Oligonucleotide targeting peripheral myelin protein-22 gene, and use thereof

Abstract

The present invention relates to an RNAi agent targeting peripheral myelin protein-22 (PMP22), for example, a double-stranded small interfering RNA (siRNA) agent. The present invention further relates to a method for inhibiting PMP22 gene expression by means of using such an RNAi agent and a method for preventing and treating PMP22-related diseases by means of using such an RNAi agent. The siRNA significantly inhibits the expression level of the PMP22 gene, and exhibits a long-lasting efficacy.

Description

Oligonucleotides targeting the peripheral myelin protein-22 gene and uses thereof TECHNICAL FIELD

[0001] The present disclosure relates to an oligonucleotide, in particular for the inhibition of peripheral myelin protein-22 (PMP22) gene expression and the treatment of related diseases caused by mutations or overexpression of this gene. BACKGROUND

[0002] PMP22 was first isolated from mouse NIH3T3 fibroblasts as one of the growth-arrest-specific genes gas3 (Schneider et al., Cell. 1988; 54: 787-793). Gas3 was upregulated in serum-starved NIH3T3 cells (Manfioletti et al., Mol Cell Biol. 1990; 10: 2924-2930). Subsequently, a transcript, SR13, isolated from rat nerves was found to be strongly downregulated in the acute phase after sciatic nerve injury. SR13 had a highly homologous sequence to gas3, possibly from the same gene (Welcher et al., Nature. 1992b; 356: 241-244.). Gas3 / SR13 (also known as PASII) was then localized to the compact myelin of peripheral nerves with a molecular weight of 22 kD. Thus, the protein was renamed peripheral myelin protein-22 (PMP22).

[0003] In the human genome, PMP22 is located on chromosome 17pl l.2. PMP22 is a 40 kb gene composed of 6 exons that are conserved in humans and rodents (Fig. 1A). Two alternatively transcribed exons (la and lb) make up the first exon of the gene and give rise to two distinct transcripts (Jetten, Suter, 2000. Prog Nucleic Acid Res Mol Biol. 2000;64:97-129). The coding sequences of these two transcripts are identical, but their 5' untranslated regions differ, suggesting that two different promoters (P1 and P2) regulate the expression of each transcript. Indeed, two different PMP22 transcripts, exon la (also known as CD25 or la-PMP22) and exon lb (SR13 or lb-PMP22), have been isolated in rats (Spreyer et al., EMBO J. 1991; 10:3661-3668.). Similar transcripts have also been found in humans and mice (Suter et al., Hum Mutat. 1994; 3:95-102.). The coding region of PMP22 extends from exon 2 to exon 5. Exon 2 encodes the first transmembrane domain of PMP22. Exon 3 encodes the first extracellular loop. Exon 4 encodes the second transmembrane domain and half of the third transmembrane domain. Exon 5 encodes the remaining half of the third transmembrane domain, the second extracellular domain, the fourth transmembrane domain, and the 3' untranslated region (Suter and Patel, Hum Mutat. 1994; 3:95-102.; Chen et al., Genomics. 1997; 41:40-48.; Jetten and Suter, Prog Nucleic Acid Res Mol Biol. 2000; 64:97-129.). PMP22 transcripts have been consistently shown to be most abundant in the myelinating Schwann cells of the peripheral nerves (Snipes et al., J Cell Biol. 1992; 117:225-238.; Parmantier et al., Eur J Neurosci. 1995; 7:1080-1088.; Roux et al., J Comp Neurol. 2004; 474:578-588.; Ohsawa et al., J Neurol Sci. 2006; 247:11-15.). The temporal course of PMP22 transcription in the central nervous system motor neurons shows a rostral-caudal pattern, with cranial neuronal expression first during the embryonic period and spinal motor neuron expression after birth. In contrast, sensory neurons in the cranial nuclei express PMP22 during the embryonic period but are undetectable in young adults.Different PMP22 transcripts are differentially distributed in tissues. Exon lb transcripts are present in the brainstem, spinal cord, skeletal muscle, heart, and sciatic nerve, while exon la transcripts are predominantly present in the sciatic nerve (Parmantier et al., Eur J Neurosci. 1995; 7: 1080-1088. Parmantier et al., J Comp Neurol. 1997; 378: 159-172.).

[0004] PMP22 mutations, including duplications, deletions, and point mutations, all result in increased apoptosis in CMT1A mice and in human cultured Schwann cells, fibroblasts, and myelinating Schwann cells. Dyck and Lambert classified autosomal dominant inherited neuropathies into two groups, demyelinating (hereditary motor and sensory neuropathy-1 (HMSN-1, now designated CMT1) and axonal (HMSN-2 or CMT2), based on electrophysiological and pathological criteria (Dyck, Lambert, Arch Neurol. 1968; 18: 603-618.). Nerve conduction velocity is markedly slowed in the CMT1 group; while conduction velocity is usually normal or slightly slowed in CMT2, but the amplitude of motor and sensory responses is diminished. Pathologically, CMT1 shows prominent onion bulbs, representing excess Schwann cell membrane around myelinated nerve fibers that fail to form compact myelin. In contrast, axonal loss is the main feature of CMT2. Although the prevalence of CMT is as high as 1:2500 (Skre, Clin Genet. 1974; 6: 98-118.), over 50% of CMT cases are caused by PMP22 gene mutations, including heterozygous duplication (CMT1A), deletion (HNPP), and point mutations (CMT1E) (Figure 2).

[0005] There is strong evidence that duplication of PMP22 is the cause of this disease, and not other genes. First, point mutations in the PMP22 gene are sufficient to cause peripheral neuropathy (Suter et al., J Cell Biol. 1992; 117:225-238.). In rodents, increasing the copy number of PMP22 to overexpress the protein produces a pathological phenotype similar to human CMT1A subjects (Sereda et al., Neuron. 1996; 16: 1049-1060.; Huxley et al., Hum Mol Genet. 1998; 7:449-458.; Magyar et al., 1996). Finally, heterozygous truncating mutations that inactivate one of the two copies of PMP22 also cause peripheral neuropathy (Nicholson et al., Nat Genet. 1994; 6:263-266.; Li J et al., Archives of Neurology. 2007; 64:974-978.).

[0006] Clinical phenotype - Most patients with Charcot-Marie-Tooth disease type 1A (CMT1A) develop symptoms in the first 20 years of life. They usually run slowly, have poor motor skills as children, develop foot deformities (high arches and hammer toes) in their teens, and require orthotics to support their ankles as adults. They usually have varying degrees of hand weakness that lags behind the development of foot weakness. Sensory deficits occur in both large (vibration and proprioceptive) and small (pain and temperature) modalities. While the combination of ankle weakness and decreased proprioception often leads to balance problems, the vast majority of patients are still able to walk throughout their life cycle, which is not shortened by the disease. Almost all CMT1A patients lack deep tendon reflexes (Thomas et al., Brain. 1997; 120(Pt 3):465-478.; Krajewski et al., Ann N Y Acad Sci. 1999; 883:490-492). Other features, including possible development of postural tremor and muscle spasms. While this phenotype is typical in CMT1A patients, it can be variable. Some patients develop a severe phenotype in infancy, while others have only mild disability throughout their life.

[0007] Neurophysiology and pathology of CMT1A - CMT1A patients typically have slowed conduction velocities, ranging from 7 to 40 meters / second. However, the magnitude of the reduction in conduction velocity is minimal between different nerves of the same limb and between corresponding nerves of different limbs in individuals with CMT1A. This feature is an impressive stereotype in CMT1A patients, in sharp contrast to the electrophysiological features of acquired demyelinating neuropathies. The former is referred to as the "uniform slowing" pattern (Lewis et al., Muscle Nerve. 2000; 23: 1472-1487; Lupski et al., Cell. 1991; 66: 219-232.). The latter typically exhibits non-uniform or asymmetric changes. The conduction velocity of one of the nerves can be severely reduced, while that of the other nerve can be normal or mildly slowed. Non-uniform slowing is typically associated with temporal dispersion and conduction block of compound muscle action potentials, which are typically absent in CMT1A. In addition, a reduction in motor and sensory response amplitudes invariably occurs in all patients with CMT1A. They reflect axonal loss secondary to abnormal myelination and have been shown to be more relevant to the neurological dysfunction of CMT1A patients than conduction velocities (Krajewski et al., Ann N Y Acad Sci. 1999; 883: 490-492; Krajewski et al., Brain. 2000; 123(Pt 7): 1516-1527.; Thomas et al., Brain. 1997; 120(Pt 3): 465-478.).

[0008] Pathological changes in CMT1A nerves: Biopsies of the sural nerve in CMT1A patients show extensive onion bulb formation, affecting almost every myelinated nerve fiber (Figure 3A). The onion bulb is formed by multiple Schwann cells that extend their membrane processes around the axon, but fail to form a compact myelin sheath (Gabreels-Festen and Wetering, Ann N Y Acad Sci. 1999; 883: 336-343.; Gabreels-Festen et al., Acta Neuropathol. 1995; 90: 645-649.). In addition, there is a marked loss of axons in the myelinated nerve fibers. The space between surviving myelinated nerve fibers is occupied by a large number of collagen fibers, which can originate from fibroblasts. This loss of axons is consistent with the severe reduction in motor and sensory response amplitudes in CMT1A patients.

[0009] Current treatment options for PMP22-associated diseases and disorders are limited and have modest efficacy. Current methods of treating CMT1A are mainly symptomatic supportive treatment, including rehabilitation, drug symptomatic treatment, orthopedic surgery, etc. There is no marketed targeted drug for PMP22. CMT1A is a progressive neuromuscular genetic disease, which is autosomal dominant and can cause lifelong muscle function loss and disability. At present, there is no approved treatment targeting the underlying genetic cause of PMP22 for CMT1A, and about 150,000 patients in the United States and Europe suffer from this life-disabling disease. According to the summary of domestic reported cases, 88% have a genetic family history, and 12% are sporadic cases, similar to foreign reports. siRNA drugs with silent PMP22 genes that ultimately reduce PMP22 expression are potential candidate drugs for PMP22. The drug has shown strong preclinical performance in reversing the disease in animal models. SUMMARY

[0010] The present disclosure relates to RNAi agents targeting peripheral myelin protein-22, e.g., double-stranded small interfering RNA (siRNA) agents. The present disclosure aims to provide an inhibitor with good efficacy, high safety, and long-lasting drug efficacy.

[0011] The present disclosure provides an oligonucleotide or a pharmaceutically acceptable salt thereof and a method of inhibiting PMP22 gene expression in a cell or a mammal using the oligonucleotide or the pharmaceutically acceptable salt thereof, wherein the oligonucleotide targets the PMP22 gene. Also provided herein are compositions and methods for treating pathological conditions and diseases in a mammal caused by PMP22 overexpression or mutation. The oligonucleotide is a double-stranded RNA (dsRNA) that directs sequence-specific degradation of mRNA through a process called RNA interference (RNAi).

[0012] In one aspect, the present disclosure provides an oligonucleotide or a pharmaceutically acceptable salt thereof for inhibiting PMP22 gene expression, the aforementioned oligonucleotide comprising a sense strand and an antisense strand, the aforementioned sense strand having a sequence with at least 80% or more sequence identity to a sequence set forth in any one of SEQ ID NO. SEQ ID NO. 1-547 or a fragment thereof, or a modified sequence of the aforementioned sequence or fragment thereof, preferably a sequence with 70%, 75%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity; the aforementioned antisense strand having a sequence with at least 70% or more sequence identity to a sequence set forth in any one of SEQ ID NO. 548-1094, 1733-1738 or a fragment thereof, or a modified sequence of the aforementioned sequence or fragment thereof, preferably a sequence with 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity.

[0013] In another aspect, the present disclosure provides a conjugate or a pharmaceutically acceptable salt thereof for inhibiting PMP22 expression, comprising: (i) a foregoing oligonucleotide or a pharmaceutically acceptable salt thereof, and (ii) a targeting ligand and / or a lipophilic moiety, wherein at least one of the sense strand and the antisense strand of the oligonucleotide is conjugated to the targeting ligand and / or at least one of the sense strand and the antisense strand of the oligonucleotide is conjugated to one or more of the lipophilic moiety.

[0014] In another aspect, the present disclosure provides a composition comprising a foregoing oligonucleotide or a pharmaceutically acceptable salt thereof, or a foregoing conjugate or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier.

[0015] In another aspect, the present disclosure provides a use of a foregoing oligonucleotide or a pharmaceutically acceptable salt thereof, or a conjugate or a salt thereof, or a composition in the manufacture of a medicament for treating or / and preventing a PMP22-related disorder, disease and / or condition.

[0016] In another aspect, the present disclosure provides a method of treating and / or preventing a PMP22-related disorder, disease and / or condition in a subject by administering to the subject a therapeutic agent (e.g., a foregoing oligonucleotide or a pharmaceutically acceptable salt thereof, or a foregoing conjugate or a pharmaceutically acceptable salt thereof, or a foregoing composition, or a vector or transgene encoding the oligonucleotide).

[0017] In another aspect, the present disclosure provides a method of treating and / or preventing a PMP22-related disorder, disease and / or condition in a subject by administering to the subject a therapeutic agent (e.g., a foregoing oligonucleotide or a pharmaceutically acceptable salt thereof, or a foregoing conjugate or a pharmaceutically acceptable salt thereof, or a foregoing composition, or a vector or transgene encoding the oligonucleotide).

[0018] The present disclosure also relates to methods of using such RNAi agents to inhibit PMP22 gene expression and methods of preventing and treating PMP22-related disorders. Experiments demonstrate that the oligonucleotides of the present disclosure can effectively reduce PMP22 levels in vivo and are effective inhibitors of CMT1A-related disease characteristics in animals. BRIEF DESCRIPTION OF DRAWINGS

[0019] FIG. 1 shows the gene structure of PMP22 (FIG. 1A) and predicted structural information (FIG. IB).

[0020] FIG. 2 shows a hypothetical mechanism of PMP22-related disease.

[0021] Figure 3 shows pathological manifestations of CMT1A and HNPP, wherein: A. A sural nerve biopsy was performed on a 70-year-old male patient with CMT1A. Semithin sections showed numerous onion bulbs scattered throughout the field (from Berciano et al., JNNP 2006; 77: 1169-1176). B. Photomicrograph of a nerve fiber section of a single sural nerve biopsy specimen from a 23-year-old female patient with HNPP, showing areas of myelin thickening. C. Photomicrograph of an epoxy semithin section of a sural nerve biopsy specimen from a patient, showing a myelinic fiber with a thickened myelin sheath in transverse section (methyl blue).

[0022] Figure 4 shows a flow chart of solid phase synthesis of oligonucleotides. DETAILED DESCRIPTION

[0023] In the present disclosure, the scientific and technical terms used herein have the meanings commonly understood by a person of ordinary skill in the art, unless otherwise indicated. Also, the terms related to protein and nucleic acid chemistry, molecular biology, cell and tissue culture, microbiology, immunology, and laboratory operation procedures used herein are terms and procedures widely used in the corresponding fields. Meanwhile, for better understanding of the present disclosure, the definitions and explanations of the related terms are provided below.

[0024] As used herein, the term “about” or “approximately,” as applied to one or more target values, refers to a value similar to a reference value. In some embodiments, unless otherwise stated or otherwise clear from context, the term “approximately” or “about” refers to a range of values that fall 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 either direction (greater than or less than), unless such number would exceed 100% of the possible values.

[0025] As used herein, the term “complementary” refers to a structural relationship between nucleotides (e.g., on opposite nucleic acids or on opposite regions of a single nucleic acid strand) that allows the nucleotides to form base pairs with one another. For example, a purine nucleotide of one nucleic acid that is complementary to a pyrimidine nucleotide of an opposite nucleic acid can base pair together by forming hydrogen bonds with one another. In some embodiments, complementary nucleotides can base pair in a Watson-Crick manner or in any other manner that allows for the formation of a stable duplex. In some embodiments, two nucleic acids can have nucleotide sequences that are complementary to one another so as to form a region of complementarity, as described herein.

[0026] As used herein, the term "strand" refers to a single continuous sequence of nucleotides linked together by internucleotide linkages (e.g., phosphodiester linkages, phosphorothioate linkages). In some embodiments, a strand has two free ends, e.g., a 5 '-end and a 3 '-end.

[0027] As used herein, the term "deoxyribonucleotide" refers to a nucleotide having a hydrogen at the 2' position of its pentose sugar as compared to a ribonucleotide. A modified deoxyribonucleotide is a deoxyribonucleotide having one or more modifications or substitutions (including modifications or substitutions in or of the sugar, phosphate group, or base or modifications or substitutions of the sugar, phosphate group, or base) other than at the 2' position.

[0028] As used herein, the term "oligonucleotide" refers to a short nucleic acid, e.g., a short nucleic acid less than 100 nucleotides in length. An oligonucleotide can comprise ribonucleotides, deoxyribonucleotides, and / or modified nucleotides, including, e.g., modified ribonucleotides. An oligonucleotide can be single-stranded or double-stranded. An oligonucleotide can or can not have duplex regions. As a non-limiting example, an oligonucleotide can be, but is not limited to, a small interfering RNA (siRNA), a microRNA (miRNA), a short hairpin RNA (shRNA), a Dicer substrate interfering RNA (dsiRNA), an antisense oligonucleotide, a short siRNA, or a single-stranded siRNA. In some embodiments, a double-stranded oligonucleotide is an RNAi oligonucleotide.

[0029] As used herein, the term "double-stranded oligonucleotide" refers to an oligonucleotide that is substantially in duplex form. In some embodiments, one or more duplex regions of a double-stranded oligonucleotide form complementary base pairing between antiparallel sequences of nucleotides of covalently separate nucleic acid strands. In some embodiments, one or more duplex regions of a double-stranded oligonucleotide form complementary base pairing between antiparallel sequences of nucleotides of covalently linked nucleic acid strands. In some embodiments, one or more duplex regions of a double-stranded oligonucleotide form complementary base pairing of antiparallel sequences of nucleotides that are together base paired from a single nucleic acid strand that is folded (e.g., via a hairpin). In some embodiments, a double-stranded oligonucleotide comprises two covalently separate nucleic acid strands that are fully duplexed with each other. However, in some embodiments, a double-stranded oligonucleotide comprises two covalently separate nucleic acid strands that are partially duplexed, e.g., have overhangs at one or both ends. In some embodiments, a double-stranded oligonucleotide comprises antiparallel sequences of nucleotides that are partially complementary, and thus, can have one or more mismatches, which can include internal mismatches or terminal mismatches.

[0030] As used herein, the term "double-stranded RNA" or "dsRNA" refers to a complex of ribonucleic acid molecules having a duplex structure comprising two antiparallel and substantially complementary nucleic acid strands having "sense" and "antisense" orientation with respect to a target RNA (i.e., a PMP22 gene). In some embodiments of the disclosure, double-stranded RNA (dsRNA) triggers the degradation of a target RNA (e.g., mRNA) through a post-transcriptional gene-silencing mechanism referred to herein as RNA interference or RNAi. Generally, most of the nucleotides of each strand of a dsRNA molecule are ribonucleotides, but as described in detail herein, each strand or both strands can also comprise one or more non-ribonucleotides, such as deoxyribonucleotides or modified nucleotides. In addition, as used herein, "RNAi" can comprise ribonucleotides having chemical modifications; RNAi can comprise substantial modifications at multiple nucleotides.

[0031] As used herein, the terms "RNAi", "iRNA", "RNAi agent", "RNA interference agent" are used interchangeably herein to refer to an agent comprising the term as defined herein and which mediates the targeted cleavage of an RNA transcript through the RNA-induced silencing complex (RISC) pathway. RNA interference (RNAi) is a process that directs the sequence-specific degradation of mRNA. RNAi modulation, e.g., inhibits the expression of PMP22 in a cell, e.g., a cell in a subject, e.g., a mammalian subject.

[0032] As used herein, the term "modified nucleotide" refers to a nucleotide independently having a modified sugar moiety, a modified internucleotide linkage, or a modified nucleobase, or any combination thereof. Thus, the term "modified nucleotide" encompasses substitutions, additions, or deletions to the internucleosidic linkage, sugar moiety, or nucleobase, such as functional groups or atoms. Modifications suitable for the agents of the disclosure include all types of modifications disclosed herein or known in the art.

[0033] As used herein, "conjugate" refers to the linkage of two or more chemical moieties each having a specific function to each other in a covalent linkage; correspondingly, "conjugate" refers to a compound formed by the covalent linkage between the respective chemical moieties. Further, "siRNA conjugate" denotes a compound formed by the covalent linkage of one or more chemical moieties having a specific function to an siRNA. In the following, the siRNA conjugate of the disclosure is sometimes also referred to simply as "conjugate". The siRNA conjugate should be understood in the context of the siRNA conjugate in general, the first siRNA conjugate or the second siRNA conjugate, or the siRNA sense strand conjugate or the siRNA antisense strand conjugate.

[0034] As used herein, the term "nucleotide overhang" refers to at least one unpaired nucleotide that overhangs from the duplex structure of a double-stranded RNAi. For example, a nucleotide overhang is present when the 3' end of one strand of a dsRNA extends beyond the 5' end of the other strand, or vice versa. A dsRNA can include an overhang of at least one nucleotide; alternatively, the overhang can include at least two nucleotides, at least three nucleotides, at least four nucleotides, at least five nucleotides, or more. A nucleotide overhang can include or consist of nucleotides / nucleoside analogs, including deoxynucleotides / nucleosides. The overhang can be on the sense strand, the antisense strand, or any combination thereof. Further, the nucleotides of the overhang can be present on the 5' end, the 3' end, or both ends of the antisense strand or the sense strand of a dsRNA.

[0035] As used herein, the term "naked sequence" refers to a nucleotide sequence that is unmodified.

[0036] As used herein, the term "inhibit" is used interchangeably with "knock down," "reduce," "silence," "down-regulate," "suppress," and other like terms, and includes any degree of inhibitory effect.

[0037] As used herein, the term "lipophilic" or "lipophilic moiety" broadly refers to any compound or chemical moiety that has an affinity for lipids.

[0038] The phrase "inhibiting expression of PMP22" is intended to refer to inhibiting expression of any PMP22 gene, such as, for example, a mouse PMP22 gene, a rat PMP22 gene, a monkey PMP22 gene, or a human PMP22 gene, as well as variants or mutants of PMP22 genes. Thus, in the context of genetically manipulating a cell, a population of cells, or an organism, the PMP22 gene can be a wild-type PMP22 gene, a mutant PMP22 gene, or a transgenic PMP22 gene.

