Oligonucleotide composition and method of use thereof

Abstract

This invention relates to oligonucleotide compositions and methods for using the same. [Solution] In particular, this disclosure provides designed oligonucleotides, compositions thereof and methods of use. In some embodiments, this disclosure provides techniques useful for reducing transcript levels. In some embodiments, this disclosure provides techniques useful for modulating transcript splicing. In some embodiments, the techniques provided can alter the splicing of dystrophin (DMD) transcripts. In some embodiments, this disclosure provides methods for treating diseases such as Duchenne muscular dystrophy and Becker muscular dystrophy.

Claims

1. 1) Base sequence; 2) Patterns of skeletal connection; 3) Patterns of skeletal chiral centers; and 4) Patterns of skeletal phosphorus modification An oligonucleotide composition comprising multiple oligonucleotides of a specific oligonucleotide type as defined by, The plurality of oligonucleotides comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 chiral controlled internucleotide links; and The plurality of oligonucleotides are oligonucleotide compositions comprising at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 non-negatively charged internucleotide bonds.

2. 1) Base sequence; 2) Patterns of skeletal connection; 3) Patterns of skeletal chiral centers; and 4) Patterns of skeletal phosphorus modification An oligonucleotide composition comprising multiple oligonucleotides of a specific oligonucleotide type as defined by, The plurality of oligonucleotides comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 chiral controlled internucleotide links; and The oligonucleotide composition is characterized in that, when it comes into contact with a transcript in a transcript splicing system, the splicing of the transcript is altered compared to what is observed under reference conditions selected from the group consisting of the absence of the composition, the presence of a reference composition, and combinations thereof.

3. The oligonucleotide according to claim 2, wherein the pattern of the skeletal linkage includes at least one non-negatively charged internucleotide bond.

4. The oligonucleotide composition according to claim 1, wherein when the oligonucleotide composition is brought into contact with a transcript in a transcript splicing system, the splicing of the transcript is altered compared to what is observed under reference conditions selected from the group consisting of the absence of the composition, the presence of a reference composition, and combinations thereof.

5. The oligonucleotide according to any one of claims 1 to 4, wherein one or more non-negatively charged internucleotide bonds are independently chiral-controlled.

6. Non-negative charge internucleotide bonding is represented by formula I: 【Chemistry 1】 (In the formula, P Ｌ P (=W), P or P → B (R') ３ And; W is O, N (-L-R ５ ), S or Se; R １ and R ５ Each of these is independently -H, -L-R', halogen, -CN, -NO ２ , - L-Si(R') ３ , -OR', -SR', or -N(R') ２ And; X is -N(-L-R ５ )-; Each of Y and Z is independently -O-, -S-, -N(-L-R ５ ) - or L; Each L is independently covalently bonded or C １～３０ C having an aliphatic group and 1 to 10 heteroatoms １～３０ A divalent, optionally substituted linear or branched group selected from heteroaliphatic groups, wherein one or more methylene units are optionally and independently C １～６ Alkylene, C １～６ Alkenylene, -C≡C-, divalent carbon having 1 to 5 heteroatoms １ ~C ６ Heteroaliphatic group, -C(R') ２ -, -Cy-, -O-, -S-, -S-S-, -N(R')-, -C(O)-, -C(S)-, -C(NR')-, -C(O)N(R')-, -N(R')C(O)N(R')-, -N(R')C(O)O-, -S(O)-, -S(O) ２ -, -S(O) ２ N(R')-, -C(O)S-, -C(O)O-, -P(O)(OR')-, -P(O)(SR')-, -P(O)(R')-, -P(O)(NR')-, -P(S)(OR')-, -P(S)(SR')-, -P(S)(R')-, -P(S)(NR')-, -P(R')-, -P(OR')-, -P(SR')-, -P(NR')-, -P(OR') [B(R') ３ ]-, -OP(O)(OR')O-, -OP(O)(SR')O-, -OP(O)(R')O-, -OP(O)(NR')O-, -OP(OR')O-, -OP(SR')O-, -OP(NR')O-, -OP(R')O- or -OP(OR') [B(R') ３ ]O- is replaced, and one or more CH or carbon atoms are optionally and independently replaced with Cy Ｌ Replaced with; Each -Cy- is independent of C ３～２０ alicyclic ring, C ６～２０ A divalent group that is optionally substituted, selected from an aryl ring, a 5-20 membered heteroaryl ring having 1-10 heteroatoms, and a 3-20 membered heterocyclyl ring having 1-10 heteroatoms; Each Cy Ｌ Independently, C ３～２０ alicyclic ring, C ６～２０ A trivalent or tetravalent group that is optionally substituted, selected from an aryl ring, a 5-20 membered heteroaryl ring having 1-10 heteroatoms, and a 3-20 membered heterocyclyl ring having 1-10 heteroatoms; Each R' is independently -R, -C(O)R, -C(O)OR, or -S(O) ２ It is R; Each R is independently -H or C １～３０ Aliphatic carbon atoms containing 1 to 10 heteroatoms １～３０ Heteroliphatic, C ６～３０ Ariel, C ６～３０ Aryl aliphatic carbon atoms containing 1 to 10 heteroatoms ６～３０ The group is optionally substituted, selected from aryl heteroaliphatic groups, 5-30 membered heteroaryl rings having 1-10 heteroatoms, and 3-30 membered heterocyclyl rings having 1-10 heteroatoms, or The two R groups can, by choice and independently, come together to form a covalent bond, or Two or more R groups on the same atom may, optionally and independently, combine with the atom to form an optionally substituted 3-30 membered monocyclic, bicyclic, or polycyclic ring having 0-10 heteroatoms in addition to the atom, or Two or more R groups on two or more atoms can be optionally and independently combined with their intercalating atoms to form an optionally substituted 3- to 30-membered monocyclic, bicyclic, or polycyclic ring having 0 to 10 heteroatoms in addition to the intercalating atoms. The composition according to claim 5, or having the structure in the form of a salt thereof.

