Modified short interfering nucleic acid (SINA) molecules and their uses

Abstract

This invention provides siNA molecules with improved delivery and stability. [Solution] Short interfering nucleic acid (siNA) molecules containing modified nucleotides and their use are disclosed herein. The siNA molecule may be double-stranded and may contain modified nucleotides selected from 2'-O-methylnucleotides and 2'-fluoronucleotides. A siNA molecule comprising (a) a phosphorylation blocker, a conjugated moiety, or a 5'-stabilizing end cap and (b) a short interfering nucleic acid (siNA) is further disclosed herein.

Claims

1. Short interfering nucleic acid (SINA) molecules, (a) A sense strand comprising a first nucleotide sequence which is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the RNA corresponding to the target gene, wherein the first nucleotide sequence is (i) 15 to 30 nucleotides in length, (ii) A sense strand comprising 15 or more modified nucleotides independently selected from 2'-O-methylnucleotides and 2'-fluoronucleotides, wherein at least one modified nucleotide is a 2'-O-methylnucleotide, and the nucleotides at positions 3, 5, 7, 8, 9, 10, 11, 12, 14, 17, and / or 19 from the 5' end of the first nucleotide sequence are 2'-fluoronucleotides, (b) an antisense strand comprising a second nucleotide sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% complementary to the RNA corresponding to the target gene, wherein the second nucleotide sequence is (i) 15 to 30 nucleotides in length, (ii) A short interfering nucleic acid (SINA) molecule comprising an antisense chain containing 15 or more modified nucleotides independently selected from 2'-O-methylnucleotides and 2'-fluoronucleotides, wherein at least one modified nucleotide is a 2'-O-methylnucleotide and at least one modified nucleotide is a 2'-fluoronucleotide.

2. Short interfering nucleic acid (SINA) molecules, (a) A sense strand comprising a first nucleotide sequence which is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the RNA corresponding to the target gene, wherein the first nucleotide sequence is (i) 15 to 30 nucleotides in length, (ii) A sense strand comprising 15 or more modified nucleotides independently selected from 2'-O-methylnucleotides and 2'-fluoronucleotides, wherein at least one modified nucleotide is a 2'-O-methylnucleotide and at least one modified nucleotide is a 2'-fluoronucleotide, (b) an antisense strand comprising a second nucleotide sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% complementary to the RNA corresponding to the target gene, wherein the second nucleotide sequence is (i) 15 to 30 nucleotides in length, (ii) A short interfering nucleic acid (SINA) molecule comprising an antisense strand comprising 15 or more modified nucleotides independently selected from 2'-O-methylnucleotides and 2'-fluoronucleotides, wherein at least one modified nucleotide is a 2'-O-methylnucleotide, and the nucleotides at positions 2, 5, 6, 8, 10, 14, 16, 17, and / or 18 from the 5' end of the second nucleotide sequence are 2'-fluoronucleotides.

3. The siNA according to claim 1 or 2, wherein the first nucleotide sequence comprises 16, 17, 18, 19, 20, 21, 22, 23 or more modified nucleotides independently selected from 2'-O-methylnucleotides and 2'-fluoronucleotides.

4. The siNA according to claim 1 or 2, wherein 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the nucleotides in the first nucleotide sequence are modified nucleotides independently selected from 2'-O-methylnucleotides and 2'-fluoronucleotides.

5. (i) At least 2, 3, 4, 5, or 6 modified nucleotides of the first nucleotide sequence are 2'-fluoronucleotides, (ii) The 10, 9, 8, 7, 6, 5, 4, 3 or 2 or fewer modified nucleotides in the first nucleotide sequence are 2'-fluoronucleotides, (iii) At least 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22 modified nucleotides of the first nucleotide sequence are 2'-O-methyl nucleotides and / or (iv) The siNA according to any one of claims 1 to 4, wherein 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3 or two or fewer modified nucleotides of the first nucleotide sequence are 2'-O-methyl nucleotides.