[0039] "Inhibiting expression of a PMP22 gene" includes inhibition of a PMP22 gene at any level, e.g., at least partial inhibition of expression of a PMP22 gene. Expression of a PMP22 gene can be assessed based on the level or change in level of any variable associated with PMP22 gene expression, e.g., mRNA level or PMP22 protein level, or indirectly by inhibiting the mRNA level of a Gluc and PMP22 fusion protein gene, which in turn reflects inhibition of the level of a Gluc protein, which is indicative of the level of PMP22 protein.

[0040] The term "pharmaceutically acceptable salt" refers to those salts of the free base or free acid that retain the biological effectiveness and properties of the free base or free acid, which are not biologically or otherwise undesirable. These salts are prepared from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and especially hydrochloric acid, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcystein. In addition, these salts can be prepared as alkaline metal or organic amine salts. Salts derived from inorganic bases include, but are not limited to, alkali metal salts (e.g., sodium salt, potassium salt, and lithium salt), ammonium salt, alkaline earth metal salts (e.g., calcium salt and magnesium salt). Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion-exchange resins such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyamine resins. The oligonucleotides of the present disclosure can also exist in a zwitterionic form. Particularly preferred pharmaceutically acceptable salts of the present disclosure are sodium, lithium, potassium, and trialkylammonium salts.

[0041] As used herein, the term "subject" is an animal, such as a mammal, including a primate (such as a human, a non-human primate, e.g., a monkey and a chimpanzee), a non-primate (such as a cow, pig, horse, goat, rabbit, sheep, hamster, guinea pig, cat, dog, rat, or mouse), or a bird, that endogenously or heterologously expresses a target gene. In one embodiment, the subject is a human.

[0042] As used herein, the term "treating" or "treatment" refers to a beneficial or desired result, such as a reduction in at least one sign or symptom of a PMP22-associated disorder in a subject. Treatment also includes reducing one or more signs or symptoms associated with undesirable PMP22 expression; lessening the extent of undesirable PMP22 activation or stabilization; ameliorating or palliating undesirable PMP22 activation or stabilization. Treatment also includes reducing one or more signs or symptoms associated with undesirable PMP22 expression. "Treatment" can also mean prolonging survival as compared to the expected survival without treatment.

[0043] As used herein, the term "prevention" or "preventing" when used in reference to a disease or disorder, will benefit from a reduction in PMP22 gene expression or PMP22 protein production.

[0044] As used herein, the term "therapeutically effective amount" is intended to encompass an amount of an RNAi agent that, when administered to a subject having a PMP22-associated disorder, is sufficient to affect treatment of the disease (e.g., by reducing, ameliorating, or maintaining an existing disease or one or more symptoms of the disease). A "therapeutically effective amount" can vary depending on the RNAi agent, how the agent is administered, the disease and its severity and history, the age, weight, family history, genetic makeup, type of prior or concomitant treatments, if any, and other individual characteristics of the subject to be treated.

[0045] As used herein, the term "prophylactically effective amount" is intended to encompass an amount of an RNAi agent that, when administered to a subject having a PMP22-associated disorder, is sufficient to prevent or ameliorate the disorder or one or more symptoms of the disorder. Ameliorating a disease includes slowing the progression of the disease or reducing the severity of the disease that develops later. A "prophylactically effective amount" can vary depending on the RNAi agent, how the agent is administered, the extent of risk of disease, and the history, age, weight, family history, genetic makeup, type of prior or concomitant treatments, if any, and other individual characteristics of the patient to be treated.

[0046] As used herein, the term "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc, magnesium stearate, or stearic acid, or salts thereof, or any combination thereof), or solvent encapsulation material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the subject being treated. Such carriers are known in the art. Pharmaceutically acceptable carriers include those used for injection.

[0047] This level can be assessed in an individual cell or population of cells, including, for example, a sample from a subject. It can be appreciated that PMP22 is primarily expressed in the liver, belonging to transmembrane and intracellular proteins.

[0048] Inhibition can be assessed by a decrease in the absolute or relative level of one or more variables associated with PMP22 expression compared to a control level. The control level can be any type of control level used in the art, for example, a pre-dose baseline level, or a level determined from a similar subject that has not been treated or treated with a control, such as, for example, a buffer control or a non-active agent control.

[0049] In an aspect, the present disclosure provides an oligonucleotide or a pharmaceutically acceptable salt thereof for inhibiting PMP22 expression, the oligonucleotide comprising a sense strand and an antisense strand, the sense strand having a sequence of at least 80% or more sequence identity to a sequence set forth in any one of SEQ ID NOs. 1-547 or a fragment thereof, or a modified sequence of said sequence or fragment thereof, preferably having a sequence of 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or more sequence identity; the antisense strand having a sequence of at least 80% or more sequence identity to a sequence set forth in any one of SEQ ID NOs. 548-1094, 1733-1738 or a fragment thereof, or a modified sequence of said sequence or fragment thereof, preferably having a sequence of 70%, 75%, 80%, 85%, 90%, 95%, 99% or more sequence identity. In some embodiments of the present disclosure, the modified sequence of the foregoing sense strand is selected from any one of SEQ ID NOs: 1096-1352.

[0050] In some embodiments, the sense strand and / or the antisense strand is 15-30, 17-25, or 19 to 25 nucleotides in length.

[0051] In some embodiments, each strand is independently 15-30, 17-25, or 19 to 25 nucleotides in length.

[0052] In some embodiments, the antisense strand is 19 to 23 nucleotides in length.

[0053] In some embodiments, the sense strand is 19 to 23 nucleotides in length.

[0054] In some embodiments, the oligonucleotide comprises a 5' and / or 3'-overhang sequence of one or more nucleotides in length, wherein the 5' and / or 3'-overhang sequence is present on the antisense strand and / or the sense strand. In one embodiment, the antisense strand of the oligonucleotide has an overhang of 1 to 10 nucleotides, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides, at the 3' end or the 5' end. In one embodiment, the sense strand of the dsRNA has an overhang of 1 to 10 nucleotides, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides, at the 3' end or the 5' end. In another embodiment, one or more of the nucleotides in the overhang is replaced by a nucleoside phosphorothioate.

[0055] In some embodiments, the antisense strand bears 1 or 2 overhangs.

[0056] In some embodiments, the sense strand bears 1 or 2 overhangs.

[0057] In some embodiments, the oligonucleotide comprises a 3 '-overhang sequence of 1 or 2 nucleotides in length.

[0058] In some embodiments, the oligonucleotide comprises a 5 '-overhang sequence of 1 or 2 nucleotides in length.

[0059] In some embodiments, the 3 '-overhang sequence is present on the antisense strand. In some embodiments, the overhang sequence is selected from the group consisting of: AA, AC, AG, AU, CA, CC, CG, CU, GA, GC, GG, GU, UA, UC, UG, and UU.

[0060] In some embodiments, the 5 '-overhang sequence is present on the antisense strand. In some embodiments, the overhang sequence is selected from the group consisting of: A and G.

[0061] In some embodiments, the oligonucleotide comprises an antisense strand and a sense strand each in the range of 19 to 25 nucleotides in length.

[0062] In some embodiments, the oligonucleotide comprises an antisense strand and a sense strand each in the range of 19 to 23 nucleotides in length.

[0063] In some embodiments, the sense strand forms a duplex region with the antisense strand.

[0064] In some embodiments, the sense strand and the antisense strand are 19 / 21, 21 / 21, 21 / 23, or 23 / 23 paired duplex structures, respectively.

[0065] In some embodiments, the oligonucleotide comprises a 5 '-overhang of 1 nucleotide in length and a 3 '-overhang sequence of 1 nucleotide in length, wherein the 5 '-overhang and the 3 '-overhang sequence are present on the antisense strand, and wherein the sense strand is 19 nucleotides in length and the antisense strand is 21 nucleotides in length, such that the sense strand and the antisense strand form a duplex of 19 nucleotides in length.

[0066] In some embodiments, the oligonucleotide comprises a 3 '-overhang sequence of 2 nucleotides in length, wherein the 3 '-overhang sequence is present on the antisense strand, and wherein the sense strand is 19 nucleotides in length and the antisense strand is 21 nucleotides in length, such that the sense strand and the antisense strand form a duplex of 19 nucleotides in length.

[0067] In some embodiments, the oligonucleotide comprises a 3 '-overhang sequence of 2 nucleotides in length, wherein the 3 '-overhang sequence is present on the antisense strand and the sense strand, and wherein the sense strand is 21 nucleotides in length and the antisense strand is 21 nucleotides in length, such that the sense strand and the antisense strand form a duplex of 19 nucleotides in length.

[0068] In some embodiments, the oligonucleotide comprises a 3 '-overhang sequence of 2 nucleotides in length, wherein the 3 '-overhang sequence is present on the antisense strand, and wherein the sense strand is 21 nucleotides in length and the antisense strand is 23 nucleotides in length, such that the sense strand and the antisense strand form a duplex of 21 nucleotides in length.

[0069] In some embodiments, the oligonucleotide comprises a 3 '-overhang sequence of 2 nucleotides in length, wherein the 3 '-overhang sequence is present on the antisense strand and the sense strand, and wherein the sense strand is 23 nucleotides in length and the antisense strand is 23 nucleotides in length, such that the sense strand and the antisense strand form a duplex of 21 nucleotides in length.

[0070] In some embodiments, the pharmaceutically acceptable salt of the oligonucleotide can be prepared by adding an inorganic or organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, alkali metal salts (such as sodium salts, potassium salts, and lithium salts), ammonium salts, alkaline earth metal salts (such as calcium salts and magnesium salts). Salts derived from organic bases (e.g., organic amines) include, but are not limited to, salts formed with primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion-exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyamine resins.

[0071] In some embodiments, examples of the pharmaceutically acceptable salt of the oligonucleotide include, but are not limited to, ammonium salts, such as salts of tertiary alkylamine compounds (e.g., triethylamine salts), metal salts such as sodium salts, potassium salts, and magnesium salts, and the like.

[0072] In some embodiments, the oligonucleotide or salt thereof can be in the form of a hydrate or solvate.

[0073] In some embodiments, the oligonucleotide comprises at least one modified nucleotide.

[0074] In some embodiments, at least one of the modified nucleotides in the modified nucleotide is selected from the group consisting of: a deoxy nucleotide, a 3' terminal deoxythymidine (dT) nucleotide, a 2'-0-methyl modified nucleotide, a 2'-fluoro modified nucleotide, a 2'-deoxy modified nucleotide, a locked nucleotide, a 2'-5'-linked ribonucleotide (3'-RNA), an unlocked nucleotide, a conformationally restricted nucleotide, a constrained ethyl nucleotide, an abasic nucleotide, a 2'-amino modified nucleotide, a 2'-0-allyl modified nucleotide, a 2'-0-alkyl modified nucleotide, a 2'-hydroxyl modified nucleotide, a 2'-methoxyethyl modified nucleotide, a 2'-0-alkyl modified nucleotide, a morpholino nucleotide, a phosphoramidate, a nucleotide comprising a non-natural base, a tetrahydropyranyl modified nucleotide, a 1,5-anhydrohexitol modified nucleotide, a cyclohexenyl modified nucleotide, a nucleotide comprising a phosphorothioate group, a nucleotide comprising a methylphosphonate group, a nucleotide comprising a 5'-phosphate, a nucleotide comprising a 5'-phosphate mimic, a vinyl-phosphonate nucleotide, a thermally unstable nucleotide, a glycol modified nucleotide, a nucleotide comprising a 2' phosphate, and a 2-O-(N-methylacetamide) modified nucleotide; and combinations thereof.

[0075] In some embodiments, at least one of the modified nucleotides in the modified nucleotide is selected from the group consisting of: a LNA modified nucleotide, a HNA modified nucleotide, a CeNA modified nucleotide, a 2'-methoxyethyl modified nucleotide, a 2'-0-alkyl modified nucleotide, a 2'-0-allyl modified nucleotide, a 2'-C-allyl modified nucleotide, a 2'-fluoro modified nucleotide, a 2'-deoxy modified nucleotide, a 2'-hydroxyl modified nucleotide, and a glycol modified nucleotide; and combinations thereof.

[0076] In some embodiments, at least one of the modified nucleotides in the modified nucleotide is selected from the group consisting of: a deoxy nucleotide, a 2'-0-methyl modified nucleotide, a 2'-fluoro modified nucleotide, a 2'-deoxy modified nucleotide, a glycol modified nucleotide (GNA), a nucleotide comprising a 2' phosphate, and a nucleotide comprising a phosphorothioate group; and combinations thereof.

[0077] In some embodiments, the oligonucleotide comprises at least one 2'-modified nucleotide.

[0078] In some embodiments, the 2’-modified nucleotides are selected from the group consisting of 2’-alkoxy modified nucleotides, 2’-substituted alkoxy modified nucleotides, 2’-alkyl modified nucleotides, 2’-substituted alkyl modified nucleotides, 2’-amino modified nucleotides, 2’-substituted amino modified nucleotides, 2’-deoxy nucleotides; and combinations thereof. For example, C1-C3 alkoxy (e.g., methoxy); substituted alkoxy (e.g., C1-C3 alkoxy substituted C1-C3 alkoxy, e.g., methoxyethoxy); alkyl (e.g., C1-C3 alkyl, e.g., methyl), substituted alkyl (e.g., C1-C3 alkoxy substituted C1-C3 alkyl, e.g., methoxymethyl, methoxyethyl); amino (-NH2), substituted amino (e.g., C1-C3 alkyl mono or di-substituted amino, e.g., methylamino, ethylamino), but are not limited thereto.

[0079] In some embodiments, the 2’-modified nucleotides are selected from the group consisting of 2’-alkoxy modified nucleotides, 2’-substituted alkoxy modified nucleotides, 2’-alkyl modified nucleotides, 2’-substituted alkyl modified nucleotides, 2’-amino modified nucleotides, 2’-substituted amino modified nucleotides, 2’-deoxy nucleotides; and combinations thereof.

[0080] In some embodiments, the 2’-modification is selected from the group consisting of 2’-methoxy, 2’-acetamido, 2’-aminoethyl, 2’-fluoro, 2’-O-methyl, 2’-O-methoxyethyl, and 2’-deoxy-2’-fluoro-beta-d-arabinonucleic acid; and combinations thereof.

[0081] In some embodiments, the 2’-modification is a 2’-methoxy modification.

[0082] In some embodiments, the 2’-modification is a 2’-acetamido modification.

[0083] In some embodiments, all of the nucleotides of the oligonucleotide are modified.

[0084] In some embodiments, the oligonucleotide comprises a modification at the 5’ end comprising a 5’-phosphate analog or a 6-(3-(2-carboxyethyl)phenyl)purine (6-mCEPh-purine).

[0085] In some embodiments, the oligonucleotide has a 5'-phosphate analog modified nucleotide at the 5' terminal nucleotide.

[0086] In some embodiments, the 5'-phosphate analog modification is a 5'-(E)-vinylphosphonate (5'-VP).

[0087] In some embodiments, the oligonucleotide comprises a modification at the 5' terminus, the modification comprising a 5'-(E)-vinylphosphonate (5'-VP) or a 6-(3-(2-carboxyethyl)phenyl) purine (6-mCEPh-purine).

[0088] In some embodiments, the 5' terminal nucleotide comprising a 5'-(E)-vinylphosphonate modification has a structure shown in Formula (I); wherein Base represents a natural or modified base; preferably Base is selected from A, G, C and U; R is selected from H, fluoro, 2'-methoxy, 2'-acetamido, 2'-aminoethyl and 2'-O-methoxyethyl.

[0089] In some embodiments, the oligonucleotide comprises a 5'-(E)-vinylphosphonate modified nucleotide at the 5' terminus, which has a structure shown in Formula (II-1) or Formula (II-2); wherein R is selected from H, fluoro, 2'-methoxy, 2'-acetamido, 2'-aminoethyl and 2'-O-methoxyethyl; preferably, the oligonucleotide has APU at the 5' terminus, which is a 5'-phosphate analog modified uridine acid (2'-acetamido-5'-vinylphosphonate-uridine acid) shown in Formula (III); preferably, the oligonucleotide has VPUm at the 5' terminus, which is a 5'-phosphate analog modified uridine acid (2'-methoxy-5'-vinylphosphonate-uridine acid) shown in Formula (IV-1); preferably, the oligonucleotide has VPAm at the 5' terminus, which is a 5'-phosphate analog modified uridine acid (2'-methoxy-5'-vinylphosphonate-adenosine acid) shown in Formula (IV-2);

[0090] In some embodiments, the modification is a modification selected from the group consisting of: 5'-phosphate analog modification, 2'-methoxy (CH3O-, m), 2'-fluoro (f), 2'-acetamido (CH3CO-NH-) and phosphorothioate (s).

[0091] In some embodiments, the oligonucleotide comprises a 6-(3-(2-carboxyethyl)phenyl) purine modified nucleotide at the 5' terminus. In some embodiments, the oligonucleotide comprises Formula mAPP001, which is a 2'-methoxy-5'-vinylphosphonate-6-(3-(2-carboxyethyl)phenyl) purine nucleotide shown in Formula (V);

[0092] In some embodiments, the oligonucleotide can comprise 2'-5'-phosphodiester linkages. In some embodiments, the oligonucleotide comprises a uridine-2'-phosphate (U-2'5') selected from Formula (VI), a guanosine-2'-phosphate (G-2'5') selected from Formula (VII), a cytidine-2'-phosphate (C-2'5') selected from Formula (VIII), an adenosine-2'-phosphate (A-2'5') selected from Formula (IX), and a thymidine-2'-phosphate (T-2'5') selected from Formula (X);

[0093] In some embodiments, the oligonucleotide comprises at least one modified internucleotide linkage.

[0094] In some embodiments, at least one modified internucleotide linkage is a phosphorothioate linkage. The phosphorothioate internucleotide linkage modification can occur at any nucleotide on either the sense strand, the antisense strand, or both strands of the chain. For example, the internucleotide linkage modification can occur at every nucleotide on either the sense strand or the antisense strand; every internucleotide linkage modification can occur in an alternating pattern on either the sense strand or the antisense strand; or either the sense strand or the antisense strand can contain both internucleotide linkage modifications in an alternating pattern. The alternating pattern of internucleotide linkage modifications on the sense strand can be the same or different from the antisense strand, and the alternating pattern of internucleotide linkage modifications on the sense strand can have an offset relative to the alternating pattern of internucleotide linkages on the antisense strand. In one embodiment, the double stranded RNAi agent comprises from 6 to 8 phosphorothioate internucleotide linkages. In some embodiments, the antisense strand comprises two phosphorothioate internucleotide linkages at the 5' end and two phosphorothioate internucleotide linkages at the 3' end, and the sense strand comprises at least two phosphorothioate internucleotide linkages at either the 5' end or the 3' end.

[0095] In some embodiments, the sense strand comprises an unmodified oligonucleotide selected from any one of SEQ ID NO. 3, 8, 13, 16, 18, 19, 20, 23, 24, 25, 32, 33, 36, 38, 39, 40, 42, 43, 44, 45, 46, 49, 51, 52, 53, 54, 55, 56, 57, 60, 61, 63, 64, 65, 67, 68, 73, 74, 75, 76, 79, 80, 84, 86, 91, 102, 122, 131, 132, 135, 136, 144, 151, 155, 163, 164, 198, 230, 246, and 254, or a modified oligonucleotide of any one of SEQ ID NO. 1098, 1103, 1108, 1111, 1113, 1114, 1115, 1118, 1119, 1120, 1127, 1128, 1131, 1133, 1134, 1135, 1137, 1138, 1139, 1140, 1141, 1144, 1146, 1147, 1148, 1149, 1150, 1151, 1152, 1155, 1156, 1158, 1159, 1160, 1162, 1163, 1164, 1165, 1166, 1167, 1168, 1169, 1170, 1171, 1172, 1173, 1174, 1175, 1176, 1177, 1178, 1179, 1180, 1181, 1182, 1183, 1184, 1185, 1186, 1192, 1197, 1211, 1213, 1217, 1226, 1227, 1230, 1231, 1235, 1239, 1246, 1248, 1249, 1250, 1252, 1253, 1255, 1256, 1258, 1260, 1264, 1293, 1297, 1306, 1310, 1314, 1317, 1318, 1325, 1341, 1352, 1613, 1614, 1615, 1618, 1619, 1620, 1622, 1623, 1624, 1625, 1626, 1627, 1628, 1633, 1634, 1637, 1638, and 1640; and the antisense strand is selected from SEQ ID NO.550, 555, 560, 563, 565, 566, 567, 570, 571, 572, 579, 580, 583, 585, 586, 587, 589, 590, 591, 592, 593, 596, 598, 599, 600, 601, 602, 603, 604, 607, 608, 610, 611, 612, 614, 615, 620, 621, 622, 623, 626, 627, 631, 633, 638, 649, 669, 678, 679, 682, 683, 691, 698, 702, 710, 711, 745, 777, 793, 801, and 804, or a SEQ ID NO.1357, 1362, 1367, 1370, 1372, 1373, 1374, 1377, 1378, 1379, 1386, 1387, 1390, 1392, 1393, 1394, 1396, 1397, 1398, 1399, 1400, 1403, 1405, 1406, 1407, 1408, 1409, 1410, 1411, 1414, 1415, 1417, 1418, 1419, 1421, 1422, 1423, 1424, 1425, 1426, 1427, 1428, 1429, 1430, 1431, 1432, 1433, 1434, 1435, 1436, 1437, 1438, 1439, 1440, 1441, 1442, 1443, 1444, 1445, 1451, 1456, 1470, 1472, 1476, 1485, 1486, 1489, 1490, 1494, 1498, 1505, 1507, 1508, 1509, 1511, 1512, 1514, 1515, 1517, 1519, 1523, 1552, 1556, 1565, 1569, 1573, 1576, 1577, 1584, 1600, 1611, 1643, 1644, 1645, 1646, 1647, 1648, 1649, 1650, 1651, 1652, 1653, 1654, 1655, 1656, 1657, 1659, 1663, 1665, 1666, 1667, 1670, 1671, 1672, 1674, 1677, 1678, 1679, 1682, 1685, 1686, 1687, 1688, 1689, 1690, 1691, 1692, 1693, 1694, 1695, 1696, 1697, 1698, 1699, 1700, 1701, 1702, 1703, 1704, 1714, 1715, 1716, 1721, 1722, and 1725.