7. Non-negative charge internucleotide bonding is represented by formula I-n-3: 【Chemistry 2】 (In the formula, P Ｌ P (=W), P or P → B (R') ３ And; W is O, N (-L-R ５ ), S or Se; R １ and R ５ Each of these is independently -H, -L-R', halogen, -CN, -NO ２ , -L-Si(R') ３ , -OR', -SR', or -N(R') ２ And; Each of Y and Z is independently -O-, -S-, -N(-L-R ５ ) - or L; Each L is independently covalently bonded or C １～３０ C having an aliphatic group and 1 to 10 heteroatoms １～３０ A divalent, optionally substituted linear or branched group selected from heteroaliphatic groups, wherein one or more methylene units are optionally and independently C １～６ Alkylene, C １～６ Alkenylene, -C≡C-, divalent carbon having 1 to 5 heteroatoms １ ~C ６ Heteroaliphatic group, -C(R') ２ -, -Cy-, -O-, -S-, -S-S-, -N(R')-, -C(O)-, -C(S)-, -C(NR')-, -C(O)N(R')-, -N(R')C(O)N(R')-, -N(R')C(O)O-, -S(O)-, -S(O) ２ -, -S(O) ２ N(R')-, -C(O)S-, -C(O)O-, -P(O)(OR')-, -P(O)(SR')-, -P(O)(R')-, -P(O)(NR')-, -P(S)(OR')-, -P(S)(SR')-, -P(S)(R')-, -P(S)(NR')-, -P(R')-, -P(OR')-, -P(SR')-, -P(NR')-, -P(OR') [B(R') ３ ]-, -OP(O)(OR')O-, -OP(O)(SR')O-, -OP(O)(R')O-, -OP(O)(NR')O-, -OP(OR')O-, -OP(SR')O-, -OP(NR')O-, -OP(R')O- or -OP(OR') [B(R') ３ ]O- is replaced, and one or more CH or carbon atoms are optionally and independently replaced with Cy Ｌ Replaced with; Each -Cy- is independent of C ３～２０ alicyclic ring, C ６～２０ A divalent group that is optionally substituted, selected from an aryl ring, a 5-20 membered heteroaryl ring having 1-10 heteroatoms, and a 3-20 membered heterocyclyl ring having 1-10 heteroatoms; Each Cy Ｌ Independently, C ３～２０ alicyclic ring, C ６～２０ A trivalent or tetravalent group that is optionally substituted, selected from an aryl ring, a 5-20 membered heteroaryl ring having 1-10 heteroatoms, and a 3-20 membered heterocyclyl ring having 1-10 heteroatoms; Each R' is independently -R, -C(O)R, -C(O)OR, or -S(O) ２ It is R; Each R is independently -H or C １～３０ Aliphatic carbon atoms containing 1 to 10 heteroatoms １～３０ Heteroliphatic, C ６～３０ Ariel, C ６～３０ Aryl aliphatic carbon atoms containing 1 to 10 heteroatoms ６～３０ The group is optionally substituted, selected from aryl heteroaliphatic groups, 5-30 membered heteroaryl rings having 1-10 heteroatoms, and 3-30 membered heterocyclyl rings having 1-10 heteroatoms, or The two R groups can, by choice and independently, come together to form a covalent bond, or Two or more R groups on the same atom may, optionally and independently, combine with the atom to form an optionally substituted 3-30 membered monocyclic, bicyclic, or polycyclic ring having 0-10 heteroatoms in addition to the atom, or Two or more R groups on two or more atoms can be optionally and independently combined with their intercalating atoms to form an optionally substituted 3- to 30-membered monocyclic, bicyclic, or polycyclic ring having 0 to 10 heteroatoms in addition to the intercalating atoms. The composition according to claim 5, or having the structure in the form of a salt thereof.