6. The siRNA according to any one of claims 1 to 5, wherein the second nucleotide sequence comprises 16, 17, 18, 19, 20, 21, 22, 23 or more modified nucleotides independently selected from 2'-O-methylnucleotides and 2'-fluoronucleotides.

7. The siNA according to any one of claims 1 to 6, wherein 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the nucleotides in the second nucleotide sequence are modified nucleotides independently selected from 2'-O-methylnucleotides and 2'-fluoronucleotides.

8. (i) At least 2, 3, 4, 5, or 6 modified nucleotides of the second nucleotide sequence are 2'-fluoronucleotides, (ii) The 10, 9, 8, 7, 6, 5, 4, 3 or 2 or fewer modified nucleotides in the second nucleotide sequence are 2'-fluoronucleotides, (iii) At least 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22 modified nucleotides of the second nucleotide sequence are 2'-O-methyl nucleotides and / or (iv) The siNA according to any one of claims 1 to 7, wherein 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3 or two or fewer modified nucleotides of the second nucleotide sequence are 2'-O-methyl nucleotides.

9. Short interfering nucleic acid (SINA) molecules, (a) A sense strand comprising a first nucleotide sequence which is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the RNA corresponding to the target gene, wherein the first nucleotide sequence is (i) 15 to 30 nucleotides in length, (ii) comprising 15 or more modified nucleotides independently selected from 2'-O-methylnucleotides and 2'-fluoronucleotides, wherein at least one modified nucleotide is a 2'-O-methylnucleotide and at least one modified nucleotide is a 2'-fluoronucleotide, (iii) a sense strand comprising one or more phosphorothioate nucleoside linkages, and (b) an antisense strand comprising a second nucleotide sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% complementary to the RNA corresponding to the target gene, wherein the second nucleotide sequence is (i) 15 to 30 nucleotides in length, (ii) comprising 15 or more modified nucleotides independently selected from 2'-O-methylnucleotides and 2'-fluoronucleotides, wherein at least one modified nucleotide is a 2'-O-methylnucleotide and at least one modified nucleotide is a 2'-fluoronucleotide, (iii) A short interfering nucleic acid (SINA) molecule comprising an antisense chain containing one or more phosphorothioate nucleoside links.

10. Short interfering nucleic acid (SINA) molecules, (a) A sense strand comprising a first nucleotide sequence which is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the RNA corresponding to the target gene, wherein the first nucleotide sequence is (i) 15 to 30 nucleotides in length, (ii) A sense strand comprising 15 or more modified nucleotides independently selected from 2'-O-methylnucleotides and 2'-fluoronucleotides, wherein at least one modified nucleotide is a 2'-O-methylnucleotide and at least one modified nucleotide is a 2'-fluoronucleotide, (b) an antisense strand comprising a second nucleotide sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% complementary to the RNA corresponding to the target gene, wherein the second nucleotide sequence is (i) 15 to 30 nucleotides in length, (ii) an antisense chain comprising 15 or more modified nucleotides independently selected from 2'-O-methylnucleotides and 2'-fluoronucleotides, wherein at least one modified nucleotide is a 2'-O-methylnucleotide and at least one modified nucleotide is a 2'-fluoronucleotide, siNA is a short interfering nucleic acid (siNA) molecule that further contains a phosphorylation blocker, galactosamine, or a 5' stabilizing end cap.

11. The siNA according to any one of the prior claims, wherein at least 1, 2, 3, 4, 5, 6, or 7 nucleotides at positions 3, 5, 7, 8, 9, 10, 11, 12, and / or 17 from the 5' end of the first nucleotide sequence are 2'-fluoronucleotides.

12. The siNA according to any one of the prior claims, wherein at least 1, 2, 3, 4, 5, 6, 7, 8, or 9 nucleotides at positions 2, 5, 6, 8, 8, 10, 14, 16, 17, and / or 18 from the 5' end of the second nucleotide sequence are 2'-fluoronucleotides.