[0096] In some embodiments, the oligonucleotide is selected from any of the following combinations of sense and antisense strands:

[0097] (1) the sense strand comprises the sequence set forth in SEQ ID NO. 3, and the antisense strand comprises the sequence set forth in SEQ ID NO. 550;

[0098] (2) the sense strand comprises the sequence set forth in SEQ ID NO. 8, and the antisense strand comprises the sequence set forth in SEQ ID NO. 555;

[0099] (3) the sense strand comprises the sequence set forth in SEQ ID NO. 13, and the antisense strand comprises the sequence set forth in SEQ ID NO. 560;

[0100] (4) the sense strand comprises the sequence set forth in SEQ ID NO. 16, and the antisense strand comprises the sequence set forth in SEQ ID NO. 563;

[0101] (5) the sense strand comprises the sequence set forth in SEQ ID NO. 18, and the antisense strand comprises the sequence set forth in SEQ ID NO. 565;

[0102] (6) the sense strand comprises the sequence set forth in SEQ ID NO. 19, and the antisense strand comprises the sequence set forth in SEQ ID NO. 566;

[0103] (7) the sense strand comprises the sequence set forth in SEQ ID NO. 20, and the antisense strand comprises the sequence set forth in SEQ ID NO. 567;

[0104] (8) the sense strand comprises the sequence set forth in SEQ ID NO. 23, and the antisense strand comprises the sequence set forth in SEQ ID NO. 570;

[0105] (9) the sense strand comprises the sequence set forth in SEQ ID NO. 24, and the antisense strand comprises the sequence set forth in SEQ ID NO. 571;

[0106] (10) the sense strand comprises the sequence set forth in SEQ ID NO. 25, and the antisense strand comprises the sequence set forth in SEQ ID NO. 572;

[0107] (11) the sense strand comprises the sequence set forth in SEQ ID NO. 32, and the antisense strand comprises the sequence set forth in SEQ ID NO. 579;

[0108] (12) the sense strand comprises the sequence set forth in SEQ ID NO. 33, and the antisense strand comprises the sequence set forth in SEQ ID NO. 580;

[0109] (13) the sense strand comprises the sequence set forth in SEQ ID NO. 36, and the antisense strand comprises the sequence set forth in SEQ ID NO. 583;

[0110] (14) the sense strand comprises the sequence set forth in SEQ ID NO. 38, and the antisense strand comprises the sequence set forth in SEQ ID NO. 585;

[0111] (15) the sense strand comprises the sequence set forth in SEQ ID NO. 39, and the antisense strand comprises the sequence set forth in SEQ ID NO. 586;

[0112] (16) the sense strand comprises the sequence set forth in SEQ ID NO. 40, and the antisense strand comprises the sequence set forth in SEQ ID NO. 587;

[0113] (17) the sense strand comprises the sequence set forth in SEQ ID NO. 42, and the antisense strand comprises the sequence set forth in SEQ ID NO. 589;

[0114] (18) the sense strand comprises the sequence set forth in SEQ ID NO. 43, and the antisense strand comprises the sequence set forth in SEQ ID NO. 590;

[0115] (19) the sense strand comprises the sequence set forth in SEQ ID NO. 44, and the antisense strand comprises the sequence set forth in SEQ ID NO. 591;

[0116] (20) the sense strand comprises the sequence set forth in SEQ ID NO. 45, and the antisense strand comprises the sequence set forth in SEQ ID NO. 592;

[0117] (21) the sense strand comprises the sequence set forth in SEQ ID NO. 46, and the antisense strand comprises the sequence set forth in SEQ ID NO. 593;

[0118] (22) the sense strand comprises the sequence set forth in SEQ ID NO. 49, and the antisense strand comprises the sequence set forth in SEQ ID NO. 596;

[0119] (23) the sense strand comprises the sequence set forth in SEQ ID NO. 51, and the antisense strand comprises the sequence set forth in SEQ ID NO. 598;

[0120] (24) the sense strand comprises the sequence set forth in SEQ ID NO. 52, and the antisense strand comprises the sequence set forth in SEQ ID NO. 599;

[0121] (25) the sense strand comprises the sequence set forth in SEQ ID NO. 53, and the antisense strand comprises the sequence set forth in SEQ ID NO. 600;

[0122] (26) the sense strand comprises the sequence set forth in SEQ ID NO. 54, and the antisense strand comprises the sequence set forth in SEQ ID NO. 601;

[0123] (27) the sense strand comprises the sequence set forth in SEQ ID NO. 55, and the antisense strand comprises the sequence set forth in SEQ ID NO. 602;

[0124] (28) the sense strand comprises the sequence set forth in SEQ ID NO. 56, and the antisense strand comprises the sequence set forth in SEQ ID NO. 603;

[0125] (29) the sense strand comprises the sequence set forth in SEQ ID NO. 57, and the antisense strand comprises the sequence set forth in SEQ ID NO. 604;

[0126] (30) the sense strand comprises the sequence set forth in SEQ ID NO. 60, and the antisense strand comprises the sequence set forth in SEQ ID NO. 607;

[0127] (31) the sense strand comprises the sequence set forth in SEQ ID NO. 61, and the antisense strand comprises the sequence set forth in SEQ ID NO. 608;

[0128] (32) the sense strand comprises the sequence set forth in SEQ ID NO. 63, and the antisense strand comprises the sequence set forth in SEQ ID NO. 610;

[0129] (33) the sense strand comprises the sequence set forth in SEQ ID NO. 64, and the antisense strand comprises the sequence set forth in SEQ ID NO. 611;

[0130] (34) the sense strand comprises the sequence set forth in SEQ ID NO. 73, and the antisense strand comprises the sequence set forth in SEQ ID NO. 620;

[0131] (35) the sense strand comprises the sequence set forth in SEQ ID NO. 74, and the antisense strand comprises the sequence set forth in SEQ ID NO. 621;

[0132] (36) the sense strand comprises the sequence set forth in SEQ ID NO. 75, and the antisense strand comprises the sequence set forth in SEQ ID NO. 622;

[0133] (37) the sense strand comprises the sequence set forth in SEQ ID NO. 76, and the antisense strand comprises the sequence set forth in SEQ ID NO. 623;

[0134] (38) the sense strand comprises the sequence set forth in SEQ ID NO. 79, and the antisense strand comprises the sequence set forth in SEQ ID NO. 626;

[0135] (39) the sense strand comprises the sequence set forth in SEQ ID NO. 80, and the antisense strand comprises the sequence set forth in SEQ ID NO. 627;

[0136] (40) the sense strand comprises the sequence set forth in SEQ ID NO. 84, and the antisense strand comprises the sequence set forth in SEQ ID NO. 631;

[0137] (41) the sense strand comprises the sequence set forth in SEQ ID NO. 86, and the antisense strand comprises the sequence set forth in SEQ ID NO. 633;

[0138] (42) the sense strand comprises the sequence set forth in SEQ ID NO. 91, and the antisense strand comprises the sequence set forth in SEQ ID NO. 638;

[0139] (43) the sense strand comprises the sequence set forth in SEQ ID NO. 102, and the antisense strand comprises the sequence set forth in SEQ ID NO. 649;

[0140] (44) the sense strand comprises the sequence set forth in SEQ ID NO. 122, and the antisense strand comprises the sequence set forth in SEQ ID NO. 669;

[0141] (45) the sense strand comprises the sequence set forth in SEQ ID NO. 131, and the antisense strand comprises the sequence set forth in SEQ ID NO. 678;

[0142] (46) the sense strand comprises the sequence set forth in SEQ ID NO. 132, and the antisense strand comprises the sequence set forth in SEQ ID NO. 679;

[0143] (47) the sense strand comprises the sequence set forth in SEQ ID NO. 135, and the antisense strand comprises the sequence set forth in SEQ ID NO. 682;

[0144] (48) the sense strand comprises the sequence set forth in SEQ ID NO. 136, and the antisense strand comprises the sequence set forth in SEQ ID NO. 683;

[0145] (49) the sense strand comprises the sequence set forth in SEQ ID NO. 144, and the antisense strand comprises the sequence set forth in SEQ ID NO. 691;

[0146] (50) the sense strand comprises the sequence set forth in SEQ ID NO. 151, and the antisense strand comprises the sequence set forth in SEQ ID NO. 698;

[0147] (51) the sense strand comprises the sequence set forth in SEQ ID NO. 155, and the antisense strand comprises the sequence set forth in SEQ ID NO. 702;

[0148] (52) the sense strand comprises the sequence set forth in SEQ ID NO. 163, and the antisense strand comprises the sequence set forth in SEQ ID NO. 710;

[0149] (53) the sense strand comprises the sequence set forth in SEQ ID NO. 164, and the antisense strand comprises the sequence set forth in SEQ ID NO. 711;

[0150] (54) the sense strand comprises the sequence set forth in SEQ ID NO. 198, and the antisense strand comprises the sequence set forth in SEQ ID NO. 745;

[0151] (55) the sense strand comprises the sequence set forth in SEQ ID NO. 230, and the antisense strand comprises the sequence set forth in SEQ ID NO. 777;

[0152] (56) the sense strand comprises the sequence set forth in SEQ ID NO. 246, and the antisense strand comprises the sequence set forth in SEQ ID NO. 793;

[0153] (57) the sense strand comprises the sequence set forth in SEQ ID NO. 254, and the antisense strand comprises the sequence set forth in SEQ ID NO. 801;

[0154] (58) the sense strand comprises the sequence set forth in SEQ ID NO. 257, and the antisense strand comprises the sequence set forth in SEQ ID NO. 804;

[0155] Preferably, the oligonucleotide comprises any one selected from the group consisting of the following combinations of sense strands and antisense strands:

[0156] (1) the sense strand comprises the sequence set forth in SEQ ID NO. 18, and the antisense strand comprises the sequence set forth in SEQ ID NO. 565;

[0157] (2) the sense strand comprises the sequence set forth in SEQ ID NO. 19, and the antisense strand comprises the sequence set forth in SEQ ID NO. 566;

[0158] (3) the sense strand comprises the sequence set forth in SEQ ID NO. 20, and the antisense strand comprises the sequence set forth in SEQ ID NO. 567;

[0159] (4) the sense strand comprises the sequence set forth in SEQ ID NO. 24, and the antisense strand comprises the sequence set forth in SEQ ID NO. 571;

[0160] (5) the sense strand comprises the sequence set forth in SEQ ID NO. 32, and the antisense strand comprises the sequence set forth in SEQ ID NO. 579;

[0161] (6) the sense strand comprises the sequence set forth in SEQ ID NO. 33, and the antisense strand comprises the sequence set forth in SEQ ID NO. 580;

[0162] (7) the sense strand comprises the sequence set forth in SEQ ID NO. 36, and the antisense strand comprises the sequence set forth in SEQ ID NO. 583;

[0163] (8) the sense strand comprises the sequence set forth in SEQ ID NO. 38, and the antisense strand comprises the sequence set forth in SEQ ID NO. 585;

[0164] (9) the sense strand comprises the sequence set forth in SEQ ID NO. 40, and the antisense strand comprises the sequence set forth in SEQ ID NO. 587;

[0165] (10) the sense strand comprises the sequence set forth in SEQ ID NO. 42, and the antisense strand comprises the sequence set forth in SEQ ID NO. 589;

[0166] (11) the sense strand comprises the sequence set forth in SEQ ID NO. 43, and the antisense strand comprises the sequence set forth in SEQ ID NO. 590;

[0167] (12) the sense strand comprises the sequence set forth in SEQ ID NO. 45, and the antisense strand comprises the sequence set forth in SEQ ID NO. 592;

[0168] (13) the sense strand comprises the sequence set forth in SEQ ID NO. 46, and the antisense strand comprises the sequence set forth in SEQ ID NO. 593;

[0169] (14) the sense strand comprises the sequence set forth in SEQ ID NO. 49, and the antisense strand comprises the sequence set forth in SEQ ID NO. 596;

[0170] (15) the sense strand comprises the sequence set forth in SEQ ID NO. 52, and the antisense strand comprises the sequence set forth in SEQ ID NO. 599;

[0171] (16) the sense strand comprises the sequence set forth in SEQ ID NO. 54, and the antisense strand comprises the sequence set forth in SEQ ID NO. 601;

[0172] (17) the sense strand comprises the sequence set forth in SEQ ID NO. 56, and the antisense strand comprises the sequence set forth in SEQ ID NO. 603;

[0173] (18) the sense strand comprises the sequence set forth in SEQ ID NO. 57, and the antisense strand comprises the sequence set forth in SEQ ID NO. 604;

[0174] (19) the sense strand comprises the sequence set forth in SEQ ID NO. 61, and the antisense strand comprises the sequence set forth in SEQ ID NO. 608;

[0175] (20) the sense strand comprises the sequence set forth in SEQ ID NO. 64, and the antisense strand comprises the sequence set forth in SEQ ID NO. 611;

[0176] (21) the sense strand comprises the sequence set forth in SEQ ID NO. 73, and the antisense strand comprises the sequence set forth in SEQ ID NO. 620;

[0177] (22) the sense strand comprises the sequence set forth in SEQ ID NO. 74, and the antisense strand comprises the sequence set forth in SEQ ID NO. 621;

[0178] (23) the sense strand comprises the sequence set forth in SEQ ID NO. 75, and the antisense strand comprises the sequence set forth in SEQ ID NO. 622;

[0179] (24) the sense strand comprises the sequence set forth in SEQ ID NO. 76, and the antisense strand comprises the sequence set forth in SEQ ID NO. 623;

[0180] (25) the sense strand comprises the sequence set forth in SEQ ID NO. 79, and the antisense strand comprises the sequence set forth in SEQ ID NO. 626;

[0181] (26) the sense strand comprises the sequence set forth in SEQ ID NO. 80, and the antisense strand comprises the sequence set forth in SEQ ID NO. 627;

[0182] (27) the sense strand comprises the sequence set forth in SEQ ID NO. 84, and the antisense strand comprises the sequence set forth in SEQ ID NO. 631;

[0183] (28) the sense strand comprises the sequence set forth in SEQ ID NO. 86, and the antisense strand comprises the sequence set forth in SEQ ID NO. 633;

[0184] (29) the sense strand comprises the sequence set forth in SEQ ID NO. 91, and the antisense strand comprises the sequence set forth in SEQ ID NO. 638;

[0185] (30) the sense strand comprises the sequence set forth in SEQ ID NO. 102, and the antisense strand comprises the sequence set forth in SEQ ID NO. 649;

[0186] (31) the sense strand comprises the sequence set forth in SEQ ID NO. 122, and the antisense strand comprises the sequence set forth in SEQ ID NO. 669;

[0187] (32) the sense strand comprises the sequence set forth in SEQ ID NO. 131, and the antisense strand comprises the sequence set forth in SEQ ID NO. 678;

[0188] (33) the sense strand comprises the sequence set forth in SEQ ID NO. 132, and the antisense strand comprises the sequence set forth in SEQ ID NO. 679;

[0189] (34) the sense strand comprises the sequence set forth in SEQ ID NO. 135, and the antisense strand comprises the sequence set forth in SEQ ID NO. 682;

[0190] (35) the sense strand comprises the sequence set forth in SEQ ID NO. 136, and the antisense strand comprises the sequence set forth in SEQ ID NO. 683;

[0191] (36) the sense strand comprises the sequence set forth in SEQ ID NO. 144, and the antisense strand comprises the sequence set forth in SEQ ID NO. 691;

[0192] (37) the sense strand comprises the sequence set forth in SEQ ID NO. 151, and the antisense strand comprises the sequence set forth in SEQ ID NO. 698;

[0193] (38) the sense strand comprises the sequence set forth in SEQ ID NO. 155, and the antisense strand comprises the sequence set forth in SEQ ID NO. 702;

[0194] (39) the sense strand comprises the sequence set forth in SEQ ID NO. 163, and the antisense strand comprises the sequence set forth in SEQ ID NO. 710;

[0195] (40) the sense strand comprises the sequence set forth in SEQ ID NO. 164, and the antisense strand comprises the sequence set forth in SEQ ID NO. 711;

[0196] (41) the sense strand comprises the sequence set forth in SEQ ID NO. 198, and the antisense strand comprises the sequence set forth in SEQ ID NO. 745;

[0197] (42) the sense strand comprises the sequence set forth in SEQ ID NO. 230, and the antisense strand comprises the sequence set forth in SEQ ID NO. 777;

[0198] (43) the sense strand comprises the sequence set forth in SEQ ID NO. 246, and the antisense strand comprises the sequence set forth in SEQ ID NO. 793;

[0199] (44) the sense strand comprises the sequence set forth in SEQ ID NO. 254, and the antisense strand comprises the sequence set forth in SEQ ID NO. 801; and

[0200] (45) the sense strand comprises the sequence set forth in SEQ ID NO. 257, and the antisense strand comprises the sequence set forth in SEQ ID NO. 804.

[0201] In some embodiments, the oligonucleotide comprises any one of the following combinations of sense and antisense strands:

[0202] (1) the sense strand comprises the sequence set forth in SEQ ID NO. 1098, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1357;

[0203] (2) the sense strand comprises the sequence set forth in SEQ ID NO. 1103, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1362;

[0204] (3) the sense strand comprises the sequence set forth in SEQ ID NO. 1108, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1367;

[0205] (4) the sense strand comprises the sequence set forth in SEQ ID NO. 1111, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1370;

[0206] (5) the sense strand comprises the sequence set forth in SEQ ID NO. 1113, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1372;

[0207] (6) the sense strand comprises the sequence set forth in SEQ ID NO. 1114, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1373;

[0208] (7) the sense strand comprises the sequence set forth in SEQ ID NO. 1115, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1374;

[0209] (8) the sense strand comprises the sequence set forth in SEQ ID NO. 1118, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1377;

[0210] (9) the sense strand comprises the sequence set forth in SEQ ID NO. 1119, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1378;

[0211] (10) the sense strand comprises the sequence set forth in SEQ ID NO. 1120, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1379;

[0212] (11) the sense strand comprises the sequence set forth in SEQ ID NO. 1127, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1386;

[0213] (12) the sense strand comprises the sequence set forth in SEQ ID NO. 1128, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1387;

[0214] (13) the sense strand comprises the sequence set forth in SEQ ID NO. 1131, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1390;

[0215] (14) the sense strand comprises the sequence set forth in SEQ ID NO. 1133, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1392;

[0216] (15) the sense strand comprises the sequence set forth in SEQ ID NO. 1134, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1393;

[0217] (16) the sense strand comprises the sequence set forth in SEQ ID NO. 1135, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1394;

[0218] (17) the sense strand comprises the sequence set forth in SEQ ID NO. 1137, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1396;

[0219] (18) the sense strand comprises the sequence set forth in SEQ ID NO. 1138, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1397;

[0220] (19) the sense strand comprises the sequence set forth in SEQ ID NO. 1139, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1398;

[0221] (20) the sense strand comprises the sequence set forth in SEQ ID NO. 1140, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1399;

[0222] (21) the sense strand comprises the sequence set forth in SEQ ID NO. 1141, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1400;

[0223] (22) the sense strand comprises the sequence set forth in SEQ ID NO. 1144, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1403;

[0224] (23) the sense strand comprises the sequence set forth in SEQ ID NO. 1146, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1405;

[0225] (24) the sense strand comprises the sequence set forth in SEQ ID NO. 1147, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1406;

[0226] (25) the sense strand comprises the sequence set forth in SEQ ID NO. 1148, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1407;

[0227] (26) the sense strand comprises the sequence set forth in SEQ ID NO. 1149, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1408;

[0228] (27) the sense strand comprises the sequence set forth in SEQ ID NO. 1150, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1409;

[0229] (28) the sense strand comprises the sequence set forth in SEQ ID NO. 1151, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1410;

[0230] (29) the sense strand comprises the sequence set forth in SEQ ID NO. 1152, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1411;

[0231] (30) the sense strand comprises the sequence set forth in SEQ ID NO. 1155, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1414;

[0232] (31) the sense strand comprises the sequence set forth in SEQ ID NO. 1156, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1415;

[0233] (32) the sense strand comprises the sequence set forth in SEQ ID NO. 1158, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1417;

[0234] (33) the sense strand comprises the sequence set forth in SEQ ID NO. 1159, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1418;

[0235] (34) the sense strand comprises the sequence set forth in SEQ ID NO. 1160, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1419;

[0236] (35) the sense strand comprises the sequence set forth in SEQ ID NO. 1162, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1421;

[0237] (36) the sense strand comprises the sequence set forth in SEQ ID NO. 1163, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1422;

[0238] (37) the sense strand comprises the sequence set forth in SEQ ID NO. 1164, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1423;

[0239] (38) the sense strand comprises the sequence set forth in SEQ ID NO. 1165, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1424;

[0240] (39) the sense strand comprises the sequence set forth in SEQ ID NO. 1166, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1425;

[0241] (40) the sense strand comprises the sequence set forth in SEQ ID NO. 1167, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1426;

[0242] (41) the sense strand comprises the sequence set forth in SEQ ID NO. 1168, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1427;

[0243] (42) the sense strand comprises the sequence set forth in SEQ ID NO. 1169, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1428;

[0244] (43) the sense strand comprises the sequence set forth in SEQ ID NO. 1170, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1429;

[0245] (44) the sense strand comprises the sequence set forth in SEQ ID NO. 1171, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1430;

[0246] (45) the sense strand comprises the sequence set forth in SEQ ID NO. 1172, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1431;

[0247] (46) the sense strand comprises the sequence set forth in SEQ ID NO. 1173, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1432;

[0248] (47) the sense strand comprises the sequence set forth in SEQ ID NO. 1174, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1433;

[0249] (48) the sense strand comprises the sequence set forth in SEQ ID NO. 1175, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1434;

[0250] (49) the sense strand comprises the sequence set forth in SEQ ID NO. 1176, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1435;

[0251] (50) the sense strand comprises the sequence set forth in SEQ ID NO. 1177, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1436;

[0252] (51) the sense strand comprises the sequence set forth in SEQ ID NO. 1178, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1437;

[0253] (52) the sense strand comprises the sequence set forth in SEQ ID NO. 1179, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1438;

[0254] (53) the sense strand comprises the sequence set forth in SEQ ID NO. 1180, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1439;

[0255] (54) the sense strand comprises the sequence set forth in SEQ ID NO. 1181, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1440;

[0256] (55) the sense strand comprises the sequence set forth in SEQ ID NO. 1182, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1441;

[0257] (56) the sense strand comprises the sequence set forth in SEQ ID NO. 1183, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1442;

[0258] (57) the sense strand comprises the sequence set forth in SEQ ID NO. 1184, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1443;

[0259] (58) the sense strand comprises the sequence set forth in SEQ ID NO. 1185, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1444;

[0260] (59) the sense strand comprises the sequence set forth in SEQ ID NO. 1115, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1643;

[0261] (60) the sense strand comprises the sequence set forth in SEQ ID NO. 1127, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1644;

[0262] (61) the sense strand comprises the sequence set forth in SEQ ID NO. 1128, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1645;

[0263] (62) the sense strand comprises the sequence set forth in SEQ ID NO. 1128, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1663;

[0264] (63) the sense strand comprises the sequence set forth in SEQ ID NO. 1144, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1646;

[0265] (64) the sense strand comprises the sequence set forth in SEQ ID NO. 1159, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1647;