8. Non-negative charge internucleotide binding is 【Transformation 3】 The composition according to claim 5, having the structure of [the specified structure].

9. The non-negative charge internucleotide bond 【Chemistry 4】 The composition according to claim 8, wherein is chiral controlled and Rp.

10. The composition according to claim 8, wherein the aforementioned transcript is a dystrophin transcript.

11. The composition according to claim 10, wherein the splicing of the transfer is modified to increase the level of skipping of exons 45, 51, or 53 or multiple exons.

12. The composition according to claim 8, wherein each chiral internucleotide bond of the plurality of oligonucleotides is independently a chiral-controlled internucleotide bond.

13. The composition according to claim 8, wherein the base sequence is the base sequence of any oligonucleotide in Table A1, or contains thereof, or contains 15 adjacent bases thereof.

14. The composition according to claim 11, wherein the oligonucleotide type comprises any of the following: cholesterol; L-carnitine (amide and carbamate bonded); folic acid; gumbogic acid; cleavable lipids (1,2-dilaurin and ester bonded); insulin receptor ligand; CPP; glucose (triantenna and hexantenna type); or mannose (triantenna and hexantenna type, α and β).

15. The composition according to claim 11, wherein each non-negatively charged internucleotide bond is independently an internucleotide bond, and at least 50% of them are internucleotide bonds that exist in their non-negatively charged form at pH 7.

4.

16. The composition according to claim 11, wherein each of the plurality of oligonucleotides comprises one or more sugar modifications.

17. The composition according to claim 16, wherein one or more sugar modifications are 2'-F modifications.

18. The composition according to any one of claims 1 to 17, wherein each heteroatom is independently boron, nitrogen, oxygen, silicon, sulfur, or phosphorus.

19. A pharmaceutical composition comprising an oligonucleotide composition according to any one of claims 1 to 18 and a pharmaceutically acceptable carrier.

20. A method for altering the splicing of a target transcript, comprising administering an oligonucleotide composition according to any one of claims 1 to 18.

21. The method according to claim 20, wherein the target transcript is the premRNA of dystrophin.

22. The method according to claim 21, wherein exon 45 of dystrophin is skipped at an increased level compared to when the composition is absent.

23. The method according to claim 21, wherein exon 51 of dystrophin is skipped at an increased level compared to when the composition is not present.

24. The method according to claim 21, wherein exon 53 of dystrophin is skipped at an increased level compared to when the composition is not present.

25. A method for treating muscular dystrophy, Duchenne muscular dystrophy (DMD), or Becker muscular dystrophy (BMD), comprising administering a composition according to any one of claims 1 to 19 to a subject who is susceptible to or suffering from the same.