13. The siNA according to any one of the prior claims, wherein the nucleotides in the second nucleotide sequence are aligned in an alternating 1:3 modification pattern, one nucleotide is a 2'-fluoronucleotide, and three nucleotides are 2'-O-methylnucleotides.

14. The siNA according to claim 13, wherein the alternating 1:3 modification pattern occurs 2 to 5 times.

15. (i) At least two of the alternating 1:3 modification patterns occur consecutively, (ii) At least two of the alternating 1:3 modification patterns occur discontinuously, and / or (iii) The siNA according to claim 13 or 14, wherein at least one, two, three, four, or five alternating 1:3 modification patterns begin at nucleotide positions 2, 6, 10, 14, and / or 18 from the 5' end of the antisense strand.

16. (i) The nucleotides in the second nucleotide sequence are arranged in an alternating 1:2 modification pattern, (ii) The siNA according to any one of claims 1 to 12, wherein one nucleotide is a 2'-fluoronucleotide and two nucleotides are 2'-O-methylnucleotides.

17. The siNA according to claim 16, wherein the alternating 1:2 modification pattern occurs 2 to 5 times.

18. (i) At least two of the alternating 1:2 modification patterns occur consecutively, (ii) At least two of the alternating 1:2 modification patterns occur discontinuously, and / or (iii) The siNA according to claim 16 or 17, wherein at least one, two, three, four, or five alternating 1:2 modification patterns begin at nucleotide positions 2, 5, 8, 14, and / or 17 from the 5' end of the antisense strand.

19. A short interfering nucleic acid (SINA) molecule represented by formula (VIII), 5’-A ｎ １ B ｎ ２ A ｎ ３ B ｎ ４ A ｎ ５ B ｎ ６ A ｎ ７ B ｎ ８ A ｎ ９ -3’ 3’-C ｑ １ A ｑ ２ B ｑ ３ A ｑ ４ B ｑ ５ A ｑ ６ B ｑ ７ A ｑ ８ B ｑ ９ A ｑ １０ B ｑ １１ A ｑ １２ -5’ The upper strand is a sense strand containing a first nucleotide sequence that is at least approximately 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the RNA corresponding to the target gene, wherein the first nucleotide sequence contains 15 to 30 nucleotides. The lower strand is an antisense strand comprising a second nucleotide sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% complementary to the RNA corresponding to the target gene, wherein the second nucleotide sequence comprises 15 to 30 nucleotides. Each A is independently a nucleotide containing a 2'-O-methyl nucleotide, or a 5'-stabilizing end cap or phosphorylation blocker. B is a 2'-fluoronucleotide, C represents an overhanging nucleotide, which is a 2'-O-methyl nucleotide. n １ = 1 to 4 nucleotides in length, each n ２ , n ６ , n ８ , q ３ , q ５ , q ７ , q ９ , q １１ , and q １２ However, they are independent and have a length of 0 to 1 nucleotide. each n ３ and n ４ However, they are independent and have a length of 1 to 3 nucleotides. n ５ However, they are 1 to 10 nucleotides long, n ７ However, they are 0 to 4 nucleotides long, each n ９ , q １ , and q ２ However, they are independent and have a length of 0 to 2 nucleotides. q ４ However, they are 0 to 3 nucleotides long, q ６ However, they are 0 to 5 nucleotides long, q ８ However, they are 2 to 7 nucleotides long, q １０ However, these are short interfering nucleic acid (SINA) molecules, ranging in length from 2 to 11 nucleotides.