[0266] (65) the sense strand comprises the sequence set forth in SEQ ID NO. 1169, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1648;

[0267] (66) the sense strand comprises the sequence set forth in SEQ ID NO. 1170, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1649;

[0268] (67) the sense strand comprises the sequence set forth in SEQ ID NO. 1171, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1650;

[0269] (68) the sense strand comprises the sequence set forth in SEQ ID NO. 1179, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1651;

[0270] (69) the sense strand comprises the sequence set forth in SEQ ID NO. 1181, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1652;

[0271] (70) the sense strand comprises the sequence set forth in SEQ ID NO. 1186, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1445;

[0272] (71) the sense strand comprises the sequence set forth in SEQ ID NO. 1186, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1653;

[0273] (72) the sense strand comprises the sequence set forth in SEQ ID NO. 1226, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1485;

[0274] (73) the sense strand comprises the sequence set forth in SEQ ID NO. 1226, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1654;

[0275] (74) the sense strand comprises the sequence set forth in SEQ ID NO. 1227, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1486;

[0276] (75) the sense strand comprises the sequence set forth in SEQ ID NO. 1227, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1655;

[0277] (76) the sense strand comprises the sequence set forth in SEQ ID NO. 1230, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1489;

[0278] (77) the sense strand comprises the sequence set forth in SEQ ID NO. 1230, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1656;

[0279] (78) the sense strand comprises the sequence set forth in SEQ ID NO. 1231, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1490;

[0280] (79) the sense strand comprises the sequence set forth in SEQ ID NO. 1239, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1498;

[0281] (80) the sense strand comprises the sequence set forth in SEQ ID NO. 1246, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1505;

[0282] (81) the sense strand comprises the sequence set forth in SEQ ID NO. 1250, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1509;

[0283] (82) the sense strand comprises the sequence set forth in SEQ ID NO. 1250, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1657;

[0284] (83) the sense strand comprises the sequence set forth in SEQ ID NO. 1258, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1517;

[0285] (84) the sense strand comprises the sequence set forth in SEQ ID NO. 1293, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1552;

[0286] (85) the sense strand comprises the sequence set forth in SEQ ID NO. 1325, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1584;

[0287] (86) the sense strand comprises the sequence set forth in SEQ ID NO. 1325, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1659;

[0288] (87) the sense strand comprises the sequence set forth in SEQ ID NO. 1341, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1600;

[0289] (88) the sense strand comprises the sequence set forth in SEQ ID NO. 1352, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1611;

[0290] (89) the sense strand comprises the sequence set forth in SEQ ID NO. 1613, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1665;

[0291] (90) the sense strand comprises the sequence set forth in SEQ ID NO. 1613, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1674;

[0292] (91) the sense strand comprises the sequence set forth in SEQ ID NO. 1614, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1666;

[0293] (92) the sense strand comprises the sequence set forth in SEQ ID NO. 1614, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1679;

[0294] (93) the sense strand comprises the sequence set forth in SEQ ID NO. 1615, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1667;

[0295] (94) the sense strand comprises the sequence set forth in SEQ ID NO. 1615, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1685;

[0296] (95) the sense strand comprises the sequence set forth in SEQ ID NO. 1618, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1670;

[0297] (96) the sense strand comprises the sequence set forth in SEQ ID NO. 1618, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1690;

[0298] (97) the sense strand comprises the sequence set forth in SEQ ID NO. 1618, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1690;

[0299] (98) the sense strand comprises the sequence set forth in SEQ ID NO. 1619, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1671;

[0300] (99) the sense strand comprises the sequence set forth in SEQ ID NO. 1620, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1672;

[0301] (100) the sense strand comprises the sequence set forth in SEQ ID NO. 1620, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1694;

[0302] (101) the sense strand comprises the sequence set forth in SEQ ID NO. 1620, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1695;

[0303] (102) the sense strand comprises the sequence set forth in SEQ ID NO. 1622, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1677;

[0304] (103) the sense strand comprises the sequence set forth in SEQ ID NO. 1622, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1678;

[0305] (104) the sense strand comprises the sequence set forth in SEQ ID NO. 1623, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1682;

[0306] (105) the sense strand comprises the sequence set forth in SEQ ID NO. 1624, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1686;

[0307] (106) the sense strand comprises the sequence set forth in SEQ ID NO. 1624, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1687;

[0308] (107) the sense strand comprises the sequence set forth in SEQ ID NO. 1624, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1688;

[0309] (108) the sense strand comprises the sequence set forth in SEQ ID NO. 1625, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1691;

[0310] (109) the sense strand comprises the sequence set forth in SEQ ID NO. 1625, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1692;

[0311] (110) the sense strand comprises the sequence set forth in SEQ ID NO. 1625, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1693;

[0312] (111) the sense strand comprises the sequence set forth in SEQ ID NO. 1626, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1696;

[0313] (112) the sense strand comprises the sequence set forth in SEQ ID NO. 1626, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1697;

[0314] (113) the sense strand comprises the sequence set forth in SEQ ID NO. 1626, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1698;

[0315] (114) the sense strand comprises the sequence set forth in SEQ ID NO. 1627, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1699;

[0316] (115) the sense strand comprises the sequence set forth in SEQ ID NO. 1627, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1700;

[0317] (116) the sense strand comprises the sequence set forth in SEQ ID NO. 1627, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1701;

[0318] (117) the sense strand comprises the sequence set forth in SEQ ID NO. 1628, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1702;

[0319] (118) the sense strand comprises the sequence set forth in SEQ ID NO. 1628, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1703;

[0320] (119) the sense strand comprises the sequence set forth in SEQ ID NO. 1628, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1704;

[0321] (120) the sense strand comprises the sequence set forth in SEQ ID NO. 1633, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1714;

[0322] (121) the sense strand comprises the sequence set forth in SEQ ID NO. 1633, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1715;

[0323] (122) the sense strand comprises the sequence set forth in SEQ ID NO. 1634, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1716;

[0324] (123) the sense strand comprises the sequence set forth in SEQ ID NO. 1637, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1721;

[0325] (124) the sense strand comprises the sequence set forth in SEQ ID NO. 1638, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1722; and

[0326] (125) the sense strand comprises the sequence set forth in SEQ ID NO. 1640, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1725;

[0327] In some embodiments, the oligonucleotide comprises any one of the sense and antisense strand combinations selected from:

[0328] (1) the sense strand comprises the sequence set forth in SEQ ID NO. 1113, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1372;

[0329] (2) the sense strand comprises the sequence set forth in SEQ ID NO. 1115, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1374;

[0330] (3) the sense strand comprises the sequence set forth in SEQ ID NO. 1115, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1643;

[0331] (4) the sense strand comprises the sequence set forth in SEQ ID NO. 1119, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1378;

[0332] (5) the sense strand comprises the sequence set forth in SEQ ID NO. 1127, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1386;

[0333] (6) the sense strand comprises the sequence set forth in SEQ ID NO. 1127, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1644;

[0334] (7) the sense strand comprises the sequence set forth in SEQ ID NO. 1128, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1387;

[0335] (8) the sense strand comprises the sequence set forth in SEQ ID NO. 1128, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1645;

[0336] (9) the sense strand comprises the sequence set forth in SEQ ID NO. 1128, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1663;

[0337] (10) the sense strand comprises the sequence set forth in SEQ ID NO. 1133, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1392;

[0338] (11) the sense strand comprises the sequence set forth in SEQ ID NO. 1135, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1394;

[0339] (12) the sense strand comprises the sequence set forth in SEQ ID NO. 1137, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1396;

[0340] (13) the sense strand comprises the sequence set forth in SEQ ID NO. 1138, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1397;

[0341] (14) the sense strand comprises the sequence set forth in SEQ ID NO. 1140, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1399;

[0342] (15) the sense strand comprises the sequence set forth in SEQ ID NO. 1141, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1400;

[0343] (16) the sense strand comprises the sequence set forth in SEQ ID NO. 1144, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1403;

[0344] (17) the sense strand comprises the sequence set forth in SEQ ID NO. 1144, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1646;

[0345] (18) the sense strand comprises the sequence set forth in SEQ ID NO. 1149, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1408;

[0346] (19) the sense strand comprises the sequence set forth in SEQ ID NO. 1151, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1410;

[0347] (20) the sense strand comprises the sequence set forth in SEQ ID NO. 1156, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1415;

[0348] (21) the sense strand comprises the sequence set forth in SEQ ID NO. 1159, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1418;

[0349] (22) the sense strand comprises the sequence set forth in SEQ ID NO. 1159, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1647;

[0350] (23) the sense strand comprises the sequence set forth in SEQ ID NO. 1168, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1427;

[0351] (24) the sense strand comprises the sequence set forth in SEQ ID NO. 1169, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1428;

[0352] (25) the sense strand comprises the sequence set forth in SEQ ID NO. 1169, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1648;

[0353] (26) the sense strand comprises the sequence set forth in SEQ ID NO. 1170, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1429;

[0354] (27) the sense strand comprises the sequence set forth in SEQ ID NO. 1170, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1649;

[0355] (28) the sense strand comprises the sequence set forth in SEQ ID NO. 1171, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1430;

[0356] (29) the sense strand comprises the sequence set forth in SEQ ID NO. 1171, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1650;

[0357] (30) the sense strand comprises the sequence set forth in SEQ ID NO. 1174, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1433;

[0358] (31) the sense strand comprises the sequence set forth in SEQ ID NO. 1175, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1434;

[0359] (32) the sense strand comprises the sequence set forth in SEQ ID NO. 1179, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1438;

[0360] (33) the sense strand comprises the sequence set forth in SEQ ID NO. 1179, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1651;

[0361] (34) the sense strand comprises the sequence set forth in SEQ ID NO. 1181, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1440;

[0362] (35) the sense strand comprises the sequence set forth in SEQ ID NO. 1181, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1652;

[0363] (36) the sense strand comprises the sequence set forth in SEQ ID NO. 1186, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1445;

[0364] (37) the sense strand comprises the sequence set forth in SEQ ID NO. 1186, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1653;

[0365] (38) the sense strand comprises the sequence set forth in SEQ ID NO. 1226, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1485;

[0366] (39) the sense strand comprises the sequence set forth in SEQ ID NO. 1226, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1654;

[0367] (40) the sense strand comprises the sequence set forth in SEQ ID NO. 1227, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1486;

[0368] (41) the sense strand comprises the sequence set forth in SEQ ID NO. 1227, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1655;

[0369] (42) the sense strand comprises the sequence set forth in SEQ ID NO. 1230, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1489;

[0370] (43) the sense strand comprises the sequence set forth in SEQ ID NO. 1230, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1656;

[0371] (44) the sense strand comprises the sequence set forth in SEQ ID NO. 1231, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1490;

[0372] (45) the sense strand comprises the sequence set forth in SEQ ID NO. 1239, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1498;

[0373] (46) the sense strand comprises the sequence set forth in SEQ ID NO. 1246, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1505;

[0374] (47) the sense strand comprises the sequence set forth in SEQ ID NO. 1250, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1509;

[0375] (48) the sense strand comprises the sequence set forth in SEQ ID NO. 1250, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1657;

[0376] (49) the sense strand comprises the sequence set forth in SEQ ID NO. 1258, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1517;

[0377] (50) the sense strand comprises the sequence set forth in SEQ ID NO. 1293, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1552;

[0378] (51) the sense strand comprises the sequence set forth in SEQ ID NO. 1325, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1584;

[0379] (52) the sense strand comprises the sequence set forth in SEQ ID NO. 1325, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1659;

[0380] (53) the sense strand comprises the sequence set forth in SEQ ID NO. 1341, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1600;

[0381] (54) the sense strand comprises the sequence set forth in SEQ ID NO. 1352, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1611;

[0382] (55) the sense strand comprises the sequence set forth in SEQ ID NO. 1613, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1665;

[0383] (56) the sense strand comprises the sequence set forth in SEQ ID NO. 1613, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1674;

[0384] (57) the sense strand comprises the sequence set forth in SEQ ID NO. 1614, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1666;

[0385] (58) the sense strand comprises the sequence set forth in SEQ ID NO. 1614, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1679;

[0386] (59) the sense strand comprises the sequence set forth in SEQ ID NO. 1615, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1667;

[0387] (60) the sense strand comprises the sequence set forth in SEQ ID NO. 1615, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1685;

[0388] (61) the sense strand comprises the sequence set forth in SEQ ID NO. 1618, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1670;

[0389] (62) the sense strand comprises the sequence set forth in SEQ ID NO. 1618, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1689;

[0390] (63) the sense strand comprises the sequence set forth in SEQ ID NO. 1618, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1690;

[0391] (64) the sense strand comprises the sequence set forth in SEQ ID NO. 1619, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1671;

[0392] (65) the sense strand comprises the sequence set forth in SEQ ID NO. 1620, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1672;

[0393] (66) the sense strand comprises the sequence set forth in SEQ ID NO. 1620, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1694;

[0394] (67) the sense strand comprises the sequence set forth in SEQ ID NO. 1620, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1695;

[0395] (68) the sense strand comprises the sequence set forth in SEQ ID NO. 1622, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1677;

[0396] (69) the sense strand comprises the sequence set forth in SEQ ID NO. 1622, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1678;

[0397] (70) the sense strand comprises the sequence set forth in SEQ ID NO. 1623, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1682;

[0398] (71) the sense strand comprises the sequence set forth in SEQ ID NO. 1624, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1686;

[0399] (72) the sense strand comprises the sequence set forth in SEQ ID NO. 1624, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1687;

[0400] (73) the sense strand comprises the sequence set forth in SEQ ID NO. 1624, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1688;

[0401] (74) the sense strand comprises the sequence set forth in SEQ ID NO. 1625, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1691;

[0402] (75) the sense strand comprises the sequence set forth in SEQ ID NO. 1625, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1692;

[0403] (76) the sense strand comprises the sequence set forth in SEQ ID NO. 1625, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1693;

[0404] (77) the sense strand comprises the sequence set forth in SEQ ID NO. 1626, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1696;

[0405] (78) the sense strand comprises the sequence set forth in SEQ ID NO. 1626, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1697;

[0406] (79) the sense strand comprises the sequence set forth in SEQ ID NO. 1626, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1698;

[0407] (80) the sense strand comprises the sequence set forth in SEQ ID NO. 1627, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1699;

[0408] (81) the sense strand comprises the sequence set forth in SEQ ID NO. 1627, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1700;

[0409] (82) the sense strand comprises the sequence set forth in SEQ ID NO. 1627, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1701;

[0410] (83) the sense strand comprises the sequence set forth in SEQ ID NO. 1628, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1702;

[0411] (84) the sense strand comprises the sequence set forth in SEQ ID NO. 1628, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1703;

[0412] (85) the sense strand comprises the sequence set forth in SEQ ID NO. 1628, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1704;

[0413] (86) the sense strand comprises the sequence set forth in SEQ ID NO. 1633, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1714;

[0414] (87) the sense strand comprises the sequence set forth in SEQ ID NO. 1633, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1715;

[0415] (88) the sense strand comprises the sequence set forth in SEQ ID NO. 1634, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1716;

[0416] (89) the sense strand comprises the sequence set forth in SEQ ID NO. 1637, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1721;

[0417] (90) the sense strand comprises the sequence set forth in SEQ ID NO. 1638, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1722; and

[0418] (91) the sense strand comprises the sequence set forth in SEQ ID NO. 1640, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1725.

[0419] In another aspect, the present disclosure provides a conjugate or a pharmaceutically acceptable salt thereof for inhibiting PMP22 expression, comprising: (i) the foregoing oligonucleotide or a pharmaceutically acceptable salt thereof, and (ii) a targeting ligand, wherein at least one of the sense strand and the antisense strand of the oligonucleotide is conjugated to the targeting ligand. At least one nucleotide of the oligonucleotide is conjugated to one or more targeting ligands to form an siRNA conjugate. The foregoing siRNA conjugate contains the aforementioned siRNA and a conjugate group conjugated to the siRNA. The term "oligonucleotide salt" refers to an oligonucleotide compound in the form of a salt. Oligonucleotide salts include salts of oligonucleotide conjugate compounds as well as salts of unconjugated oligonucleotide compounds. Oligonucleotide salts are advantageously present in solid, powdered form.

[0420] In some embodiments, the targeting ligand is conjugated at the 3' end or the 5' end of the sense strand. In some embodiments, the targeting ligand is conjugated at the 3' end of the sense strand.

[0421] The present disclosure also provides a conjugate or a pharmaceutically acceptable salt thereof for inhibiting PMP22 expression, comprising the foregoing oligonucleotide or a pharmaceutically acceptable salt thereof, and a ligand conjugated thereto, wherein at least one nucleotide of the oligonucleotide is conjugated to one or more targeting ligands to form an siRNA conjugate. The foregoing siRNA conjugate contains the aforementioned siRNA and a conjugate group conjugated to the siRNA. The term "oligonucleotide salt" refers to an oligonucleotide compound in the form of a salt. Oligonucleotide salts include salts of oligonucleotide conjugate compounds as well as salts of unconjugated oligonucleotide compounds. Oligonucleotide salts are advantageously present in solid, powdered form.

[0422] In general, the aforementioned conjugate group comprises at least one targeting ligand that is pharmaceutically acceptable and, optionally, a linker, and the aforementioned siRNA, the aforementioned linker, and the aforementioned targeting ligand are sequentially linked. The targeting group can be a ligand routinely used in the art of siRNA administration, such as the various ligands described in WO2009082607A2, the entire disclosure of which is incorporated herein by reference. In some embodiments, the aforementioned targeting ligand is 2-4. The aforementioned siRNA molecule can be conjugated to the aforementioned conjugate group non-covalently or covalently, such as can be covalently conjugated to the aforementioned conjugate group. The conjugation site of the siRNA to the conjugate group can be at the 3' end and / or 5' end of the sense strand and / or the antisense strand of the siRNA, and can also be in the internal sequence of the siRNA. In some embodiments, the conjugation site of the siRNA to the conjugate group is at the 3' end or 5' end of the sense strand of the siRNA. In some embodiments, the conjugation site of the siRNA to the conjugate group is at the 3' end or 5' end of the antisense strand of the siRNA. In some preferred embodiments, the conjugation site of the siRNA to the conjugate group is at the 3' end of the sense strand of the siRNA.

[0423] In some embodiments, the targeting ligand comprises an asialogycopro protein receptor ligand. In some embodiments, the asialogycopro protein receptor ligand comprises or consists of one or more galactose derivatives. As used herein, the term "galactose derivative" includes galactose and lactose derivatives having an affinity for the asialogycopro protein receptor that is equal to or greater than the affinity of galactose. Galactose derivatives include, but are not limited to, galactose, galactosamine, N-formyl galactosamine, N-acetyl galactosamine, N-propionyl-galactosamine, N-n-butyryl-galactosamine, and N-isobutyryl galactosamine. Galactose derivatives and clusters of galactose derivatives that can be used to target oligonucleotides and other molecules to the liver in vivo are known in the art. Galactose derivatives have been used to target molecules to hepatocytes in vivo by their binding to asialogycopro protein receptors (ASGPRs) expressed on the surface of hepatocytes. Binding of the ASGPR ligand to the ASGPR(s) facilitates cell-specific targeting of hepatocytes and endocytosis of the molecule into the hepatocyte. The ASGPR ligand can be monomeric (e.g., having a single galactose derivative) or multimeric (e.g., having multiple galactose derivatives). The galactose derivative or cluster of galactose derivatives can be linked to the 3' end or 5' end of the siRNA using methods known in the art.

[0424] In some embodiments, the pharmaceutically acceptable targeting ligand in the foregoing siRNA conjugate can be galactose or N-acetylgalactosamine (GalNAc), wherein the galactose or N-acetylgalactosamine molecule can be monovalent, divalent, trivalent, tetravalent. It should be understood that the monovalent, divalent, trivalent, tetravalent respectively refer to the molar ratio of the siRNA molecule to the galactose or N-acetylgalactosamine molecule in the siRNA conjugate formed after the siRNA molecule is conjugated with the conjugation group containing the galactose or N-acetylgalactosamine molecule as the targeting ligand is 1:1, 1:2, 1:3 or 1:4. In some embodiments, the pharmaceutically acceptable targeting ligand is N-acetylgalactosamine. In some embodiments, when the siRNA of the present application is conjugated with the conjugation group containing N-acetylgalactosamine, the N-acetylgalactosamine molecule is trivalent or tetravalent. In some embodiments, when the siRNA of the present application is conjugated with the conjugation group containing N-acetylgalactosamine, the N-acetylgalactosamine molecule is trivalent.

[0425] In some embodiments, the foregoing targeting ligand comprises an N-acetylgalactosamine (GalNAc) moiety.

[0426] In some embodiments, the foregoing GalNac moiety is a monovalent GalNAc moiety, a divalent GalNAc moiety, a trivalent GalNAc moiety, or a tetravalent GalNAc moiety.

[0427] In some embodiments, the foregoing targeting ligand is L96.

[0428] The present disclosure also provides a conjugate or a pharmaceutically acceptable salt thereof for inhibiting PMP22 expression, comprising: (i) the foregoing oligonucleotide or a pharmaceutically acceptable salt thereof, and (ii) a lipophilic moiety, wherein at least one of the sense strand and the antisense strand of the oligonucleotide is conjugated with one or more lipophilic moieties, optionally, the lipophilic moiety is conjugated through a linker or a carrier.

[0429] In some embodiments, the foregoing lipophilic moiety is conjugated at the 2'-position of a nucleotide or a modified nucleotide within the sense or antisense strand. The internal position includes all positions except the terminal two positions from each end of the at least one strand of the foregoing oligonucleotide. For example, the lipophilic moiety is conjugated to position 6 of the sense strand, i.e., the lipophilic moiety is located at the 6th position of the sense strand.

[0430] In some embodiments, the foregoing lipophilic moiety comprises between one and four 2'-0-alkyl modifications. Optionally, the 2'-0-alkyl modified nucleotide is a 2'-C16-modified nucleotide. Optionally, the RNAi agent comprises a single 2'-0-C16 modified nucleotide. Optionally, the single 2'-C16 modified nucleotide is located at the 6th nucleobase position from the 5' terminus on the sense strand.

