / LNA-A* / LNA-G* / LNA-A (SEQ ID NO. 295); or (28)LNA-T* / LNA-G* / LNA-G* / dA* / dT* / dG* / dT* / dA* / dA* / dT* / d(5m)C* / dG* / LNA-A* / LNA-A* / LNA-G (SEQ ID NO. 296); In this context, * represents a phosphate thioester bond between nucleotides, and 5m indicates that the 5th carbon in cytosine is methylated. The antisense oligonucleotide according to any one of claims 1-25, wherein, The modified nucleotide further comprises one or more nucleotide modifications selected from the group consisting of: 2'-deoxynucleotides, 2',3'-seco nucleotide mimics, unlocked nucleic acid nucleotides (UNA), glycol nucleic acid nucleotides (GNA), bicyclic nucleic acids (BNA), 2'-F-arabinonucleotides, 2'-methoxyethyl nucleotides, abase-free nucleotides, ribitol, reverse nucleotides, reverse abase-free nucleotides (Invab), reverse 2'-OMe nucleotides, reverse 2'-deoxynucleotides, 2'-amino-modified nucleotides, 2'-alkyl-modified nucleotides, morpholinonucleotides, 3'-OMe nucleotides, phosphate ester-modified nucleotides, terminal nucleotides linked to cholesterol derivatives or dodecanoic acid bis(decylamide) groups, 2'-amino-modified nucleotides, aminophosphates, or non-natural bases containing nucleotides. The antisense oligonucleotide according to any one of claims 1-26, wherein, The antisense oligonucleotide contains at least one modified nucleotide inter-bond. According to claim 27, the antisense oligonucleotide, wherein, The modified nucleotide inter-bonds include thiophosphate bonds and / or methanesulfonylphosphatidyl linkages; preferably, the modified nucleotide inter-bonds are thiophosphate bonds, or the modified nucleotide inter-bonds are methanesulfonylphosphatidyl linkages. The antisense oligonucleotide according to any one of claims 1-28, wherein, The antisense oligonucleotide may also optionally include one or more nucleotides conjugated to one or more targeting ligands; Preferably, the targeting ligand is conjugated to the 5' end of the antisense oligonucleotide; Preferably, the targeting ligand comprises a protein, a small molecule compound, a carbohydrate, or a lipid; Preferably, the protein is selected from natural proteins, synthetic polyamino acids, polypeptides, and antibodies; Preferably, the natural protein is selected from human serum albumin, low-density lipoprotein, or globulin; Preferably, the synthesized polyamino acid is selected from polylysine, poly-L-aspartic acid, poly-L-glutamic acid, styrene-maleic anhydride copolymer, poly(L-lactic acid-co-ethylene glycol) copolymer, diethylene ether-maleic anhydride copolymer, N-(2-hydroxypropyl)methacrylamide copolymer, polyethylene glycol, polyvinyl alcohol, polyurethane, poly(2-ethylacrylic acid), N-isopropylacrylamide polymer or polyphosphoric acid; Preferably, the carbohydrate is selected from dextran, pullulan, chitin, chitosan, inulin, cyclodextrin, amino sugars, or hyaluronic acid; Preferably, the lipid is selected from fatty acids, sterols, or phospholipids; Preferably, the fatty acid is selected from capric acid, caprylic acid, lauric acid, palmitic acid, myristic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, arachidonic acid, or eicosenoic acid; Preferably, the sterol is selected from cholesterol, cholesterol group, cholesterol alcohol, stigmasterol, cholesterol acid, or ergosterol; Preferably, the phospholipid is selected from di-hexadecyl-racemic glycerol or triethylamine 1,2-di-O-hexadecyl-racemic glycerol-3-hydrophosphonate; Preferably, the targeting ligand comprises amino sugars; Preferably, the targeting ligand comprises an N-acetylgalactosamine (GalNAc) moiety; Preferably, the GalNac portion is a monovalent GalNAc portion, a divalent GalNAc portion, a trivalent GalNAc portion, or a tetravalent GalNAc portion; Preferably, the targeting ligand has the following structure: A composition comprising the antisense oligonucleotide of any one of claims 1-29 or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier. The composition according to claim 30 further comprises one or more additional therapeutic components; Preferably, the therapeutic component is selected from dipeptidyl peptidase-4 (DPP-4) inhibitors, insulin, insulin analogs, biguanides, sulfonylureas, thiazolidinediones (TZD), α-glucosidase inhibitors or glucagon-like peptide-1 (GLP-1) receptor agonists, angiotensin-converting enzyme (ACE) inhibitors, endothelin receptor antagonists (ERA), angiotensin II receptor blockers (ARB), mineralocorticoid receptor (MR) antagonists, and aldosterone synthase (AS) inhibitors; Preferably, the DPP-4 inhibitor is selected from sitagliptin, vildagliptin, saxagliptin, linagliptin, alogliptin, tenegliptin, anagliptin, trelagliptin, and omaligliptin; Preferably, the α-glucosidase inhibitor is selected from acarbose, voglibose, and miglitol; Preferably, the GLP-1 receptor agonist is selected from semaglutide, liraglutide, exenatide, dulaglutide, and