26. A method for preparing an oligonucleotide or an oligonucleotide composition thereof, wherein the oligonucleotide comprises one or more non-negatively charged internucleotide bonds, and the method is 【Transformation 5】 (In the formula, R ５ｓ These are independently R' or -OR'; Each BA is independent of C ３～３０ alicyclic, C ６～３０ Aryl, C having 1 to 10 heteroatoms ５～３０ Heteroaryls, C having 1 to 10 heteroatoms ３～３０ A group that is optionally substituted, selected from heterocyclines, native nucleic acid base moieties, and modified nucleic acid base moieties; Each R ｓ These are independently -H, halogen, -CN, and -N ３ , -NO, -NO ２ , -LR', -L-Si(R) ３ , -L-OR', -L-SR', -L-N(R') ２ , -O-L-R', -O-L-Si(R) ３ , -OL-OR', -OL-SR' or -OL-N(R') ２ And; Each s is independently between 0 and 20; Each L ｓ Independently, -C(R ５ｓ ) ２ - or L; Each L is independently covalently bonded or C １～３０ C having an aliphatic group and 1 to 10 heteroatoms １～３０ A divalent, optionally substituted linear or branched group selected from heteroaliphatic groups, wherein one or more methylene units are optionally and independently C １～６ Alkylene, C １～６ Alkenylene, -C≡C-, divalent carbon having 1 to 5 heteroatoms １ ~C ６ Heteroaliphatic group, -C(R') ２ -, -Cy-, -O-, -S-, -S-S-, -N(R')-, -C(O)-, -C(S)-, -C(NR')-, -C(O)N(R')-, -N(R')C(O)N(R')-, -N(R')C(O)O-, -S(O)-, -S(O) ２ -, -S(O) ２ N(R')-, -C(O)S-, -C(O)O-, -P(O)(OR')-, -P(O)(SR')-, -P(O)(R')-, -P(O)(NR')-, - P(S)(OR')-, -P(S)(SR')-, -P(S)(R')-, -P(S)(NR')-, -P(R')-, -P(OR')-, -P(SR')- , -P(NR')-, -P(OR')[B(R') ３ -, -OP(O)(OR')O-, -OP(O)(SR')O-, -OP(O)(R')O-, -OP(O)(NR')O-, -OP(OR')O-, -OP(SR')O-, -OP(NR')O-, -OP(R')O- or -OP(OR')[B(R') ３ O- is replaced, and one or more CH or carbon atoms are optionally and independently replaced by Cy Ｌ ; Each -Cy- is independent of C ３～２０ alicyclic ring, C ６～２０ A divalent group that is optionally substituted, selected from an aryl ring, a 5-20 membered heteroaryl ring having 1-10 heteroatoms, and a 3-20 membered heterocyclyl ring having 1-10 heteroatoms; Each Cy Ｌ is, independently, C ３～２０ an alicyclic ring, C ６～２０ an aryl ring, a 5- to 20-membered heteroaryl ring having 1 to 10 heteroatoms, and a 3- to 20-membered heterocyclyl ring having 1 to 10 heteroatoms, which is an optionally substituted trivalent or tetravalent group selected from; Each ring A is an optionally substituted 3-20 membered monocyclic, bicyclic, or polycyclic ring having 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon; G １ G ２ G ３ G ４ G ５ and G ８ Each of them independently, R １ And; Each R １ These are independently -H, -L-R', halogen, -CN, and -NO ２ , -L-Si(R') ３ , -OR', -SR', or -N(R') ２ And; Each R' is independently -R, -C(O)R, -C(O)OR, or -S(O) ２ It is R; Each R is independently -H or C １～３０ Aliphatic carbon atoms containing 1 to 10 heteroatoms １～３０ Heteroliphatic, C ６～３０ Ariel, C ６～３０ Aryl aliphatic carbon atoms containing 1 to 10 heteroatoms ６～３０ The group is optionally substituted, selected from aryl heteroaliphatic groups, 5-30 membered heteroaryl rings having 1-10 heteroatoms, and 3-30 membered heterocyclyl rings having 1-10 heteroatoms, or The two R groups can, by choice and independently, come together to form a covalent bond, or Two or more R groups on the same atom may, optionally and independently, combine with the atom to form an optionally substituted 3-30 membered monocyclic, bicyclic, or polycyclic ring having 0-10 heteroatoms in addition to the atom, or Two or more R groups on two or more atoms may optionally and independently combine with their intervening atoms to form optionally substituted 3- to 30-membered monocyclic, bicyclic, or polycyclic rings having 0 to 10 heteroatoms in addition to the intervening atoms; and G ２ (This includes electron-withdrawing groups.) A method comprising providing a phosphoramidite compound or a salt thereof having the structure of [the specified structure].

27. G ５ And, G ３ and G ４ On the other hand, together with -NG ５ The method according to claim 26, wherein a optionally substituted 3- to 8-membered saturated ring is formed, having 0 to 3 heteroatoms in addition to the negative nitrogen.

28. The aforementioned nucleic acid is 【Transformation 6】 The method according to claim 26, comprising an internucleotide bond having the structure.

29. G ２ The method according to any one of claims 26 to 28, wherein the method includes an electron-withdrawing group.

30. G ２ is -L'-S(O) ２ R' is used, and in the formula, L' is substituted by choice. CH ２ - The method according to claim 29.

31. R' is C which has been replaced by arbitrary choice. １～６ The method according to claim 30, wherein the material is aliphatic.