[0431] In some embodiments, another modification of the RNA of the RNAi agent chemically links one or more ligands, moieties, or conjugates to the RNA that enhance the activity, cellular distribution, or cellular uptake of the RNAi. Such moieties include, but are not limited to, lipid moieties such as a cholesterol moiety (Letsinger et al. (1989) Proc. Natl. Acad. Sci. USA, 86:6553-6556), a cholic acid (Manoharan et al. (1994) Biorg. Med. Chem. Let., 4:1053-1060), a thioether, for example, a green fluorescent protein- S-tritylthiol (Manoharan et al. (1992) Ann. N.Y. Acad. Sci., 660:306-309; Manoharan et al. (1993) Biorg. Med. Chem. Let., 3:2765-2770), a sulfur containing cholesterol (Oberhauser et al. (1992) Nucl. Acids Res., 20:533-538), a fatty chain, for example, a dodecandiol or undecyl residue (Saison-Behmoaras et al. (1991) EMBO J, 10:1111-1118; Kabanov et al. (1990) FEBS Lett, 259:327-330; Svinarchuk et al. (1993) Biochimie, 75:49-54), a phospholipid, for example, di-hexadecyl-rac- glycerol or triethyl-ammonium 1,2-di-O-hexadecyl-rac-glycero-3-Hphosphocholine (Manoharan et al. (1995) Tetrahedron Lett., 36:3651-3654; Shea et al. (1990) Nucl. Acids Res., 18:3777-3783), a polyamine or a polyethylene glycol chain (Manoharan et al. (1995) Nucleosides & Nucleotides, 14:969-973), or adamantane acetic acid (Manoharan et al. (1995) Tetrahedron Lett., 36:3651-3654), a palmityl moiety (Mishra et al. (1995) Biochim. Biophys. Acta, 1264:229-237), or an octadecylamine or hexylamino-carbonyloxy cholesterol moiety (Crooke et al. (1996) J. Pharmacol. Exp. Ther., 277:923-937).

[0432] In some embodiments, the lipophilic moiety is aliphatic, cyclic, e.g., alicyclic, or polycyclic, e.g., polya!icyclic, such as a steroid (e.g., a sterol) or a straight or branched aliphatic hydrocarbon. The lipophilic moiety can generally comprise a hydrocarbon chain, which can be cyclic or acyclic. The hydrocarbon chain can comprise various substituents and / or one or more heteroatoms, such as oxygen or nitrogen atoms. Such lipophilic aliphatic moieties include, but are not limited to, saturated or unsaturated C4-C 30 hydrocarbons (e.g., C6-C 22 hydrocarbons), saturated or unsaturated fatty acids, waxes (e.g., monoalcohol esters of fatty acids and fatty diamides), terpenes (e.g., C 10 terpenes, C 15 sesquiterpenes, C 20 diterpenes, C 30 triterpenes, and C 40 tetra terpenes) and other polya!icyclic hydrocarbons. For example, the lipophilic moiety can comprise a C4to C 30 hydrocarbon chain (e.g., a C4to C 30 alkyl or alkenyl group). In some embodiments, the lipophilic moiety comprises a saturated or unsaturated C6to C 18 hydrocarbon chain (e.g., a straight chain C6to C 22 alkyl or alkenyl group). In one embodiment, the lipophilic moiety comprises a saturated or unsaturated C 16 hydrocarbon chain (e.g., a straight chain C 16 alkyl or alkenyl group). The lipid moiety is a 2'-0-alkyl, including single and or branched 10-30 hydrocarbon chain compositions.

[0433] In another embodiment, the lipophilic moiety comprises a lipid, cholesterol, retinoic acid, cholic acid, adamantane acetic acid, 1-pyrene butyric acid, dihydrotestosterone, 1,3-bis-0(hexadecyl)glycerol, geranyloxyhexanol, hexadecylglycerol, borneol, menthol, 1,3-propanediol, heptadecyl, palmitic acid, myristic acid, 03-(oleoyl)lithocholic acid, 03-(oleoyl)cholenic acid, ibuprofen, naproxen, dimethoxybenzophenone, or phenoxazine.

[0434] The lipophilic moiety is conjugated to the double stranded RNAi agent via a linker comprising an ether, a thioether, a urea, a carbonate, an amine, an amide, a maleimide-thioether, a disulfide, a phosphodiester, a sulfonamide linkage, a click reaction (e.g., a triazole from an azide-alkyne cycloaddition), or a carbamate.

[0435] In some embodiments, the foregoing ligand that enhances RNAi activity, cellular distribution, or cellular uptake comprises a C 12 alkyl group, a C 16 alkyl group, a C 18 alkyl group, a C 22alkyl, or branched lipids such as DDA (cationic dimethyl dioctadecyl ammonium), TDB (trehalose 6,6,9-ditridecanoate), and the like. For example, C16, C18, C22, DTX, and DSC-003.

[0436] The linear lipophilic moiety (C16) conjugated to one position on the chain has the following structure:

[0437] Base is a nucleotide base or nucleotide base analog. In some embodiments, Base is selected from the group consisting of adenine, guanine, cytosine, thymine, and uracil.

[0438] For example, 2'-O-hexadecyluridine has the following structure:

[0439] The present disclosure also provides a conjugate or a pharmaceutically acceptable salt thereof for inhibiting PMP22 expression, having a lipid-conjugated compound of the following formula:

[0440] A is a modified double-stranded oligonucleotide or a modified single-stranded oligonucleotide, wherein the modified double-stranded oligonucleotide or the modified single-stranded oligonucleotide is conjugated to the lipid-containing moiety at the 3' end of one strand of the modified double-stranded oligonucleotide or the 3' end of the modified single-stranded nucleic acid;

[0441] X1is:

[0442] L1is -(CH2)n-, -(CH2) n L2(CH2) n - or a bond;

[0443] L2is -C(=O)NH-, -C(=O)O-, -OC(=O)O-, -NHC(=O)O-, -NHC(=O)NH-, -C(=S)NH-, -C(=O)S-, -NH-, O (oxygen), or S (sulfur),

[0444] wherein each m is independently an integer from 10 to 18, and wherein each n is independently an integer from 1 to 6.

[0445] For example, DTX-1

[0446] For example, DSC-003:

[0447] In some embodiments, the lipophilic moiety is located at the 3' end of the sense strand.

[0448] The present disclosure also provides a conjugate or a pharmaceutically acceptable salt thereof for inhibiting PMP22 expression, comprising: (i) the foregoing oligonucleotide or a pharmaceutically acceptable salt thereof, and (ii) a targeting ligand and a lipophilic moiety, wherein at least one of the sense strand and the antisense strand of the oligonucleotide is conjugated to the targeting ligand, and at least one of the sense strand and the antisense strand of the oligonucleotide is conjugated to one or more lipophilic moieties.

[0449] In some embodiments, the dosage form of the composition is an oral dosage, an intravenous injection, a subcutaneous injection, or an intramuscular injection, preferably an intravenous injection or a subcutaneous injection.

[0450] In some embodiments, the composition further comprises other drugs for treating or / and preventing PMP22-related disorders.

[0451] In another aspect, the present disclosure provides use of the foregoing oligonucleotide or a pharmaceutically acceptable salt thereof, or the conjugate or the composition in the manufacture of a medicament for treating or / and preventing PMP22-related disorders.

[0452] In some embodiments of the methods of the present disclosure, the expression of the PMP22 gene is inhibited by at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%, or to below the level of detection of the assay. In preferred embodiments, the expression of PMP22 is inhibited by at least 70%. It will also be appreciated that it can be desirable to inhibit the expression of PMP22 in certain tissues (e.g., brain) without significantly inhibiting expression in other tissues. In preferred embodiments, the level of expression is determined in a suitable species-matched cell line using the assay method provided in Example 2 with 50 nM, 10 nM, 1 nM, and 0.1 nM siRNA concentrations.

[0453] In certain embodiments, the inhibition of expression in vivo is determined by knocking down the human gene in a rodent that expresses the human gene, e.g., a mouse infected with an AAV expressing the human target gene (i.e., PMP22), e.g., the effect of inhibition of the human gene is confirmed by the nadir of PMP22 expression after, e.g., a single dose administration, e.g., a 3 mg / kg subcutaneous injection. Such systems are useful when the nucleic acid sequences of the human gene and the model animal gene are sufficiently close that a human iRNA provides effective knockdown of the model animal gene. RNA expression in the liver is determined using the PCR method provided in Example 2.

[0454] Inhibition of PMP22 gene expression can be represented by a decrease in the amount of mRNA expressed by the cell line (such cells can be present in, for example, a sample derived from a subject), or by a decrease in luciferase expression expressed in fusion with PMP22. The PMP22 gene or luciferase-PMP22 fusion gene is transcribed in a cell or population of cells and it is treated (e.g., by contacting one or more cells with an RNAi of the disclosure, or by administering an iRNA of the disclosure to a subject in which the cells are present or were present, such that expression of the PMP22 gene or luciferase-PMP22 fusion gene is inhibited as compared to a cell line that is substantially identical to the cell line but is not treated (control cells that are not treated with RNAi or not treated with RNAi targeting the gene of interest). In preferred embodiments, inhibition is assessed in species-matched cell lines using 10 nM and 1 nM siRNA concentrations by the method provided in Example 2, using the following formula, expressed as 2^A^ACT of the amount of mRNA expression in the treated cells relative to the mRNA level in the control cells: ACT = CT PMP22 - CT GAPDH A^ACT = ACT 处理细胞 - ACT 对照细胞 mRNA level = 2^A^ACT

[0455] or relative luciferase ratio (Ratio): Relative luciferase ratio = Renilla luciferase activity (RL) / Firefly luciferase activity (FL)

[0456] Inhibition efficiency = 1 - (Ratio 给药组 / Ratio 对照组 )

[0457] In other embodiments, inhibition of PMP22 gene expression can be assessed according to a decrease in a parameter related to the function of PMP22 gene expression, for example, PMP22 protein levels in blood or serum from a subject, PMP22 mRNA levels. PMP22 gene silencing can be determined in any cell expressing PMP22, whether endogenous or heterologous from an expression construct, and by any assay known in the art.

[0458] Inhibition of PMP22 protein expression can be manifested by a decrease in the level of PMP22 mRNA expressed by the cell or cell population or in a sample from a subject (e.g., protein levels in a blood sample from a subject). As described above, to assess mRNA inhibition, inhibition of protein expression levels in treated cells or cell populations can similarly be expressed as a percentage of protein levels in control cells or cell populations, or changes in protein levels in a sample from a subject (e.g., blood or serum therefrom), inhibition assessed by the methods provided in Example 3 or Example 4, using the following formula to express the amount of PMP22 mRNA in the sample treated (e.g., blood or serum therefrom) relative to the amount of PMP22 mRNA or Gluc expressed in control cells as a percentage. Percent Inhibition of mRNA = (mRNA amount 处理细胞 - mRNA amount 对照细胞 / mRNA amount 对照细胞 * 100%

[0459] Control cells, cell populations, or samples from a subject that can be used to assess inhibition of PMP22 gene expression include cells, cell populations, or samples from a subject that have not been contacted with an RNAi agent of the disclosure. For example, control cells, cell lines, or samples from a subject can be from an individual subject (e.g., a human or animal subject) prior to treatment of the subject or appropriately matched population control with an RNAi agent.

[0460] In some embodiments of the methods of the disclosure, the RNAi is administered to a subject such that the RNAi is delivered to a specific site within the subject. Inhibition of PMP22 expression can be assessed by measuring the level or change in PMP22 mRNA or fusion secreted luciferase from a specific site or tissue in the subject (e.g., sciatic nerve, gastrocnemius muscle, or blood).

[0461] The disclosure also provides methods of using an RNAi of the disclosure or a composition comprising an RNAi of the disclosure to inhibit PMP22 expression, thereby preventing or treating a PMP22-related disorder, e.g., Charcot-Marie-Tooth (CMT), a genetically heterogeneous primary hereditary neuropathy, usually associated with sensory and motor neuropathy, known as hereditary motor and sensory neuropathy (HSMN), including Friedreich’s ataxia and other hereditary ataxias, familial amyloidosis, lysosomal storage diseases such as Pelizaeus-Merzbacher disease and Fabry disease; lipid disorders such as Tangier disease and lipoproteinemia, peroxisomal diseases, i.e., Refsum disease, porphyria, and some mitochondrial diseases, among others.

[0462] The cells suitable for treatment using the methods of the disclosure can be any cell that expresses a PMP22 gene, for example, a peripheral nerve cell, a glial cell, a muscle cell, an epidermal cell, a cardiac cell, or a kidney cell, but preferably a peripheral nerve cell. The cells suitable for use in the methods of the disclosure can be mammalian cells, for example, primate cells (such as human cells, including human cells in chimeric non-human animals, or non-human primate cells, for example, monkey cells or chimpanzee cells) or non-primate cells. In certain embodiments, the cells are human cells, for example, glial cells. In the methods of the disclosure, expression of PMP22 in the cells is inhibited by at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%, or below the level of detection of the assay.

[0463] The in vivo methods of the disclosure can comprise administering to a subject a composition comprising RNAi, wherein the RNAi comprises a nucleotide sequence complementary to at least a portion of an RNA transcript of a PMP22 gene of the mammal to which the RNAi agent is administered. The composition can be administered by any means known in the art, including, but not limited to, oral, intraperitoneal, or parenteral routes, including intracranial (e.g., intraventricular, intraparenchymal, and intrathecal), intravenous, intramuscular, subcutaneous, transdermal, airway (aerosol), nasal, rectal, and topical (including buccal and sublingual) administration. In certain embodiments, the composition is administered by intravenous infusion or injection. In certain embodiments, the composition is administered subcutaneously. In certain embodiments, the composition is administered by intrathecal injection.

[0464] In one aspect, the disclosure also provides methods for inhibiting expression of a PMP22 gene in a mammal. The methods comprise administering to the mammal an oligonucleotide or a pharmaceutically acceptable salt thereof or a composition thereof. The oligonucleotide is a double-stranded RNA (dsRNA) that targets a PMP22 gene in a mammalian cell and is maintained in the mammal for a sufficient time to obtain degradation of an mRNA transcript of the PMP22 gene, thereby inhibiting expression of a PMP22 protein in the cell. Reduction in gene expression can be assessed by any method known in the art and by methods, for example, qRT-PCR as described herein, for example, in Example 2. Reduction in the protein product can be assessed by any method known in the art (e.g., ELISA). In other embodiments, blood samples are taken as a sample from the subject for monitoring reduction in PMP22 protein expression.

[0465] The present disclosure also provides methods of treatment in a subject in need thereof, e.g., a subject diagnosed with a PMP22-associated disorder, Charcot-Marie-Tooth (CMT), a primary hereditary neuropathy that is genetically heterogeneous, usually accompanied by sensory and motor neuropathy, referred to as hereditary sensory and motor neuropathy (HSMN), including Friedreich’s ataxia and other hereditary ataxias, familial amyloidosis, lysosomal storage diseases such as metachromatic leukodystrophy and Fabry disease; lipid disorders such as Tangier disease and lipoproteinemia, peroxisomal diseases, i.e., Refsum disease, porphyria, and some mitochondrial diseases, etc.

[0466] In one embodiment, the PMP22-associated disease is Charcot-Marie-Tooth disease type 1A (CMT1A), Charcot-Marie-Tooth disease type 2A (CMT2A) Charcot-Marie-Tooth disease type 1E (CMT1E), or hereditary neuropathy with liability to pressure palsies (HNPP), etc.

[0467] The RNAi of the present disclosure can be administered as “free RNAi”. Free RNAi is administered without a pharmaceutical composition. The naked RNAi can be in a suitable buffered solution. The buffered solution can comprise acetate, citrate, lactate, tartrate, carbonate, or phosphate, or any combination thereof. In one embodiment, the buffered solution is phosphate buffered saline (PBS). The pH and osmolarity of the buffered solution containing the RNAi can be adjusted to be suitable for administration to a subject.

[0468] Administration of the RNAi according to the methods of the present disclosure can result in the prevention or treatment of a PMP22-associated disorder, e.g., CMT1A, CMT2A, CMT1E, or HNPP, etc. A therapeutic amount of RNAi can be administered to a subject, such as about 0.01 mg / kg to about 200 mg / kg. Preferably, 1 mg / kg to about 50 mg / kg. The RNAi is preferably administered intravenously, i.e., by intravenous injection. One or more injections can be used to deliver the desired dose of RNAi to a subject. The injections can be repeated over a period of time.

[0469] Administration can be repeated on a regular basis. In certain embodiments, after an initial treatment regimen, treatment can be performed at a lower frequency. Repeated dosing regimens can include periodic administration of a therapeutic amount of RNAi, such as once a month to once a year. In certain embodiments, RNAi administration is about once a month to about once every three months, or about once every three months to about once every six months, or even once a year.

[0470] The present disclosure further provides that RNAi agents or pharmaceutical compositions thereof be used in combination with other drugs and / or other treatment modalities (e.g., known drugs and / or known treatment modalities, such as, for example, those currently used to treat these conditions) to benefit subjects who would benefit from a reduction and / or inhibition of PMP22 gene expression, e.g., subjects having a PMP22-related disease. For example, other therapeutic agents and treatment modalities suitable for treating subjects who would benefit from a reduction in PMP22 expression, e.g., subjects having a PMP22-related disease, include rehabilitative therapy, drug symptomatic treatment, orthopedic surgery, neurotrophic, nerve repair-promoting drugs, e.g., B vitamins, ATP, coenzyme Q10, etc.

[0471] Examples

[0472] In cases where no specific source for a reagent is given herein, such reagents can be obtained from any molecular biology reagent supplier, with quality / purity standards appropriate for molecular biology.

[0473] Abbreviations used for nucleotide monomers in nucleic acid sequence representations. It will be understood that when a nucleotide contains a 2'-fluoro modification, then the fluorine replaces the hydroxyl group at that position in the parent nucleotide (i.e., it is a 2'-deoxy-2'-fluoro nucleotide).

[0474] Table A. Abbreviations for nucleotide monomers used in nucleic acid sequence representations

[0475] Example 1. Preparation of targeting ligands and siRNAs

[0476] Abbreviations used for nucleotide monomers in nucleic acid sequence representations. It will be understood that these monomers, when present in an oligonucleotide, are connected to one another by 5'-3' phosphodiester linkages, unless otherwise indicated.

[0477] Preparation of targeting ligands

[0478] Preparation of L96 was performed according to the method described in patent CN104717982B.

[0479] C16 was purchased from Chengdu Leadwise Pharmaceutical Co., Ltd.

[0480] DTX was prepared according to the method described in patent application CN113166191A

[0481] DSC003 was prepared according to the method described in patent application CN119528797B

[0482] Preparation of oligonucleotides

[0483] (1) Preparation of siRNA

[0484] First, computer-based algorithms were used to generate candidate oligonucleotide sequences complementary to human PMP22 mRNA (NM_000304.4, Table 1), some of which were also complementary to cynomolgus monkey PMP22 mRNA (XM_045375320.1, Table 1) or no more than 2 mismatches. Some of them were designed as double-stranded siRNA with 19 / 21 pairing of sense and antisense strands respectively, and the antisense strand had two overhanging ends complementary to the mRNA sequence, and in some cases the overhanging ends of the antisense strand were non-complementary UU; some of them were designed as double-stranded siRNA with 21 / 23 pairing of sense and antisense strands respectively, and the antisense strand had two overhanging ends complementary to the mRNA sequence; some of them were designed as double-stranded siRNA with 21 / 21 and 23 / 23 pairing. The 1st base at the 5' end of the antisense strand of some of the complementary pairing sequences (the last 1st base at the 3' end of the sense strand) was replaced with a base that did not match PMP22 mRNA.

[0485] Table 1 Human and cynomolgus monkey PMP22 mRNA sequences

[0486] The siRNA sequences were synthesized individually on a solid support via the sense strand (SS) and the antisense strand (AS), and after deprotection, cleavage, purification, annealing, purification and lyophilization, the siRNA sequences were obtained.

[0487] Solid phase synthesis (Figure 4): The sense strand and the antisense strand were synthesized separately on a solid support using the oligonucleotide synthesizer by phosphoramidite technique. The synthesizer was AKTA Oligopilot (Cytiva), Dr. Oligo 192XLc (Kunshan Boly Precision Instrument Co., Ltd.). The solid phase synthesis started from the 3' end of the sequence, and the monomers were coupled into the sequence in sequence order. Each coupling of a phosphoramidite monomer included four chemical steps: 1) deprotection or deprotection of the hydroxyl protecting group; 2) coupling; 3) oxidation; 4) capping. The phosphoramidite monomers, reagents, and purification consumables used were commercialized circulating reagents and consumables, such as various phosphoramidite monomers (such as 5'-O-(4,4'-Dimethoxytrityl)-2'-O-methyl-Uridine-3'-CE-Phosphoramidite) purchased from Shanghai Zilve Science and Technology Development Co., Ltd., and reaction reagents (such as 40wt% methylamine aqueous solution, 28wt% ammonium hydroxide aqueous solution, etc.) purchased from Sigma-Aldrich LLC. The siRNA synthesis and purification methods used in this paper are described in US20130178612A1, US2015100197A1, etc.; the synthesis method of the sequence containing VPUm and APU structure is described in J. Med. Chem. 2018, 61, 734-744.

[0488] (2) Preparation of double-stranded RNAi agent

[0489] (a) Synthesis of sense strand

[0490] Solid phase phosphoramidite method is a mature oligonucleotide synthesis method. A computer-controlled synthesizer is used to perform the reaction in a stainless steel synthesis column. In the synthesis of the sense strand, a solid support loaded with a targeting ligand (such as L96) is used as the starting material, or a solid support is directly used as the starting material. Different raw materials, reagents and solvents are injected into different pipelines in sequence 3' to 5' order by the solid phase synthesizer to connect phosphoramidite nucleoside monomers one by one. The reaction process includes four steps of deprotection of DMT protecting group reaction, condensation reaction, oxidation or thio reaction, and capping reaction. Each cycle connects one nucleotide unit to obtain an oligonucleotide sequence of 19 or 21 nucleotide units. After synthesis is completed, the protecting group (2-cyanoethyl) is removed on the solid phase synthesis column, and the synthesized sequence is then cut from the solid support by ammonolysis reaction. Filtration is performed, the filter cake is washed with ethanol, and the filtrate and washing liquid are collected and concentrated to obtain the crude sense strand. The crude product is purified by chromatography (SOURCE 15Q) and lyophilized to obtain the target product sense strand. In the synthesizer, the siRNA sense strand conjugate is synthesized using a solid support loaded with a targeting ligand (such as L96) as the starting material; and the siRNA is synthesized directly using a solid support as the starting material.

[0491] (b) synthesis of antisense strand

[0492] The antisense strand is synthesized similarly to the sense strand by solid phase synthesizer to control different pipelines to inject different raw materials, reagents and solvents according to the sequence 3' to 5' order, and to connect the phosphoramidite nucleoside monomers one by one. The reaction process includes four steps of cycles, i.e. DMT protecting group removal reaction, condensation reaction, oxidation or thio reaction, and capping reaction, one nucleotide unit is connected each cycle, and an oligonucleotide sequence of 21 or 23 nucleotide units is obtained. After the synthesis is completed, the protecting group (2-cyanoethyl) is removed on the solid phase synthesis column, and the synthesized sequence is then cut from the solid phase support through an aminolysis reaction, filtered, washed with ethanol, and the filtrate and washing liquid are collected and concentrated to obtain the crude product of the antisense strand. The crude product is purified by chromatography (SOURCE 15Q), ultrafiltration, and lyophilized to obtain the target product antisense strand siRNA.