20. A short interfering nucleic acid (SINA) molecule represented by formula (IX), 5’-A ２～４ B １ A １～３ B ２～３ A ２～１０ B ０～１ A ０～４ B ０～１ A ０～２ -3’ 3’-C ２ A ０～２ B ０～１ A ０～３ B ０～１ A ０～５ B ０～１ A ２～７ B １ A ２～１１ B １ A １ -5’ The upper strand is a sense strand containing a first nucleotide sequence that is at least approximately 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the RNA corresponding to the target gene, wherein the first nucleotide sequence contains 15 to 30 nucleotides. The lower strand is an antisense strand comprising a second nucleotide sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% complementary to the RNA corresponding to the target gene, wherein the second nucleotide sequence comprises 15 to 30 nucleotides. Each A is independently a nucleotide containing a 2'-O-methyl nucleotide, or a 5'-stabilizing end cap or phosphorylation blocker. B is a 2'-fluoronucleotide, C represents an overhanging nucleotide, which is a 2'-O-methylnucleotide, making it a short interfering nucleic acid (SINA) molecule.

21. Short interfering nucleic acid (SINA) molecules, (a) A sense strand comprising a first nucleotide sequence consisting of 17 to 23 nucleotides, wherein 2'-fluoronucleotides are located at positions 3, 7-9, 12, and 17 from the 5' end of the first nucleotide sequence, and 2'-O-methylnucleotides are located at positions 1, 2, 4-6, 10, 11, and 13-16 from the 5' end of the first nucleotide sequence, (b) A short interfering nucleic acid (SINA) molecule comprising an antisense chain comprising a second nucleotide sequence consisting of 17 to 23 nucleotides, wherein the 2'-fluoronucleotide is located at positions 2 and 14 from the 5' end of the second nucleotide sequence, and the 2'-O-methylnucleotide is located at positions 1, 3-13 and 15-17 from the 5' end of the second nucleotide sequence.

22. The siNA molecule according to claim 21, wherein the first nucleotide sequence consists of 19 nucleotides.

23. The siNA molecule according to claim 22, wherein the 2'-O-methylnucleotide is located at positions 18 and 19 from the 5' end of the first nucleotide sequence.

24. The siNA molecule according to any one of claims 21 to 23, wherein the second nucleotide sequence consists of 21 nucleotides.

25. The siNA molecule according to claim 24, wherein the 2'-O-methylnucleotide is located at positions 18 to 21 from the 5' end of the second nucleotide sequence.

26. Short interfering nucleic acid (SINA) molecules, (a) A sense strand comprising a first nucleotide sequence consisting of 17 to 23 nucleotides, wherein 2'-fluoronucleotides are located at positions 3, 7, 8 and 17 from the 5' end of the first nucleotide sequence, and 2'-O-methylnucleotides are located at positions 1, 2, 4-6 and 9-16 from the 5' end of the first nucleotide sequence, (b) A short interfering nucleic acid (SINA) molecule comprising an antisense chain comprising a second nucleotide sequence consisting of 17 to 23 nucleotides, wherein the 2'-fluoronucleotide is located at positions 2 and 14 from the 5' end of the first nucleotide sequence, and the 2'-O-methylnucleotide is located at positions 1, 3-13 and 15-17 from the 5' end of the first nucleotide sequence.

27. The siNA molecule according to claim 26, wherein the first nucleotide sequence consists of 19 nucleotides.

28. The siNA molecule according to claim 27, wherein the 2'-O-methylnucleotide is located at positions 18 and 19 from the 5' end of the first nucleotide sequence.

29. The siNA molecule according to any one of claims 26 to 28, wherein the second nucleotide sequence consists of 21 nucleotides.

30. The siNA molecule according to claim 29, wherein the 2'-O-methylnucleotide is located at positions 18 to 21 from the 5' end of the second nucleotide sequence.

31. Short interfering nucleic acid (SINA) molecules, (a) A sense strand comprising a first nucleotide sequence consisting of 17 to 23 nucleotides, wherein 2'-fluoronucleotides are located at positions 3, 7-9, 12, and 17 from the 5' end of the first nucleotide sequence, and 2'-O-methylnucleotides are located at positions 1, 2, 4-6, 10, 11, and 13-16 from the 5' end of the first nucleotide sequence, (b) A short interfering nucleic acid (SINA) molecule comprising an antisense chain comprising a second nucleotide sequence consisting of 17 to 23 nucleotides, wherein the nucleotides in the second nucleotide sequence are aligned in an alternating 1:3 modification pattern, one nucleotide being a 2'-fluoronucleotide and three nucleotides being 2'-O-methylnucleotides.