32. The method according to claim 30, wherein R' is t-butyl.

33. The method according to claim 30, wherein R' is a phenyl compound that is optionally substituted.

34. The method according to claim 30, wherein R' is phenyl.

35. One or more cycles, each independently, 1) Deprotection; 2) Coupling; 3) Optional first capping; 4) Modification; and 5) Optional second capping The method according to claim 29, comprising one or more cycles including or consisting of.

36. Formula III: 【Transformation 7】 (In the formula, P Ｎ P(=N-L-R) ５ ), 【Transformation 8】 And; Q － is an anion; R １ and R ５ Each of these is independently -H, -L-R', halogen, -CN, -NO ２ , -L-Si(R') ３ , -OR', -SR', or -N(R') ２ And; Each of Y and Z is independently -O-, -S-, -N(-L-R ５ ) - or L; Each L is independently covalently bonded or C １～３０ C having an aliphatic group and 1 to 10 heteroatoms １～３０ A divalent, optionally substituted linear or branched group selected from heteroaliphatic groups, wherein one or more methylene units are optionally and independently C １～６ Alkylene, C １～６ Alkenylene, -C≡C-, divalent carbon having 1 to 5 heteroatoms １ ~C ６ Heteroaliphatic group, -C(R') ２ -, -Cy-, -O-, -S-, -S-S-, -N(R')-, -C(O)-, -C(S)-, -C(NR')-, -C(O)N(R')-, -N(R')C(O)N(R')-, -N(R')C(O)O-, -S(O)-, -S(O) ２ -, -S(O) ２ N(R')-, -C(O)S-, -C(O)O-, -P(O)(OR')-, -P(O)(SR')-, -P(O)(R')-, -P(O)(NR')-, -P(S)(OR')-, -P(S)(SR')-, -P(S)(R')-, -P(S)(NR')-, -P(R')-, -P(OR')-, -P(SR')-, -P(NR')-, -P(OR') [B(R') ３ ]-, -OP(O)(OR')O-, -OP(O)(SR')O-, -OP(O)(R')O-, -OP(O)(NR')O -, -OP(OR')O-, -OP(SR')O-, -OP(NR')O-, -OP(R')O- or -OP(OR')[B(R') ３ ]O- is replaced, and one or more CH or carbon atoms are optionally and independently replaced with Cy Ｌ Replaced with; Each -Cy- is independent of C ３～２０ alicyclic ring, C ６～２０ A divalent group that is optionally substituted, selected from an aryl ring, a 5-20 membered heteroaryl ring having 1-10 heteroatoms, and a 3-20 membered heterocyclyl ring having 1-10 heteroatoms; Each Cy Ｌ Independently, C ３～２０ alicyclic ring, C ６～２０ A trivalent or tetravalent group that is optionally substituted, selected from an aryl ring, a 5-20 membered heteroaryl ring having 1-10 heteroatoms, and a 3-20 membered heterocyclyl ring having 1-10 heteroatoms; Each R' is independently -R, -C(O)R, -C(O)OR, or -S(O) ２ It is R; Each R is independently -H or C １～３０ Aliphatic carbon atoms containing 1 to 10 heteroatoms １～３０ Heteroliphatic, C ６～３０ Ariel, C ６～３０ Aryl aliphatic carbon atoms containing 1 to 10 heteroatoms ６～３０ The group is optionally substituted, selected from aryl heteroaliphatic groups, 5-30 membered heteroaryl rings having 1-10 heteroatoms, and 3-30 membered heterocyclyl rings having 1-10 heteroatoms, or The two R groups can, by choice and independently, come together to form a covalent bond, or Two or more R groups on the same atom may, optionally and independently, combine with the atom to form an optionally substituted 3-30 membered monocyclic, bicyclic, or polycyclic ring having 0-10 heteroatoms in addition to the atom, or Two or more R groups on two or more atoms may optionally and independently combine with their intervening atoms to form optionally substituted 3- to 30-membered monocyclic, bicyclic, or polycyclic rings having 0 to 10 heteroatoms in addition to the intervening atoms; and -X-L-R １ teeth, 【Chemistry 9】 (In the formula, G ２ (This includes electron-withdrawing groups.) (is) An oligonucleotide containing an internucleotide bond having the structure.

37. G ２ is -L'-S(O) ２ R' is the case, and in the formula, L' is substituted by any choice -CH ２ - The oligonucleotide according to claim 36.

38. R' is C which has been replaced by arbitrary choice. １～６ The oligonucleotide according to claim 37, which is aliphatic.