[0493] (c) preparation of double-stranded siRNA

[0494] The AS strand and the SS strand are dissolved in injection water respectively, mixed in a certain ratio (1.01:1.0-1.2:1.0), incubated at 30-50°C for 30-90 min, and cooled to room temperature. After freeze-drying, the double-stranded siRNA product is obtained.

[0495] According to the same method, the double-stranded siRNA agents in Tables 2, 3 and 4 below are prepared.

[0496] In Tables 2, 3 and 4, “G”, “C”, “A”, “U” and “T” generally represent nucleotides with guanine, cytosine, adenine, uracil and thymine as the base, respectively.

[0497] Modification: m represents 2'-methoxy; f represents 2'-deoxy-2'-fluorine; s represents phosphorothioate; VPUm is 2'-methoxy modified uridine; mAPP001 is 2'-O-methyl-5'-vinyl phosphonate-6-(3-(2-carboxyethyl)phenyl)-purine nucleotide; L96 is N-[tris(GalNAc-alkyl)amido decanoyl]-4-hydroxy prolinol (Hyp-(GalNAc-alkyl)3); dA represents 2'-deoxyadenosine-3'-phosphate; dG represents 2'-deoxyguanosine-3'-phosphate; dC represents 2'-deoxycytidine-3'-phosphate; dU represents 2'-deoxyuridine-3'-phosphate.

[0498] mAPP001:

[0499] Table 2: naked sequence of oligonucleotide

[0500] Table 3 Oligonucleotide modification sequences

[0501] Table 4 Oligonucleotide vector sequences

[0502] Example 2. In vitro activity screening of PMP22-siRNA (HEK293A cell reporter gene)

[0503] (1) Cell culture and transfection (HEK293A cells):

[0504] HEK293A (iCell-h086, Sbiotech (Shanghai) Biotech Co., Ltd.) was used, and the cells were placed in a 37°C, 5% CO2 incubator, and cultured using DMEM medium (iCell-h086-001b, Sbiotech (Shanghai) Biotech Co., Ltd.) added with 10% FBS (GIBCO, 12483020), 1% penicillin-streptomycin (GIBCO, 15140-122). When the cell confluence reached 90%, the cells were digested by trypsin-EDTA (Thermo, 25200-072), counted using a counting instrument (Countstar, IC1000), and 190 μl of cell suspension was inoculated per well in a 96-well plate (Shanghai Biyun Tian Biotechnology Co., Ltd., FCP968), with a cell number of 1 x 10 4Cells / well, to be adherent next day for transfection. Transfection was performed using Lipofectamine 3000 Transfection Reagent (thermofisher, L3000150), specifically: dilute siRNA to a concentration of 0.2 μM with Opti-MEM (thermofisher, 1105821), dilute psiCHECK2-hPMP22 plasmid (Universal Biological (Anhui) Co., Ltd.) to 2.5 ng / μl with Opti-MEM, system ① take 1 μl siRNA into 4 μl mixed plasmid Opti-MEM. System ② dilute 0.3 μl Lipo3000 with 5 μl Opti-MEM, respectively, stand for 5 min, then mix system ① and ②, stand for 15 min, drop into 96-well plates, the final concentration of siRNA is 10 nM, the concentration of plasmid is 10 ng per well. Place the 96-well plate in the incubator for 24 h.

[0505] (2) Detection

[0506] After transfection for 24 h, the original culture medium in the 96-well plate was discarded, each well was washed with 200 μL PBS (gibco, 20012027) and discarded, 50 μL Luciferase Assay Reagent (Progega, E2940) and 50 μL PBS were mixed, added to the cell well, and lysed on a shaker for at least 15 min. The firefly fluorescent signal was read in a microplate reader (BioTek, Synerg H1M). 50 μL of stop solution Stop & Go Reagent (Progega, E2940) was added to each well, and the renilla fluorescent signal was read.

[0507] (3) Statistical analysis of data:

[0508] Calculate the relative luciferase ratio (Ratio): relative luciferase ratio = renilla luciferase activity (RL) / firefly luciferase activity (FL)

[0509] Inhibition efficiency = 1- (Ratio 给药组 / Ratio 对照组 ).

[0510] The screening results of the cells are shown in Table 5.

[0511] As shown in Table 5, when the dosage is 10 nM, the inhibition rate of PMP22 mRNA of 94 siRNAs can reach 70% and above, and even the inhibition rate can reach 80% and above, such as AL0305020, AL0305032, AL0305033, AL0305038, AL0305040, AL0305045, AL0305046, AL0305049, AL0305054, AL0305056, AL0305061, AL0305064, AL0305073, AL0305074, AL0305075, AL0305076, AL0305079, AL0305080, AL0305084, AL0305086, AL0305091, AL0305131, AL0305132, AL0305135, AL0305144, AL0305163 and AL0305230. AL030-AL52DT01 and AL030-AL52DT02 are control sequences.

[0512] Table 5 PMP22 siRNA sequence knockdown level in HEK293A cells

[0513] Example 3. In vitro activity screening of PMP22-siRNA (HSwC cells)

[0514] (1) Cell culture and transfection (HSwC cells):

[0515] HSwC cells (BFN60803982, Qingqi Biotechnology) were used, which were placed in a 37°C, 5% CO2 incubator, and were cultured using DMEM medium (SBI, iCell-0001), added with 10% FBS (GIBCO, 12483020), 1% penicillin-streptomycin (GIBCO, 15140-122). When the cell confluence reached 90%, trypsin-EDTA (Thermo, 25200-072) was used for digestion, and the number of cells was counted using a counting instrument (Countstar, IC1000). 190 μl of cell suspension was inoculated per well, and the inoculation number of HSwC cells was 1*10 5 The cells were allowed to adhere the next day for transfection.

[0516] Lipofectamine TMRNAiMAX (thermofisher, 13778150) transfection, 2.2 μl (0.2 μM) diluted compound, 19.1 μl Opti-MEM (thermofisher, 1105821), 0.7 μl RNAiMAX were mixed to form a transfection complex, and incubated for 5 minutes, then the transfection complex was added to the cells (two technical replicates per complex), 10 μl per well, the final concentration of siRNA was 1 nM, and incubated at 37℃, 5% CO2 incubator for 24 hours.

[0517] (2) RNA extraction and detection

[0518] (i) Total RNA was extracted using an automatic nucleic acid extractor (HW-96A, Zhiang Bio) and a matching RNA extraction kit (GO-MNTR, Zhiang Bio):

[0519] The 96-well plate was removed from the incubator, the medium was aspirated, and the corresponding extraction reagents were added according to the RNA extraction kit for extraction. The extracted mRNA was transferred to an RNase-free centrifuge tube and placed on ice. The total RNA concentration was determined for subsequent experimental use.

[0520] (ii) cDNA synthesis using IIQ RT SuperMix for qPCR (+gDNA wiper) reverse transcription kit (Novozyme, R223-01):

[0521] A mixture of 4 μl 4×gDNA wiper Mix, 1 μg template RNA, and RNase-free ddH2O to 16 μl was prepared in an RNase-free centrifuge tube to remove genomic DNA, and mixed gently with a pipette. 4 μl of 5×HiScript II qRT SuperMix II was added directly to the reaction tube and mixed gently with a pipette. The tube was placed in a PCR instrument (Applied Biosystems, 9700) at 50℃ for 15 min, 85℃ for 5 sec, and 4℃. The product can be used immediately for qPCR reaction, or stored at -20℃ for use within six months. Long-term storage requires aliquoting and storage at -80℃, and cDNA should be avoided repeated freeze-thaw cycles.

[0522] (iii) qPCR quantification using Hieff qPCR TaqMan Probe Master Mix (11205ES03, yeasen):

[0523] qPCR reaction mixture was configured as follows: qPCR reaction system was configured according to the following proportion, and the final volume of each reaction tube was 20 μL. 10 μl of Hieff Unicon qPCR Taq-Man Probe Master Mix, 0.2 μl of Taq-Man Probe (10 μM), 0.5 μl of forward and reverse primers, 2 μl of cDNA, and ddH2O without RNase were added to a total volume of 20 μl. The program was executed: pre-denaturation, 95°C, 30 sec; amplification, 95°C, 10 sec, 60°C, 30 sec, 40 cycles.

[0524] (3) Statistical analysis of data:

[0525] The data was exported in EXCEL format, and CT PMP22 -CT GAPDH The control group was normalized, and in order to calculate the fold change of the relative silencing efficiency, the data was analyzed using the △△CT method. The average value and standard deviation of the obtained two parallel repeated data were calculated. The cell screening results are shown in Tables 6-11. The data in each table is obtained from a single test, and the silencing efficiency of the target gene will be different due to different batches of cells.

[0526] As shown in Table 6, when the dosage is 1 nM, the silencing effect of multiple siRNA sequences on the expression of the target gene can be greater than 50%, among which AL0305018, AL0305020, AL0305024, AL0305032, AL0305033, AL0305038, AL0305042, AL0305043, AL0305054, AL0305056, AL0305061, AL0305073, AL0305075, AL0305084, AL0305086, AL0305131, AL0305135, AL0305136, AL0305151, AL0305155, AL0305198, AL0305230, AL0305246 and AL0305257 can be close to or exceed 70% of the silencing effect on the target gene. As shown in Table 7, when the dosage is 0.5 nM, AL0305020, AL0305032, AL0305033, AL0305038, AL0305075, AL0305135, AL0305136 and AL0305230 can still exceed 70% of the silencing effect on the target gene.

[0527] Table 6 PMP22 siRNA sequence knockdown level in HSwC cells

[0528] Table 7. PMP22 siRNA sequence knockdown levels in HSwC cells

[0529] As shown in Table 8, when the dosage was 0.05 nM, AL0305258, AL0305259, AL0305260, AL0305261, AL0305262, AL0305263, AL0305264, AL0305265, AL0305266, AL0305267, AL0305268, AL0305269, AL0305270, AL0305271, AL0305272, and AL0305274 had a silencing effect on the target gene exceeding 50%; when the dosage was 0.5 nM, the silencing effect on the target gene exceeded 70%.

[0530] Table 8. PMP22 siRNA sequence knockdown levels in HSwC cells

[0531] As shown in Table 9-11, when the dosage is 0.05 nM, AL0305282, AL0305283, AL0305284, AL0305287, AL0305288, AL0305289, AL0305291, AL0305294, AL0305295, AL0305296, AL0305299, AL0305302, AL0305303, AL0305304, AL0305305, AL0305306, A L0305307, AL0305308, AL0305309, AL0305310, AL0305311, AL0305312, AL0305313, AL0305314, AL0305315, AL0305316, AL0305317, AL0305318, AL0305319, AL0305320, AL0305321, AL0305338, and AL0305342 exhibited a silencing effect of over 50% on the target gene.

[0532] Table 9. PMP22 siRNA sequence knockdown levels in HSwC cells

[0533] Table 10. PMP22 siRNA sequence knockdown levels in HSwC cells

[0534] Table 11. PMP22 siRNA sequence knockdown levels in HSwC cells

[0535] Example 4. In vitro cell free uptake pharmacodynamic evaluation of PMP22-siRNA (HSwC cells)

[0536] (1) Cell culture and transfection (HSwC cells):

[0537] HSwC cells (BFN60803982, Qingqi Bio) were used, which were placed in a 37°C, 5% CO2 incubator, and cultured using DMEM medium (SBI, iCell-0001), added with 10% FBS (GIBCO, 12483020), 1% penicillin-streptomycin (GIBCO, 15140-122). When the cell confluence reached 90%, trypsin-EDTA (Thermo, 25200-072) was used for digestion, and the cells were counted using a counting instrument (Countstar, IC1000), 190 μl of cell suspension per well, and seeded in a 96-well plate. The number of HSwC cells seeded was 6*10 4 Cells / well, and the next day, the cells were transfected after adhering. 10 μl of siRNA compounds of different concentrations (400 μM-0.36 μM, 3-fold dilution) were added to each well of cells, and each concentration of siRNA was used for two wells of cells. The cells were cultured in a 37°C, 5% CO2 incubator for 48 hours.

[0538] (2) RNA extraction and detection

[0539] (i) Total RNA was extracted using an automatic nucleic acid extractor (HW-96A, Zhiang Bio) and a matching RNA extraction kit (GO-MNTR, Zhiang Bio):

[0540] The 96-well plate was taken out of the incubator, the culture medium was aspirated, and the corresponding extraction reagents were added according to the RNA extraction kit for extraction. The extracted mRNA was transferred to an RNase-free centrifuge tube and placed on ice. The total RNA concentration was determined for subsequent experimental use.

[0541] (ii) cDNA was synthesized using IIQ RT SuperMix for qPCR (+gDNA wiper) reverse transcription kit (Novozyme, R223-01):

[0542] Prepare the mixture in a RNase-free centrifuge tube. Add 4 μl of 4x gDNA wiper Mix, 1 μg of template RNA, and RNase-free ddH2O to 16 μl to remove genomic DNA. Mix gently with a pipette, and incubate at 42°C for 2 min. Then add 4 μl of 5x HiScript II qRT SuperMix II directly to the reaction tube, mix gently with a pipette, and incubate in a PCR instrument (Applied Biosystems, 9700) at 50°C for 15 min, at 85°C for 5 sec, and at 4°C. The product can be used immediately for qPCR reaction, or stored at -20°C for use within six months. For long-term storage, the cDNA should be aliquoted and stored at -80°C to avoid repeated freeze-thaw cycles.

[0543] (iii) using Hieff qPCR TaqMan Probe Master Mix (11205ES03, yeasen) qPCR quantification:

[0544] Prepare the qPCR reaction mixture: Prepare the qPCR reaction system according to the following proportions, with a final volume of 20 μl per reaction tube. 10 μl of Hieff Unicon qPCR Taq-Man Probe Master Mix, 0.2 μl of Taq-Man Probe (10 μM), 0.5 μl of forward and reverse primers, 2 μl of cDNA, and RNase-free ddH2O to a total volume of 20 μl. Perform the program: pre-denaturation at 95°C for 30 sec; amplification at 95°C for 10 sec, at 60°C for 30 sec, for 40 cycles.

[0545] (3) Data statistical analysis:

[0546] Export the data to EXCEL format, and use CT PMP22 -CT GAPDH Normalize the control group. To calculate the fold change of the relative silencing efficiency, use the △△CT method to analyze the data, and use four parameters to fit the obtained two parallel repeat data to obtain the IC50 value and the corresponding R 2 .

[0547] The screening results of the cells are shown in Table 12.

[0548] Table 12 Silencing effect of PMP22 siRNA sequence free uptake into HSwC cells on the expression level of target genes

[0549] Example 5. In vivo testing of PMP22 RNAi agents in AAV9 mice

[0550] AAV9 virus containing mRNA sequence of human PMP22 gene (GENBANK NO. NM_000304.4) was purchased (80-1474688827, Suzhou Jinyizhi Biotechnology Co., Ltd.). SPF grade male, 6-8 weeks old C57BL / 6 mice (Sibeifeng (Beijing) Biotechnology Co., Ltd.) were used in the test. Each mouse was injected with 5.00E+10 GC / ml AAV9 virus in the tail vein, and the injection was at least 14 days before administration. Normal saline was used as the vehicle control group, and the mice were given a single intravenous administration of 3 mg / kg of RNAi agents AL0307001, AL0307002, AL0307003, AL0307004, AL0307005, AL0307006, AL0307007, AL0307008, AL0307009 and AL0307010. The mice were sacrificed 14 days after administration, and the expression of hPMP22 gene was detected by Q-PCR method. The extraction and detection of mRNA and data analysis were performed according to Example 3. The changes in the expression level of hPMP22 mRNA are shown in Table 13. As can be seen from Table 13, AL0307006, AL0307007 and AL0307010 have a silencing effect close to or greater than 50% on the target gene 14 days after administration. During the experiment, no death or near-death symptoms were observed in all animals. No obvious abnormalities were observed in clinical observation of all animals.

[0551] Table 13 Silencing effect of PMP22 siRNA on hPMP22 gene in liver of AAV9 transgenic mice

[0552] Example 6. In vivo test of PMP22 RNAi agents in transgenic mice

[0553] SPF level male, 8-9 weeks old C57BL / 6J / hPMP22 mice (Peking University Third Hospital) were used in the experiment. The hPMP22 mRNA expression level was detected by tail clipping on the 0th day of drug administration, and the mice were randomly divided according to the mRNA level. The mice were given a single intravenous dose of 30 mg / kg of RNAi agent, and a control group (NC) was set as the solvent group, which was given the same volume of 0.9% normal saline. On the 14th day or 21st day after administration, the hPMP22 expression knockdown level in different tissues was detected, with the normal saline group (solvent group) as the control. The normal saline group and the administration group were both C57BL / 6J / hPMP22 transgenic mice. WT was wild-type C57BL / 6 mice (Sibeifu (Beijing) Biotechnology Co., Ltd.), and the same volume of normal saline was given in the experiment. The extraction and detection of mRNA and data analysis were performed according to Example 3. During the experiment, no death or near-death symptoms were observed in all animals. No obvious abnormalities were observed in clinical observation of all animals. The changes in hPMP22 mRNA expression level are shown in Tables 14, 15 and 17, and Table 16 is the detection value of the electrophysiological index of the mice after 21 days of administration. The experimental results show that the silencing effect of AL0307015, AL0307017, AL0307020, AL0307025, AL0307027, AL0307033 and AL0307037 target genes is better, among which AL0307020 and AL0307025 have different degrees of improvement in electrophysiological indicators compared with normal saline.

[0554] Table 14 Silencing effect of PMP22 siRNA sequence in transgenic

[0555] Table 15 Silencing effect of PMP22 siRNA sequence in transgenic

[0556] Table 16 Electrophysiological index of mice after 21 days of administration of PMP22 siRNA sequence in transgenic

[0557] Table 17 Silencing effect of target gene in mouse nerve after 21 days of administration of PMP22 siRNA sequence in transgenic

[0558] Table 18 Silencing effect of target gene in mouse nerve after 21 days of administration of PMP22 siRNA sequence in transgenic

Claims

1. An oligonucleotide or a pharmaceutically acceptable salt thereof for inhibiting PMP22 expression, the oligonucleotide comprising a sense strand and an antisense strand, the sense strand having a sequence with at least 80% or more sequence identity to a sequence set forth in any one of SEQ ID NO. 1-547 or a fragment thereof, or a modified sequence of the sequence or the fragment thereof, preferably having 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or more sequence identity; the antisense strand having a sequence with at least 80% or more sequence identity to a sequence set forth in any one of SEQ ID NO. 548-1094, 1733-1738 or a fragment thereof, or a modified sequence of the sequence or the fragment thereof, preferably having 70%, 75%, 80%, 85%, 90%, 95%, 99% or more sequence identity.

2. The oligonucleotide or pharmaceutically acceptable salt thereof of claim 1, wherein, the oligonucleotide or the pharmaceutically acceptable salt thereof is selected from the group consisting of a carboxylate salt, an alkali metal salt, an ammonium salt, an alkaline earth metal salt, a salt with an organic base, and other pharmaceutically acceptable salts; preferably, the salt is an alkali metal salt, more preferably a sodium salt or a potassium salt thereof; preferably, the salt is an alkaline earth metal salt, more preferably a magnesium salt or a calcium salt; preferably, the salt is an ammonium salt.