32. The siNA molecule according to claim 31, wherein the first nucleotide sequence consists of 19 nucleotides.

33. The siNA molecule according to claim 32, wherein the 2'-O-methylnucleotide is located at positions 18 and 19 from the 5' end of the first nucleotide sequence.

34. The siNA molecule according to any one of claims 31 to 33, wherein the second nucleotide sequence consists of 21 nucleotides.

35. The siNA molecule according to claim 34, wherein the 2'-O-methylnucleotide is located at positions 19 to 21 from the 5' end of the second nucleotide sequence.

36. (i) The alternating 1:3 modification pattern occurs 2 to 5 times, (ii) At least two of the alternating 1:3 modification patterns occur consecutively, (iii) At least two of the alternating 1:3 modification patterns occur discontinuously, and / or (iv) The siRNA molecule according to any one of claims 31 to 35, wherein at least one, two, three, four, or five alternating 1:3 modification patterns begin at nucleotide positions 2, 6, 10, 14, and / or 18 from the 5' end of the antisense strand.

37. Short interfering nucleic acid (SINA) molecules, (a) A sense strand comprising a first nucleotide sequence consisting of 17 to 23 nucleotides, wherein the 2'-fluoronucleotides are located at positions 5 and 7-9 from the 5' end of the first nucleotide sequence, and the 2'-O-methylnucleotides are located at positions 1-4, 6 and 10-17 from the 5' end of the first nucleotide sequence, (b) A short interfering nucleic acid (SINA) molecule comprising an antisense chain comprising a second nucleotide sequence consisting of 17 to 23 nucleotides, wherein the nucleotides in the second nucleotide sequence are aligned in an alternating 1:3 modification pattern, one nucleotide being a 2'-fluoronucleotide and three nucleotides being 2'-O-methylnucleotides.

38. The siNA molecule according to claim 37, wherein the first nucleotide sequence consists of 19 nucleotides.

39. The siNA molecule according to claim 38, wherein the 2'-O-methylnucleotide is located at positions 18 and 19 from the 5' end of the first nucleotide sequence.

40. The siNA molecule according to any one of claims 37 to 39, wherein the second nucleotide sequence consists of 21 nucleotides.

41. The siNA molecule according to claim 40, wherein the 2'-O-methylnucleotide is located at positions 19 to 21 from the 5' end of the second nucleotide sequence.

42. (i) The alternating 1:3 modification pattern occurs 2 to 5 times, (ii) At least two of the alternating 1:3 modification patterns occur consecutively, (iii) At least two of the alternating 1:3 modification patterns occur discontinuously, and / or (iv) The siRNA molecule according to any one of claims 37 to 41, wherein at least one, two, three, four, or five alternating 1:3 modification patterns begin at nucleotide positions 2, 6, 10, 14, and / or 18 from the 5' end of the antisense strand.

43. Short interfering nucleic acid (SINA) molecules, (a) A sense strand comprising a first nucleotide sequence consisting of 17 to 23 nucleotides, wherein the 2'-fluoronucleotides are located at positions 5 and 7-9 from the 5' end of the first nucleotide sequence, and the 2'-O-methylnucleotides are located at positions 1-4, 6 and 10-17 from the 5' end of the first nucleotide sequence, (b) A short interfering nucleic acid (SINA) molecule comprising an antisense chain comprising a second nucleotide sequence consisting of 17 to 23 nucleotides, wherein the nucleotides in the second nucleotide sequence are aligned in an alternating 1:2 modification pattern, one nucleotide being a 2'-fluoronucleotide and two nucleotides being 2'-O-methylnucleotides.

44. The siNA molecule according to claim 43, wherein the first nucleotide sequence consists of 19 nucleotides.

45. The siNA molecule according to claim 44, wherein the 2'-O-methylnucleotide is located at positions 18 and 19 from the 5' end of the first nucleotide sequence.