tirzepatide. Preferably, the ACE inhibitor is selected from benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, and trundolapril. Preferably, the ERA is selected from Zibotentan, Atrasertan, Avosentan, and Sparsertan; Preferably, the ARB is selected from irbesartan, losartan, olmesartan, and valsartan; Preferably, the MR antagonist is selected from spironolactone, eplerenone, finerenone, esaxerenone, apararenone, balcinerone, and occedurenone; Preferably, the AS inhibitor is selected from Baxdrostat, Vicadrostat, and Lorundrostat. The composition according to claim 30 or 31, wherein, The composition is packaged in a box, container, packaging, dispenser, pre-filled syringe, or vial. The composition according to claim 30 or 31, wherein, The composition is formulated for administration via ocular, vaginal, rectal, nasal, transdermal, subcutaneous, intravenous, intra-arterial, intralymphatic, intrabronchial, intrapleural, intraperitoneal, cerebrospinal, or intramuscular injection, or for administration to the lungs, intrathecal, or intracardiac organs. A cell comprising the antisense oligonucleotide as described in any one of claims 1-29. A method for inhibiting SGLT2 and / or SGLT1 gene expression in vitro, the method comprising the following steps: Contact the cells with an effective amount of the antisense oligonucleotide of any one of claims 1-29 and / or the composition of any one of claims 30-33. A reagent kit, wherein, The kit contains the antisense oligonucleotides according to any one of claims 1-29 and / or the compositions according to any one of claims 30-33. Use of the antisense oligonucleotide of any one of claims 1-29 and / or the composition of any one of claims 30-33 in the preparation of a medicament for the prevention and / or treatment of diseases; Preferably, the disease is an sglt1 and / or sglt2 related disease; Preferably, the disease is type I diabetes, type II diabetes, diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, delayed wound healing, insulin resistance, hyperglycemia, hyperinsulinemia, chronic kidney disease, heart failure with preserved ejection fraction, heart failure with reduced ejection fraction, elevated blood levels of fatty acids or glycerol, hyperlipidemia, dyslipidemia, obesity, hypertriglyceridemia, syndrome X, diabetic complications or atherosclerosis, hypertension, hyperuricemia or cardiovascular disease. A method for preventing and / or treating a disease, comprising administering to a subject in need an effective amount of the antisense oligonucleotide of any one of claims 1-29 and / or the composition of any one of claims 30-33; Preferably, the disease is an sglt1 and / or sglt2 related disease; Preferably, the disease is type I diabetes, type II diabetes, diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, delayed wound healing, insulin resistance, hyperglycemia, hyperinsulinemia, chronic kidney disease, heart failure with preserved ejection fraction, heart failure with reduced ejection fraction, elevated blood levels of fatty acids or glycerol, hyperlipidemia, dyslipidemia, obesity, hypertriglyceridemia, syndrome X, diabetic complications or atherosclerosis, hypertension, hyperuricemia or cardiovascular disease. A pharmaceutical composition for the prevention and / or treatment of diseases, wherein, The pharmaceutical composition comprises the antisense oligonucleotide according to any one of claims 1-29 and / or the composition according to any one of claims 30-33. Preferably, the disease is an sglt1 and / or sglt2 related disease; Preferably, the disease is type I diabetes, type II diabetes, diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, delayed wound healing, insulin resistance, hyperglycemia, hyperinsulinemia, chronic kidney disease, heart failure with preserved ejection fraction, heart failure with reduced ejection fraction, elevated blood levels of fatty acids or glycerol, hyperlipidemia, dyslipidemia, obesity, hypertriglyceridemia, syndrome X, diabetic complications or atherosclerosis, hypertension, hyperuricemia or cardiovascular disease. Use of the antisense oligonucleotide of any one of claims 1-29 and / or the composition of any one of claims 30-33 for the prevention and / or treatment of diseases; Preferably, the disease is an sglt1 and / or sglt2 related disease; Preferably, the disease is type I diabetes, type II diabetes, diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, delayed wound healing, insulin resistance, hyperglycemia, hyperinsulinemia, chronic kidney disease, heart failure with preserved ejection fraction, heart failure with reduced ejection fraction, elevated blood levels of fatty acids or glycerol, hyperlipidemia, dyslipidemia, obesity, hypertriglyceridemia, syndrome X, diabetic complications or atherosclerosis, hypertension, hyperuricemia or cardiovascular disease.

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