39. The oligonucleotide according to claim 38, wherein R' is t-butyl.

40. The oligonucleotide according to claim 37, wherein R' is optionally substituted with phenyl.

41. The oligonucleotide according to claim 40, wherein R' is phenyl.

42. R １ is -C(O)R', the oligonucleotide according to any one of claims 36 to 41. Leotid.

43. R' is -CH ３ The oligonucleotide according to claim 42.

44. Q － is F － , Cl － , Br － BF ４ － , PF ６ － , TfO － , Tf ２ N － AsF ６ － , ClO ４ － or SbF ６ － The oligonucleotide according to any one of claims 36 to 41.

45. The oligonucleotide according to any one of claims 36 to 44, wherein the oligonucleotide is attached to a solid support.

46. The oligonucleotide according to claim 45, wherein the solid support is CPG.

47. A method for preparing an oligonucleotide, comprising contacting the oligonucleotide according to any one of claims 36 to 46 with a base.

48. The method according to claim 47, wherein the contact is carried out substantially without water.

49. The method according to claim 47 or 48, wherein the contact occurs after the oligonucleotide length has been achieved but before the deprotection and cleavage of the oligonucleotide.

50. The aforementioned base is NR ３ The method according to any one of claims 47 to 49, wherein the amine base has the structure.

51. The method according to claim 50, wherein the base is N,N-diethylamine.

52. An oligonucleotide, compound, or method according to any one of the exemplary embodiments 1 to 420.

53. オリゴヌクレオチドであって、WV-20104、WV- 20103、WV-20102、WV-20101、WV -201100、WV-200099、WV-200098、WV-200097、WV-200096、WV-200095、 WV-220094、WV-2201106、WV-2201119、WV-2201118、WV-113739、WV-113374 0、WV-9079、WV-9082、WV-91100、WV-9096、WV-9097、WV-91106、WV- 9133、WV-91148、WV-91154、WV-9898、WV-9899、WV-9900、WV-9906 、WV-9907、WV-9908、WV-9909、WV-9756、WV-9757、WV-95117、WV-9 711、WV-97115、WV-95119、WV-95221、WV-9747、WV-9748、WV-9749、 WV-9897、WV-9898、WV-9900、WV-9899、WV-9906、WV-9912、WV-95 24、WV-99112、WV-9906、WV-9900、WV-9899、WV-9899、WV-9898、W V-9898、WV-9898、WV-9898、WV-9898、WV-9897、WV-9897、WV-989 7、WV-9897、WV-9897、WV-9747、WV-97114、WV-9699、WV-95117、WV -9517、WV-133409、WV-133408、WV-12887、WV-1212882、WV-1212881、WV -12880、WV-12880、WV-WV12880 、WV-12878、WV-12877、WV-1287 7、WV-12876、WV-12873、WV-1212872、WV-1212559、WV-12559、WV-12125 58、WV-125558、WV-122557、WV-1122556、WV-1122556、WV-1122555、WV-1 2555、WV-12554、WV-12553、WV-121129、WV-121127、WV-121125、WV- An oligonucleotide in the form of 12123, WV-11342, WV-11342, WV-11341, WV-11341, WV-11340, WV-10672, WV-10671, WV-10670, WV-10461, WV-10455, WV-9897, WV-9898, WV-13826, WV-13827, WV-13835, WV-12880, WV-14344, WV-13864, WV-13835, WV-14791, WV-14344, WV-13754, WV-13766, WV-11086, WV-11089, WV-17859, WV-17860, WV-20070, WV-20073, WV-20076, WV-20052, WV-20099, WV-20049, WV-20085, WV-20087, WV-20034, WV-20046, WV-20052, WV-20061, WV-20064, WV-20067, WV-20092, WV-20091, WV-20093, WV-20084, WV-9738, WV-9739, WV-9740, WV-9741, WV-15860, WV-15862, WV-11084, WV-11086, WV-11088, WV-11089, WV-14522, WV-14523, WV-17861, WV-17862, WV-13815, WV-13816, WV-13817, WV-13780, WV-17862, WV-17863, WV-17864, WV-17865, WV-17866, WV-20082, WV-20081, WV-20080, WV-20079, WV-20076, WV-20075, WV-20074, WV-20073, WV-20072, WV-20071, WV-20064, WV-20059, WV-20058, WV-20057, WV-20056, WV-20053, WV-20052, WV-20051, WV-20050, WV-20049, WV-20094, WV-20095 or its salt form.

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