3. The oligonucleotide or pharmaceutically acceptable salt thereof of claim 1 or 2, wherein, the oligonucleotide comprises at least one modified nucleotide; preferably, the at least one modified nucleotide in the modified nucleotide is selected from the group consisting of a deoxynucleotide, a 3' terminal deoxythymidine (dT) nucleotide, a 2'-O-methyl modified nucleotide, a 2'-fluoro modified nucleotide, a 2'-deoxy modified nucleotide, a locked nucleotide, a 2'-5'-linked ribonucleotide (3'-RNA), an unlocked nucleotide, a conformationally restricted nucleotide, a constrained ethyl nucleotide, an abasic nucleotide, a 2'-amino modified nucleotide, a 2'-O-allyl modified nucleotide, a 2'-O-alkyl modified nucleotide, a 2'-hydroxyl modified nucleotide, a 2'-methoxyethyl modified nucleotide, a 2'-O-alkyl modified nucleotide, a morpholino nucleotide, a phosphoramidate, a nucleotide comprising a non-natural base, a tetrahydropyran modified nucleotide, a 1,5-anhydrohexitol modified nucleotide, a cyclohexenyl modified nucleotide, a nucleotide comprising a phosphorothioate group, a nucleotide comprising a methylphosphonate group, a nucleotide comprising a 5'-phosphate, a nucleotide comprising a 5'-phosphate mimic, a vinyl-phosphonate nucleotide, a thermally unstable nucleotide, a glycol modified nucleotide, a nucleotide comprising a 2' phosphate, and a 2-O-(N-methylacetamide) modified nucleotide; and combinations thereof; preferably, the at least one modified nucleotide in the modified nucleotide is selected from the group consisting of a deoxynucleotide, a 3' terminal deoxythymidine (dT) nucleotide, a 2'-O-methyl modified nucleotide, a 2'-fluoro modified nucleotide, a 2'-deoxy modified nucleotide, a locked nucleotide, a 2'-5'-linked ribonucleotide (3'-RNA), an unlocked nucleotide, a conformationally restricted nucleotide, a constrained ethyl nucleotide, an abasic nucleotide, a 2'-amino modified nucleotide, a 2'-O-allyl modified nucleotide, a 2'-O-alkyl modified nucleotide, a 2'-hydroxyl modified nucleotide, a 2'-methoxyethyl modified nucleotide, a 2'-O-alkyl modified nucleotide, a morpholino nucleotide, a phosphoramidate, a nucleotide comprising a non-natural base, a tetrahydropyran modified nucleotide, a 1,5-anhydrohexitol modified nucleotide, a cyclohexenyl modified nucleotide, a nucleotide comprising a phosphorothioate group, a nucleotide comprising a methylphosphonate group, a nucleotide comprising a 5'-phosphate, a nucleotide comprising a 5'-phosphate mimic, a vinyl-phosphonate nucleotide, a thermally unstable nucleotide, a glycol modified nucleotide, a nucleotide comprising a 2' phosphate, and a 2-O-(N-methylacetamide) modified nucleotide; and combinations thereof; Preferably, the at least one modified nucleotide in the modified nucleotide is selected from the group consisting of: LNA modified nucleotide, HNA modified nucleotide, CeNA modified nucleotide, 2'-methoxyethyl modified nucleotide, 2'-O-alkyl modified nucleotide, 2'-O-allyl modified nucleotide, 2'-C-allyl modified nucleotide, 2'-fluoro modified nucleotide, 2'-deoxy modified nucleotide, 2'-hydroxyl modified nucleotide, and glycol modified nucleotide; and combinations thereof; Preferably, the at least one modified nucleotide in the modified nucleotide is selected from the group consisting of: deoxy nucleotide, 2'-O-methyl modified nucleotide, 2'-fluoro modified nucleotide, 2'-deoxy modified nucleotide, glycol modified nucleotide, nucleotide comprising 2' phosphate, and nucleotide comprising phosphorothioate group; and combinations thereof; Preferably, the oligonucleotide comprises at least one 2'-modified nucleotide; Preferably, the 2'-modified nucleotide is selected from the group consisting of: 2'-alkoxy modified nucleotide, 2'-substituted alkoxy modified nucleotide, 2'-alkyl modified nucleotide, 2'-substituted alkyl modified nucleotide, 2'-fluoro modified nucleotide, 2'-acylamino modified nucleotide, 2'-deoxy modified nucleotide, 2'-O-allyl modified nucleotide, 2'-O-alkyl modified nucleotide, 2'-hydroxyl modified nucleotide, 2'-methoxyethyl modified nucleotide, 2'-amino modified nucleotide, 2'-substituted amino modified nucleotide, 2'-deoxy nucleotide, nucleotide comprising 2' phosphate, and 2'-O-(N-methylacetamide) modified nucleotide; and combinations thereof; Preferably, the 2'-modification is selected from the group consisting of: 2'-methoxy, 2'-acetamido, 2'-aminoethyl, 2'-fluoro, 2'-O-methyl, and 2'-O-methoxyethyl modification; and combinations thereof; Preferably, the oligonucleotide comprises a modification at the 5' end, the modification comprising a 5'-phosphate analog or 6-(3-(2-carboxyethyl)phenyl)purine (6-mCEPh-purine); Preferably, the oligonucleotide comprises a 5'-(E)-vinylphosphonate modified nucleotide at the 5' end having the structure shown in Formula (II-1) or Formula (II-2); wherein R is selected from the group consisting of H, fluoro, 2'-methoxy, 2'-acetamido, 2'-aminoethyl, and 2'-0-methoxyethyl; preferably, the oligonucleotide has an APU at the 5' end which is a 5'-phosphate analog modified uridylate (2'-acetamido-5'-vinylphosphonate-uridylate) shown in Formula (III); preferably, the oligonucleotide has a VPUm at the 5' end which is a 5'-phosphate analog modified uridylate (2'-methoxy-5'-vinylphosphonate-uridylate) shown in Formula (IV-1); preferably, the oligonucleotide has a VPAm at the 5' end which is a 5'-phosphate analog modified uridylate (2'-methoxy-5'-vinylphosphonate-adenylate) shown in Formula (IV-2); Preferably, the oligonucleotide comprises formula mAPP001, which is a 2'-methoxy-5'- vinylphosphonate-6-(3-(2-carboxyethyl)phenyl) purine nucleotide of formula (V); Preferably, the oligonucleotide can comprise 2'-5'-phosphodiester bond; more preferably, the oligonucleotide comprises a uridine-2'-phosphate (U-2'5') selected from formula (VI), a guanosine-2'-phosphate (G-2'5') selected from formula (VII), a cytidine-2'-phosphate (C-2'5') selected from formula (VIII), an adenosine-2'-phosphate (A-2'5') selected from formula (IX), and a thymidine-2'-phosphate (T-2'5') selected from formula (X); Preferably, the glycol modified nucleic acid (GNA) is selected from the group consisting of adenosine-diol nucleic acid, cytidine-diol nucleic acid, thymidine-diol nucleic acid, and guanosine-diol nucleic acid; more preferably, the glycol modified nucleic acid (GNA) is selected from the group consisting of thymidine-diol nucleic acid S-isomer (Tgn) of Formula (XI), cytidine-diol nucleic acid S-isomer (Cgn) of Formula (XII), adenosine-diol nucleic acid S-isomer (Agn) of Formula (XIII), and guanosine-diol nucleic acid S-isomer (Ggn) of Formula (XIV); Tgn Cgn Agn Ggn 4. The oligonucleotide or a pharmaceutically acceptable salt thereof according to any one of claims 1-3, wherein, the oligonucleotide comprises at least one modified internucleotide linkage; Preferably, the at least one modified internucleotide linkage is a phosphorothioate linkage.

5. The oligonucleotide or a pharmaceutically acceptable salt thereof according to any one of claims 1-4, wherein, the antisense strand is selected from the group consisting of SEQ ID NO. 1, 4, 5, 6, 7, 9, 10, 11, 12, 14, 15, 17, 21, 22, 26, 27, 28, 29, 30, 31, 34, 35, 37, 41, 42, 47, 48, 50, 58, 59, 62, 66, 69, 70, 71, 72, 77, 78, 82, 83, 87, 88, 89, 90, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 103, 104, 105, 106, 107, 108, 109, 110, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 123, 124, 125, 126, 127, 128, 129, 130, 132, 133, 134, 137, 138, 139, 140, 141, 142, 143, 145, 146, 147, 148, 149, 150, 152, 153, 154, 156, 157, 158, 159, 160, 162, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 247, 248, 249, 250, 251, 252, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, 383, 384, 385, 386, 387, 388, 389, 390, 391, 392, 393, 394, 395,550, 555, 560, 563, 565, 566, 567, 570, 571, 572, 579, 580, 583, 585, 586, 587, 589, 590, 591, 592, 593, 596, 598, 599, 600, 601, 602, 603, 604, 607, 608, 610, 611, 612, 614, 615, 620, 621, 622, 623, 626, 627, 631, 633, 638, 649, 669, 678, 679, 682, 683, 691, 698, 702, 710, 711, 745, 777, 793, 801, and 804, or a SEQ ID NO.1357, 1362, 1367, 1370, 1372, 1373, 1374, 1377, 1378, 1379, 1386, 1387, 1390, 1392, 1393, 1394, 1396, 1397, 1398, 1399, 1400, 1403, 1405, 1406, 1407, 1408, 1409, 1410, 1411, 1414, 1415, 1417, 1418, 1419, 1421, 1422, 1423, 1424, 1425, 1426, 1427, 1428, 1429, 1430, 1431, 1432, 1433, 1434, 1435, 1436, 1437, 1438, 1439, 1440, 1441, 1442, 1443, 1444, 1445, 1451, 1456, 1470, 1472, 1476, 1485, 1486, 1489, 1490, 1494, 1498, 1505, 1507, 1508, 1509, 1511, 1512, 1514, 1515, 1517, 1519, 1523, 1552, 1556, 1565, 1569, 1573, 1576, 1577, 1584, 1600, 1611, 1643, 1644, 1645, 1646, 1647, 1648, 1649, 1650, 1651, 1652, 1653, 1654, 1655, 1656, 1657, 1659, 1663, 1665, 1666, 1667, 1670, 1671, 1672, 1674, 1677, 1678, 1679, 1682, 1685, 1686, 1687, 1688, 1689, 1690, 1691, 1692, 1693, 1694, 1695, 1696, 1697, 1698, 1699, 1700, 1701, 1702, 1703, 1704, 1714, 1715, 1716, 1721, 1722, and 1725.

6. The oligonucleotide or a pharmaceutically acceptable salt thereof of any one of claims 1-5, wherein, the oligonucleotide is selected from any one of the following sense and antisense strand combinations: (1) the sense strand comprises the sequence set forth in SEQ ID NO. 3, and the antisense strand comprises the sequence set forth in SEQ ID NO. 550; (2) the sense strand comprises the sequence set forth in SEQ ID NO. 8, and the antisense strand comprises the sequence set forth in SEQ ID NO. 555; (3) the sense strand comprises the sequence set forth in SEQ ID NO. 13, and the antisense strand comprises the sequence set forth in SEQ ID NO. 560; (4) the sense strand comprises the sequence set forth in SEQ ID NO. 16, and the antisense strand comprises the sequence set forth in SEQ ID NO. 563; (5) the sense strand comprises the sequence set forth in SEQ ID NO. 18, and the antisense strand comprises the sequence set forth in SEQ ID NO. 565; (6) the sense strand comprises the sequence set forth in SEQ ID NO. 19, and the antisense strand comprises the sequence set forth in SEQ ID NO. 566; (7) the sense strand comprises the sequence set forth in SEQ ID NO. 20, and the antisense strand comprises the sequence set forth in SEQ ID NO. 567; (8) the sense strand comprises the sequence set forth in SEQ ID NO. 23, and the antisense strand comprises the sequence set forth in SEQ ID NO. 570; (9) the sense strand comprises the sequence set forth in SEQ ID NO. 24, and the antisense strand comprises the sequence set forth in SEQ ID NO. 571; (10) the sense strand comprises the sequence set forth in SEQ ID NO. 25, and the antisense strand comprises the sequence set forth in SEQ ID NO. 572; (11) the sense strand comprises the sequence set forth in SEQ ID NO. 32, and the antisense strand comprises the sequence set forth in SEQ ID NO. 579; (12) the sense strand comprises the sequence set forth in SEQ ID NO. 33, and the antisense strand comprises the sequence set forth in SEQ ID NO. 580; (13) the sense strand comprises the sequence set forth in SEQ ID NO. 36, and the antisense strand comprises the sequence set forth in SEQ ID NO. 583; (14) the sense strand comprises the sequence set forth in SEQ ID NO. 38, and the antisense strand comprises the sequence set forth in SEQ ID NO. 585; (15) the sense strand comprises the sequence set forth in SEQ ID NO. 39, and the antisense strand comprises the sequence set forth in SEQ ID NO. 586; (16) the sense strand comprises the sequence set forth in SEQ ID NO. 40, and the antisense strand comprises the sequence set forth in SEQ ID NO. 587; (17) the sense strand comprises the sequence set forth in SEQ ID NO. 42, and the antisense strand comprises the sequence set forth in SEQ ID NO. 589; (18) the sense strand comprises the sequence set forth in SEQ ID NO. 43, and the antisense strand comprises the sequence set forth in SEQ ID NO. 590; (19) the sense strand comprises a sequence set forth in SEQ ID NO. 44, and the antisense strand comprises a sequence set forth in SEQ ID NO. 591; (20) the sense strand comprises a sequence set forth in SEQ ID NO. 45, and the antisense strand comprises a sequence set forth in SEQ ID NO. 592; (21) the sense strand comprises a sequence set forth in SEQ ID NO. 46, and the antisense strand comprises a sequence set forth in SEQ ID NO. 593; (22) the sense strand comprises a sequence set forth in SEQ ID NO. 49, and the antisense strand comprises a sequence set forth in SEQ ID NO. 596; (23) the sense strand comprises a sequence set forth in SEQ ID NO. 51, and the antisense strand comprises a sequence set forth in SEQ ID NO. 598; (24) the sense strand comprises a sequence set forth in SEQ ID NO. 52, and the antisense strand comprises a sequence set forth in SEQ ID NO. 599; (25) the sense strand comprises a sequence set forth in SEQ ID NO. 53, and the antisense strand comprises a sequence set forth in SEQ ID NO. 600; (26) the sense strand comprises a sequence set forth in SEQ ID NO. 54, and the antisense strand comprises a sequence set forth in SEQ ID NO. 601; (27) the sense strand comprises a sequence set forth in SEQ ID NO. 55, and the antisense strand comprises a sequence set forth in SEQ ID NO. 602; (28) the sense strand comprises a sequence set forth in SEQ ID NO. 56, and the antisense strand comprises a sequence set forth in SEQ ID NO. 603; (29) the sense strand comprises a sequence set forth in SEQ ID NO. 57, and the antisense strand comprises a sequence set forth in SEQ ID NO. 604; (30) the sense strand comprises a sequence set forth in SEQ ID NO. 60, and the antisense strand comprises a sequence set forth in SEQ ID NO. 607; (31) the sense strand comprises a sequence set forth in SEQ ID NO. 61, and the antisense strand comprises a sequence set forth in SEQ ID NO. 608; (32) the sense strand comprises a sequence set forth in SEQ ID NO. 63, and the antisense strand comprises a sequence set forth in SEQ ID NO. 610; (33) the sense strand comprises a sequence set forth in SEQ ID NO. 64, and the antisense strand comprises a sequence set forth in SEQ ID NO. 611; (34) the sense strand comprises a sequence set forth in SEQ ID NO. 73, and the antisense strand comprises a sequence set forth in SEQ ID NO. 620; (35) the sense strand comprises a sequence set forth in SEQ ID NO. 74, and the antisense strand comprises a sequence set forth in SEQ ID NO. 621; (36) the sense strand comprises the sequence set forth in SEQ ID NO. 75, and the antisense strand comprises the sequence set forth in SEQ ID NO. 622; (37) the sense strand comprises the sequence set forth in SEQ ID NO. 76, and the antisense strand comprises the sequence set forth in SEQ ID NO. 623; (38) the sense strand comprises the sequence set forth in SEQ ID NO. 79, and the antisense strand comprises the sequence set forth in SEQ ID NO. 626; (39) the sense strand comprises the sequence set forth in SEQ ID NO. 80, and the antisense strand comprises the sequence set forth in SEQ ID NO. 627; (40) the sense strand comprises the sequence set forth in SEQ ID NO. 84, and the antisense strand comprises the sequence set forth in SEQ ID NO. 631; (41) the sense strand comprises the sequence set forth in SEQ ID NO. 86, and the antisense strand comprises the sequence set forth in SEQ ID NO. 633; (42) the sense strand comprises the sequence set forth in SEQ ID NO. 91, and the antisense strand comprises the sequence set forth in SEQ ID NO. 638; (43) the sense strand comprises the sequence set forth in SEQ ID NO. 102, and the antisense strand comprises the sequence set forth in SEQ ID NO. 649; (44) the sense strand comprises the sequence set forth in SEQ ID NO. 122, and the antisense strand comprises the sequence set forth in SEQ ID NO. 669; (45) the sense strand comprises the sequence set forth in SEQ ID NO. 131, and the antisense strand comprises the sequence set forth in SEQ ID NO. 678; (46) the sense strand comprises the sequence set forth in SEQ ID NO. 132, and the antisense strand comprises the sequence set forth in SEQ ID NO. 679; (47) the sense strand comprises the sequence set forth in SEQ ID NO. 135, and the antisense strand comprises the sequence set forth in SEQ ID NO. 682; (48) the sense strand comprises the sequence set forth in SEQ ID NO. 136, and the antisense strand comprises the sequence set forth in SEQ ID NO. 683; (49) the sense strand comprises the sequence set forth in SEQ ID NO. 144, and the antisense strand comprises the sequence set forth in SEQ ID NO. 691; (50) the sense strand comprises the sequence set forth in SEQ ID NO. 151, and the antisense strand comprises the sequence set forth in SEQ ID NO. 698; (51) the sense strand comprises the sequence set forth in SEQ ID NO. 155, and the antisense strand comprises the sequence set forth in SEQ ID NO. 702; (52) the sense strand comprises the sequence set forth in SEQ ID NO. 163, and the antisense strand comprises the sequence set forth in SEQ ID NO. 710; (53) the sense strand comprises a sequence set forth in SEQ ID NO. 164, and the antisense strand comprises a sequence set forth in SEQ ID NO. 711; (54) the sense strand comprises a sequence set forth in SEQ ID NO. 198, and the antisense strand comprises a sequence set forth in SEQ ID NO. 745; (55) the sense strand comprises a sequence set forth in SEQ ID NO. 230, and the antisense strand comprises a sequence set forth in SEQ ID NO. 777; (56) the sense strand comprises a sequence set forth in SEQ ID NO. 246, and the antisense strand comprises a sequence set forth in SEQ ID NO. 793; (57) the sense strand comprises a sequence set forth in SEQ ID NO. 254, and the antisense strand comprises a sequence set forth in SEQ ID NO. 801; (58) the sense strand comprises a sequence set forth in SEQ ID NO. 257, and the antisense strand comprises a sequence set forth in SEQ ID NO. 804; Preferably, the oligonucleotide comprises any one of a sense strand and an antisense strand combination selected from: (1) the sense strand comprises a sequence set forth in SEQ ID NO. 18, and the antisense strand comprises a sequence set forth in SEQ ID NO. 565; (2) the sense strand comprises a sequence set forth in SEQ ID NO. 19, and the antisense strand comprises a sequence set forth in SEQ ID NO. 566; (3) the sense strand comprises a sequence set forth in SEQ ID NO. 20, and the antisense strand comprises a sequence set forth in SEQ ID NO. 567; (4) the sense strand comprises a sequence set forth in SEQ ID NO. 24, and the antisense strand comprises a sequence set forth in SEQ ID NO. 571; (5) the sense strand comprises a sequence set forth in SEQ ID NO. 32, and the antisense strand comprises a sequence set forth in SEQ ID NO. 579; (6) the sense strand comprises a sequence set forth in SEQ ID NO. 33, and the antisense strand comprises a sequence set forth in SEQ ID NO. 580; (7) the sense strand comprises a sequence set forth in SEQ ID NO. 36, and the antisense strand comprises a sequence set forth in SEQ ID NO. 583; (8) the sense strand comprises a sequence set forth in SEQ ID NO. 38, and the antisense strand comprises a sequence set forth in SEQ ID NO. 585; (9) the sense strand comprises a sequence set forth in SEQ ID NO. 40, and the antisense strand comprises a sequence set forth in SEQ ID NO. 587; (10) the sense strand comprises a sequence set forth in SEQ ID NO. 42, and the antisense strand comprises a sequence set forth in SEQ ID NO. 589; (11) the sense strand comprises a sequence set forth in SEQ ID NO. 43, and the antisense strand comprises a sequence set forth in SEQ ID NO. 590; (12) the sense strand comprises the sequence set forth in SEQ ID NO. 45, and the antisense strand comprises the sequence set forth in SEQ ID NO. 592; (13) the sense strand comprises the sequence set forth in SEQ ID NO. 46, and the antisense strand comprises the sequence set forth in SEQ ID NO. 593; (14) the sense strand comprises the sequence set forth in SEQ ID NO. 49, and the antisense strand comprises the sequence set forth in SEQ ID NO. 596; (15) the sense strand comprises the sequence set forth in SEQ ID NO. 52, and the antisense strand comprises the sequence set forth in SEQ ID NO. 599; (16) the sense strand comprises the sequence set forth in SEQ ID NO. 54, and the antisense strand comprises the sequence set forth in SEQ ID NO. 601; (17) the sense strand comprises the sequence set forth in SEQ ID NO. 56, and the antisense strand comprises the sequence set forth in SEQ ID NO. 603; (18) the sense strand comprises the sequence set forth in SEQ ID NO. 57, and the antisense strand comprises the sequence set forth in SEQ ID NO. 604; (19) the sense strand comprises the sequence set forth in SEQ ID NO. 61, and the antisense strand comprises the sequence set forth in SEQ ID NO. 608; (20) the sense strand comprises the sequence set forth in SEQ ID NO. 64, and the antisense strand comprises the sequence set forth in SEQ ID NO. 611; (21) the sense strand comprises the sequence set forth in SEQ ID NO. 73, and the antisense strand comprises the sequence set forth in SEQ ID NO. 620; (22) the sense strand comprises the sequence set forth in SEQ ID NO. 74, and the antisense strand comprises the sequence set forth in SEQ ID NO. 621; (23) the sense strand comprises the sequence set forth in SEQ ID NO. 75, and the antisense strand comprises the sequence set forth in SEQ ID NO. 622; (24) the sense strand comprises the sequence set forth in SEQ ID NO. 76, and the antisense strand comprises the sequence set forth in SEQ ID NO. 623; (25) the sense strand comprises the sequence set forth in SEQ ID NO. 79, and the antisense strand comprises the sequence set forth in SEQ ID NO. 626; (26) the sense strand comprises the sequence set forth in SEQ ID NO. 80, and the antisense strand comprises the sequence set forth in SEQ ID NO. 627; (27) the sense strand comprises the sequence set forth in SEQ ID NO. 84, and the antisense strand comprises the sequence set forth in SEQ ID NO. 631; (28) the sense strand comprises the sequence set forth in SEQ ID NO. 86, and the antisense strand comprises the sequence set forth in SEQ ID NO. 633; (29) The sense chain comprises the sequence shown in SEQ ID NO.91, and the antisense chain comprises the sequence shown in SEQ ID NO.638; (30) The sense chain comprises the sequence shown in SEQ ID NO.102, and the antisense chain comprises the sequence shown in SEQ ID NO.649; (31) The sense chain comprises the sequence shown in SEQ ID NO.122, and the antisense chain comprises the sequence shown in SEQ ID NO.669; (32) The sense chain comprises the sequence shown in SEQ ID NO.131, and the antisense chain comprises the sequence shown in SEQ ID NO.678; (33) The sense chain comprises the sequence shown in SEQ ID NO.132, and the antisense chain comprises the sequence shown in SEQ ID NO.679; (34) The sense chain comprises the sequence shown in SEQ ID NO.135, and the antisense chain comprises the sequence shown in SEQ ID NO.682; (35) The sense chain comprises the sequence shown in SEQ ID NO.136, and the antisense chain comprises the sequence shown in SEQ ID NO.683; (36) The sense chain comprises the sequence shown in SEQ ID NO.144, and the antisense chain comprises the sequence shown in SEQ ID NO.691; (37) The sense chain comprises the sequence shown in SEQ ID NO.151, and the antisense chain comprises the sequence shown in SEQ ID NO.698; (38) The sense chain comprises the sequence shown in SEQ ID NO.155, and the antisense chain comprises the sequence shown in SEQ ID NO.702; (39) The sense chain comprises the sequence shown in SEQ ID NO.163, and the antisense chain comprises the sequence shown in SEQ ID NO.710; (40) The sense chain comprises the sequence shown in SEQ ID NO.164, and the antisense chain comprises the sequence shown in SEQ ID NO.711; (41) The positive chain contains the sequence shown in SEQ ID NO.198, and the negative chain contains the sequence shown in SEQ ID NO.745; (42) The sense chain comprises the sequence shown in SEQ ID NO.230, and the antisense chain comprises the sequence shown in SEQ ID NO.777; (43) The sense chain comprises the sequence shown in SEQ ID NO.246, and the antisense chain comprises the sequence shown in SEQ ID NO.793; (44) The sense chain comprises the sequence shown in SEQ ID NO. 254, and the antisense chain comprises the sequence shown in SEQ ID NO. 801; and (45) The positive chain contains the sequence shown in SEQ ID NO.257, and the negative chain contains the sequence shown in SEQ ID NO.

804.

7. The oligonucleotide or a pharmaceutically acceptable salt thereof of any one of claims 1-6, wherein, The oligonucleotide comprises any of the following combinations of sense and antisense strands: (1) the sense strand comprises the sequence set forth in SEQ ID NO. 1098, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1357; (2) the sense strand comprises the sequence set forth in SEQ ID NO. 1103, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1362; (3) the sense strand comprises the sequence set forth in SEQ ID NO. 1108, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1367; (4) the sense strand comprises the sequence set forth in SEQ ID NO. 1111, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1370; (5) the sense strand comprises the sequence set forth in SEQ ID NO. 1113, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1372; (6) the sense strand comprises the sequence set forth in SEQ ID NO. 1114, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1373; (7) the sense strand comprises the sequence set forth in SEQ ID NO. 1115, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1374; (8) the sense strand comprises the sequence set forth in SEQ ID NO. 1118, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1377; (9) the sense strand comprises the sequence set forth in SEQ ID NO. 1119, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1378; (10) the sense strand comprises the sequence set forth in SEQ ID NO. 1120, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1379; (11) the sense strand comprises the sequence set forth in SEQ ID NO. 1127, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1386; (12) the sense strand comprises the sequence set forth in SEQ ID NO. 1128, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1387; (13) the sense strand comprises the sequence set forth in SEQ ID NO. 1131, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1390; (14) the sense strand comprises the sequence set forth in SEQ ID NO. 1133, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1392; (15) the sense strand comprises the sequence set forth in SEQ ID NO. 1134, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1393; (16) the sense strand comprises the sequence set forth in SEQ ID NO. 1135, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1394; (17) the sense strand comprises the sequence set forth in SEQ ID NO. 1137, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1396; (18) the sense strand comprises the sequence set forth in SEQ ID NO. 1138, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1397; (19) the sense strand comprises the sequence set forth in SEQ ID NO. 1139, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1398; (20) the sense strand comprises the sequence set forth in SEQ ID NO. 1140, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1399; (21) the sense strand comprises the sequence set forth in SEQ ID NO. 1141, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1400; (22) the sense strand comprises the sequence set forth in SEQ ID NO. 1144, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1403; (23) the sense strand comprises the sequence set forth in SEQ ID NO. 1146, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1405; (24) the sense strand comprises the sequence set forth in SEQ ID NO. 1147, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1406; (25) the sense strand comprises the sequence set forth in SEQ ID NO. 1148, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1407; (26) the sense strand comprises the sequence set forth in SEQ ID NO. 1149, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1408; (27) the sense strand comprises the sequence set forth in SEQ ID NO. 1150, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1409; (28) the sense strand comprises the sequence set forth in SEQ ID NO. 1151, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1410; (29) the sense strand comprises the sequence set forth in SEQ ID NO. 1152, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1411; (30) the sense strand comprises the sequence set forth in SEQ ID NO. 1155, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1414; (31) the sense strand comprises the sequence set forth in SEQ ID NO. 1156, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1415; (32) the sense strand comprises the sequence set forth in SEQ ID NO. 1158, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1417; (33) the sense strand comprises the sequence set forth in SEQ ID NO. 1159, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1418; (34) the sense strand comprises the sequence set forth in SEQ ID NO. 1160, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1419; (35) the sense strand comprises the sequence set forth in SEQ ID NO. 1162, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1421; (36) the sense strand comprises the sequence set forth in SEQ ID NO. 1163, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1422; (37) the sense strand comprises the sequence set forth in SEQ ID NO. 1164, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1423; (38) the sense strand comprises the sequence set forth in SEQ ID NO. 1165, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1424; (39) the sense strand comprises the sequence set forth in SEQ ID NO. 1166, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1425; (40) the sense strand comprises the sequence set forth in SEQ ID NO. 1167, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1426; (41) the sense strand comprises the sequence set forth in SEQ ID NO. 1168, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1427; (42) the sense strand comprises the sequence set forth in SEQ ID NO. 1169, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1428; (43) the sense strand comprises the sequence set forth in SEQ ID NO. 1170, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1429; (44) the sense strand comprises the sequence set forth in SEQ ID NO. 1171, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1430; (45) the sense strand comprises the sequence set forth in SEQ ID NO. 1172, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1431; (46) the sense strand comprises the sequence set forth in SEQ ID NO. 1173, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1432; (47) the sense strand comprises the sequence set forth in SEQ ID NO. 1174, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1433; (48) the sense strand comprises the sequence set forth in SEQ ID NO. 1175, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1434; (49) the sense strand comprises the sequence set forth in SEQ ID NO. 1176, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1435; (50) the sense strand comprises the sequence set forth in SEQ ID NO. 1177, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1436; (51) the sense strand comprises the sequence set forth in SEQ ID NO. 1178, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1437; (52) the sense strand comprises the sequence set forth in SEQ ID NO. 1179, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1438; (53) the sense strand comprises the sequence set forth in SEQ ID NO. 1180, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1439; (54) the sense strand comprises the sequence set forth in SEQ ID NO. 1181, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1440; (55) the sense strand comprises the sequence set forth in SEQ ID NO. 1182, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1441; (56) the sense strand comprises the sequence set forth in SEQ ID NO. 1183, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1442; (57) the sense strand comprises the sequence set forth in SEQ ID NO. 1184, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1443; (58) the sense strand comprises the sequence set forth in SEQ ID NO. 1185, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1444; (59) the sense strand comprises the sequence set forth in SEQ ID NO. 1115, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1643; (60) the sense strand comprises the sequence set forth in SEQ ID NO. 1127, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1644; (61) the sense strand comprises the sequence set forth in SEQ ID NO. 1128, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1645; (62) the sense strand comprises the sequence set forth in SEQ ID NO. 1128, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1663; (63) the sense strand comprises the sequence set forth in SEQ ID NO. 1144, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1646; (64) the sense strand comprises the sequence set forth in SEQ ID NO. 1159, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1647; (65) the sense strand comprises the sequence set forth in SEQ ID NO. 1169, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1648; (66) the sense strand comprises the sequence set forth in SEQ ID NO. 1170, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1649; (67) the sense strand comprises the sequence set forth in SEQ ID NO. 1171, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1650; (68) the sense strand comprises the sequence set forth in SEQ ID NO. 1179, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1651; (69) the sense strand comprises the sequence set forth in SEQ ID NO. 1181, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1652; (70) the sense strand comprises the sequence set forth in SEQ ID NO. 1186, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1445; (71) the sense strand comprises the sequence set forth in SEQ ID NO. 1186, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1653; (72) the sense strand comprises the sequence set forth in SEQ ID NO. 1226, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1485; (73) the sense strand comprises the sequence set forth in SEQ ID NO. 1226, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1654; (74) the sense strand comprises the sequence set forth in SEQ ID NO. 1227, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1486; (75) the sense strand comprises the sequence set forth in SEQ ID NO. 1227, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1655; (76) the sense strand comprises the sequence set forth in SEQ ID NO. 1230, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1489; (77) the sense strand comprises the sequence set forth in SEQ ID NO. 1230, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1656; (78) the sense strand comprises the sequence set forth in SEQ ID NO. 1231, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1490; (79) the sense strand comprises the sequence set forth in SEQ ID NO. 1239, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1498; (80) the sense strand comprises the sequence set forth in SEQ ID NO. 1246, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1505; (81) the sense strand comprises the sequence set forth in SEQ ID NO. 1250, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1509; (82) the sense strand comprises the sequence set forth in SEQ ID NO. 1250, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1657; (83) the sense strand comprises the sequence set forth in SEQ ID NO. 1258, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1517; (84) the sense strand comprises the sequence set forth in SEQ ID NO. 1293, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1552; (85) the sense strand comprises the sequence set forth in SEQ ID NO. 1325, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1584; (86) the sense strand comprises the sequence set forth in SEQ ID NO. 1325, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1659; (87) the sense strand comprises the sequence set forth in SEQ ID NO. 1341, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1600; (88) the sense strand comprises the sequence set forth in SEQ ID NO. 1352, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1611; (89) the sense strand comprises the sequence set forth in SEQ ID NO. 1613, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1665; (90) the sense strand comprises the sequence set forth in SEQ ID NO. 1613, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1674; (91) the sense strand comprises the sequence set forth in SEQ ID NO. 1614, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1666; (92) the sense strand comprises the sequence set forth in SEQ ID NO. 1614, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1679; (93) the sense strand comprises the sequence set forth in SEQ ID NO. 1615, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1667; (94) the sense strand comprises the sequence set forth in SEQ ID NO. 1615, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1685; (95) the sense strand comprises the sequence set forth in SEQ ID NO. 1618, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1670; (96) the sense strand comprises the sequence set forth in SEQ ID NO. 1618, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1689; (97) the sense strand comprises the sequence set forth in SEQ ID NO. 1618, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1690; (98) the sense strand comprises the sequence set forth in SEQ ID NO. 1619, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1671; (99) the sense strand comprises the sequence set forth in SEQ ID NO. 1620, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1672; (100) the sense strand comprises the sequence set forth in SEQ ID NO. 1620, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1694; (101) the sense strand comprises the sequence set forth in SEQ ID NO. 1620, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1695; (102) the sense strand comprises the sequence set forth in SEQ ID NO. 1622, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1677; (103) the sense strand comprises the sequence set forth in SEQ ID NO. 1622, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1678; (104) the sense strand comprises the sequence set forth in SEQ ID NO. 1623, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1682; (105) the sense strand comprises the sequence set forth in SEQ ID NO. 1624, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1686; (106) the sense strand comprises the sequence set forth in SEQ ID NO. 1624, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1687; (107) the sense strand comprises the sequence set forth in SEQ ID NO. 1624, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1688; (108) the sense strand comprises the sequence set forth in SEQ ID NO. 1625, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1691; (109) the sense strand comprises the sequence set forth in SEQ ID NO. 1625, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1692; (110) the sense strand comprises the sequence set forth in SEQ ID NO. 1625, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1693; (111) the sense strand comprises the sequence set forth in SEQ ID NO. 1626, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1696; (112) the sense strand comprises the sequence set forth in SEQ ID NO. 1626, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1697; (113) the sense strand comprises the sequence set forth in SEQ ID NO. 1626, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1698; (114) the sense strand comprises a sequence set forth in SEQ ID NO. 1627, and the antisense strand comprises a sequence set forth in SEQ ID NO. 1699; (115) the sense strand comprises a sequence set forth in SEQ ID NO. 1627, and the antisense strand comprises a sequence set forth in SEQ ID NO. 1700; (116) the sense strand comprises a sequence set forth in SEQ ID NO. 1627, and the antisense strand comprises a sequence set forth in SEQ ID NO. 1701 ; (117) the sense strand comprises a sequence set forth in SEQ ID NO. 1628, and the antisense strand comprises a sequence set forth in SEQ ID NO. 1702; (118) the sense strand comprises a sequence set forth in SEQ ID NO. 1628, and the antisense strand comprises a sequence set forth in SEQ ID NO. 1703; (119) the sense strand comprises a sequence set forth in SEQ ID NO. 1628, and the antisense strand comprises a sequence set forth in SEQ ID NO. 1704; (120) the sense strand comprises a sequence set forth in SEQ ID NO. 1633, and the antisense strand comprises a sequence set forth in SEQ ID NO. 1714; (121) the sense strand comprises a sequence set forth in SEQ ID NO. 1633, and the antisense strand comprises a sequence set forth in SEQ ID NO. 1715; (122) the sense strand comprises a sequence set forth in SEQ ID NO. 1634, and the antisense strand comprises a sequence set forth in SEQ ID NO. 1716; (123) the sense strand comprises a sequence set forth in SEQ ID NO. 1637, and the antisense strand comprises a sequence set forth in SEQ ID NO. 1721 ; (124) the sense strand comprises a sequence set forth in SEQ ID NO. 1638, and the antisense strand comprises a sequence set forth in SEQ ID NO. 1722; and (125) the sense strand comprises a sequence set forth in SEQ ID NO. 1640, and the antisense strand comprises a sequence set forth in SEQ ID NO. 1725; Preferably, the oligonucleotide comprises any one of a sense strand and an antisense strand combination selected from: (1) the sense strand comprises a sequence set forth in SEQ ID NO. 1113, and the antisense strand comprises a sequence set forth in SEQ ID NO. 1372; (2) the sense strand comprises a sequence set forth in SEQ ID NO. 1115, and the antisense strand comprises a sequence set forth in SEQ ID NO. 1374; (3) the sense strand comprises a sequence set forth in SEQ ID NO. 1115, and the antisense strand comprises a sequence set forth in SEQ ID NO. 1643; (4) the sense strand comprises a sequence set forth in SEQ ID NO. 1119, and the antisense strand comprises a sequence set forth in SEQ ID NO. 1378; (5) the sense strand comprises the sequence set forth in SEQ ID NO. 1127, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1386; (6) the sense strand comprises the sequence set forth in SEQ ID NO. 1127, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1644; (7) the sense strand comprises the sequence set forth in SEQ ID NO. 1128, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1387; (8) the sense strand comprises the sequence set forth in SEQ ID NO. 1128, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1645; (9) the sense strand comprises the sequence set forth in SEQ ID NO. 1128, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1663; (10) the sense strand comprises the sequence set forth in SEQ ID NO. 1133, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1392; (11) the sense strand comprises the sequence set forth in SEQ ID NO. 1135, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1394; (12) the sense strand comprises the sequence set forth in SEQ ID NO. 1137, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1396; (13) the sense strand comprises the sequence set forth in SEQ ID NO. 1138, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1397; (14) the sense strand comprises the sequence set forth in SEQ ID NO. 1140, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1399; (15) the sense strand comprises the sequence set forth in SEQ ID NO. 1141, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1400; (16) the sense strand comprises the sequence set forth in SEQ ID NO. 1144, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1403; (17) the sense strand comprises the sequence set forth in SEQ ID NO. 1144, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1646; (18) the sense strand comprises the sequence set forth in SEQ ID NO. 1149, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1408; (19) the sense strand comprises the sequence set forth in SEQ ID NO. 1151, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1410; (20) the sense strand comprises the sequence set forth in SEQ ID NO. 1156, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1415; (21) the sense strand comprises the sequence set forth in SEQ ID NO. 1159, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1418; (22) the sense strand comprises the sequence set forth in SEQ ID NO. 1159, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1647; (23) the sense strand comprises the sequence set forth in SEQ ID NO. 1168, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1427; (24) the sense strand comprises the sequence set forth in SEQ ID NO. 1169, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1428; (25) the sense strand comprises the sequence set forth in SEQ ID NO. 1169, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1648; (26) the sense strand comprises the sequence set forth in SEQ ID NO. 1170, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1429; (27) the sense strand comprises the sequence set forth in SEQ ID NO. 1170, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1649; (28) the sense strand comprises the sequence set forth in SEQ ID NO. 1171, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1430; (29) the sense strand comprises the sequence set forth in SEQ ID NO. 1171, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1650; (30) the sense strand comprises the sequence set forth in SEQ ID NO. 1174, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1433; (31) the sense strand comprises the sequence set forth in SEQ ID NO. 1175, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1434; (32) the sense strand comprises the sequence set forth in SEQ ID NO. 1179, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1438; (33) the sense strand comprises the sequence set forth in SEQ ID NO. 1179, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1651; (34) the sense strand comprises the sequence set forth in SEQ ID NO. 1181, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1440; (35) the sense strand comprises the sequence set forth in SEQ ID NO. 1181, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1652; (36) the sense strand comprises the sequence set forth in SEQ ID NO. 1186, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1445; (37) the sense strand comprises the sequence set forth in SEQ ID NO. 1186, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1653; (38) the sense strand comprises the sequence set forth in SEQ ID NO. 1226, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1485; (39) the sense strand comprises the sequence set forth in SEQ ID NO. 1226, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1654; (40) the sense strand comprises the sequence set forth in SEQ ID NO. 1227, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1486; (41) the sense strand comprises the sequence set forth in SEQ ID NO. 1227, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1655; (42) the sense strand comprises the sequence set forth in SEQ ID NO. 1230, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1489; (43) the sense strand comprises the sequence set forth in SEQ ID NO. 1230, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1656; (44) the sense strand comprises the sequence set forth in SEQ ID NO. 1231, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1490; (45) the sense strand comprises the sequence set forth in SEQ ID NO. 1239, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1498; (46) the sense strand comprises the sequence set forth in SEQ ID NO. 1246, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1505; (47) the sense strand comprises the sequence set forth in SEQ ID NO. 1250, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1509; (48) the sense strand comprises the sequence set forth in SEQ ID NO. 1250, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1657; (49) the sense strand comprises the sequence set forth in SEQ ID NO. 1258, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1517; (50) the sense strand comprises the sequence set forth in SEQ ID NO. 1293, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1552; (51) the sense strand comprises the sequence set forth in SEQ ID NO. 1325, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1584; (52) the sense strand comprises the sequence set forth in SEQ ID NO. 1325, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1659; (53) the sense strand comprises the sequence set forth in SEQ ID NO. 1341, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1600; (54) the sense strand comprises the sequence set forth in SEQ ID NO. 1352, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1611; (55) the sense strand comprises the sequence set forth in SEQ ID NO. 1613, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1665; (56) the sense strand comprises the sequence set forth in SEQ ID NO. 1613, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1674; (57) the sense strand comprises the sequence set forth in SEQ ID NO. 1614, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1666; (58) the sense strand comprises the sequence set forth in SEQ ID NO. 1614, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1679; (59) the sense strand comprises the sequence set forth in SEQ ID NO. 1615, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1667; (60) the sense strand comprises the sequence set forth in SEQ ID NO. 1615, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1685; (61) the sense strand comprises the sequence set forth in SEQ ID NO. 1618, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1670; (62) the sense strand comprises the sequence set forth in SEQ ID NO. 1618, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1689; (63) the sense strand comprises the sequence set forth in SEQ ID NO. 1618, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1690; (64) the sense strand comprises the sequence set forth in SEQ ID NO. 1619, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1671; (65) the sense strand comprises the sequence set forth in SEQ ID NO. 1620, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1672; (66) the sense strand comprises the sequence set forth in SEQ ID NO. 1620, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1694; (67) the sense strand comprises the sequence set forth in SEQ ID NO. 1620, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1695; (68) the sense strand comprises the sequence set forth in SEQ ID NO. 1622, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1677; (69) the sense strand comprises the sequence set forth in SEQ ID NO. 1622, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1678; (70) the sense strand comprises the sequence set forth in SEQ ID NO. 1623, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1682; (71) the sense strand comprises the sequence set forth in SEQ ID NO. 1624, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1686; (72) the sense strand comprises the sequence set forth in SEQ ID NO. 1624, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1687; (73) the sense strand comprises the sequence set forth in SEQ ID NO. 1624, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1688; (74) the sense strand comprises the sequence set forth in SEQ ID NO. 1625, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1691; (75) the sense strand comprises the sequence set forth in SEQ ID NO. 1625, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1692; (76) the sense strand comprises the sequence set forth in SEQ ID NO. 1625, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1693; (77) the sense strand comprises the sequence set forth in SEQ ID NO. 1626, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1696; (78) the sense strand comprises the sequence set forth in SEQ ID NO. 1626, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1697; (79) the sense strand comprises the sequence set forth in SEQ ID NO. 1626, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1698; (80) the sense strand comprises the sequence set forth in SEQ ID NO. 1627, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1699; (81) the sense strand comprises the sequence set forth in SEQ ID NO. 1627, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1700; (82) the sense strand comprises the sequence set forth in SEQ ID NO. 1627, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1701; (83) the sense strand comprises the sequence set forth in SEQ ID NO. 1628, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1702; (84) the sense strand comprises the sequence set forth in SEQ ID NO. 1628, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1703; (85) the sense strand comprises the sequence set forth in SEQ ID NO. 1628, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1704; (86) the sense strand comprises the sequence set forth in SEQ ID NO. 1633, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1714; (87) the sense strand comprises the sequence set forth in SEQ ID NO. 1633, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1715; (88) the sense strand comprises the sequence set forth in SEQ ID NO. 1634, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1716; (89) the sense strand comprises the sequence set forth in SEQ ID NO. 1637, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1721; (90) the sense strand comprises the sequence set forth in SEQ ID NO. 1638, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1722; and (91) the sense strand comprises the sequence set forth in SEQ ID NO. 1640, and the antisense strand comprises the sequence set forth in SEQ ID NO. 1725.

8. A conjugate for inhibiting PMP22 expression, or a pharmaceutically acceptable salt thereof, comprising: (i) the oligonucleotide of any one of claims 1-7 or a pharmaceutically acceptable salt thereof, and (ii) a targeting ligand and / or a lipophilic moiety, wherein at least one of the sense strand and the antisense strand of the oligonucleotide is conjugated to the targeting ligand and / or at least one of the sense strand and the antisense strand of the oligonucleotide is conjugated to one or more of the lipophilic moieties; Preferably, the targeting ligand comprises an N-acetylgalactosamine (GalNAc) moiety; preferably, the GalNac moiety is a monovalent GalNAc moiety, a bivalent GalNAc moiety, a trivalent GalNAc moiety or a tetravalent GalNAc moiety; more preferably, the targeting ligand is L96; Preferably, the targeting ligand is conjugated to the 3' end or the 5' end of the sense strand; more preferably, the targeting ligand is conjugated to the 3' end of the sense strand; Preferably, the lipophilic moiety is an aliphatic, alicyclic or polyalicyclic compound; preferably, the lipophilic moiety contains a saturated or unsaturated C16 hydrocarbon chain; Preferably, the lipophilic moiety comprises a lipid moiety; C16, C18, C22, DTX and DSC-003; Preferably, the targeting ligand lipophilic moiety is DTX and DSC-003; Preferably, the lipophilic moiety is located at the 3' end of the sense strand; 9. A composition comprising the oligonucleotide of any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, or the conjugate of claim 8 or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier; Preferably, the dosage form of the composition is an oral dosage, an intravenous injection, a subcutaneous injection, an intramuscular injection, preferably an intravenous injection or a subcutaneous injection; Preferably, the composition further comprises other therapeutic or / and prophylactic agents for PMP22-related disorders.

10. The oligonucleotide of any one of claims 1-7 or a pharmaceutically acceptable salt thereof, the conjugate of claim 8 or the pharmaceutically acceptable salt of the conjugate, or the composition of claim 9 for use in the treatment or / and prevention of PMP22-related disorders; the PMP22-related disorder is selected from Charcot-Marie-Tooth or hereditary motor and sensory neuropathy; Preferably, the PMP22-related disease is selected from Charcot-Marie-Tooth disease type 1A (CMT1A), Charcot-Marie-Tooth disease type 2A (CMT2A), Charcot-Marie-Tooth disease type 1E (CMT1E) or hereditary pressure-sensitive neuropathy (HNPP).

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