46. The siNA molecule according to any one of claims 43 to 45, wherein the second nucleotide sequence consists of 21 nucleotides.

47. The siNA molecule according to claim 46, wherein the 2'-O-methylnucleotide is located at positions 18 to 21 from the 5' end of the second nucleotide sequence.

48. (i) The alternating 1:2 modification pattern occurs 2 to 5 times, (ii) At least two of the alternating 1:2 modification patterns occur consecutively, (iii) At least two of the alternating 1:2 modification patterns occur discontinuously, and / or (iv) The siRNA molecule according to any one of claims 43 to 47, wherein at least one, two, three, four, or five alternating 1:2 modification patterns begin at nucleotide positions 2, 5, 8, 14, and / or 17 from the 5' end of the antisense strand.

49. Short interfering nucleic acid (SINA) molecules, (a) A sense strand comprising a first nucleotide sequence consisting of 17 to 23 nucleotides, wherein the 2'-fluoronucleotides are located at positions 5 and 7-9 from the 5' end of the first nucleotide sequence, and the 2'-O-methylnucleotides are located at positions 1-4, 6 and 10-17 from the 5' end of the first nucleotide sequence, (b) A short interfering nucleic acid (SINA) molecule comprising an antisense chain comprising a second nucleotide sequence consisting of 17 to 23 nucleotides, wherein 2'-fluoronucleotides are located at positions 2, 6, 14, and 16 from the 5' end of the second nucleotide sequence, and 2'-O-methylnucleotides are located at positions 1, 3-5, 7-13, 15, and 17 from the 5' end of the second nucleotide sequence.

50. The siNA molecule according to claim 49, wherein the first nucleotide sequence consists of 19 nucleotides.

51. The siNA molecule according to claim 50, wherein the 2'-O-methylnucleotide is located at positions 18 and 19 from the 5' end of the first nucleotide sequence.

52. The siNA molecule according to any one of claims 49 to 51, wherein the second nucleotide sequence consists of 21 nucleotides.

53. The siNA molecule according to claim 52, wherein the 2'-O-methylnucleotide is located at positions 18 to 21 from the 5' end of the second nucleotide sequence.

54. Short interfering nucleic acid (SINA) molecules, (a) A sense strand comprising a first nucleotide sequence consisting of 17 to 23 nucleotides, wherein the 2'-fluoronucleotides are located at positions 5, 9-11, and 14 from the 5' end of the first nucleotide sequence, and the 2'-O-methylnucleotides are located at positions 1-4, 6-8, and 12-17 from the 5' end of the first nucleotide sequence, (b) A short interfering nucleic acid (SINA) molecule comprising an antisense chain comprising a second nucleotide sequence consisting of 17 to 23 nucleotides, wherein the 2'-fluoronucleotide is located at positions 2 and 14 from the 5' end of the second nucleotide sequence, and the 2'-O-methylnucleotide is located at positions 1, 3-13 and 15-17 from the 5' end of the second nucleotide sequence.

55. The siNA molecule according to claim 54, wherein the first nucleotide sequence consists of 21 nucleotides.

56. The siNA molecule according to claim 55, wherein the 2'-O-methylnucleotide is located at positions 18 to 21 from the 5' end of the first nucleotide sequence.

57. The siNA molecule according to any one of claims 53 to 55, wherein the second nucleotide sequence consists of 23 nucleotides.

58. The siNA molecule according to claim 57, wherein the 2'-O-methylnucleotide is located at positions 18 to 23 from the 5' end of the second nucleotide sequence.

59. The siNA according to any one of the prior claims, wherein the sense strand further comprises a TT sequence adjacent to the first nucleotide sequence.

60. The siNA according to any one of the prior claims, wherein the sense chain further comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or more phosphorothioate nucleoside linkages.

61. (i) At least one phosphorothioate nucleoside linkage is located between the nucleotides at positions 1 and 2 from the 5' end of the first nucleotide sequence, (ii) The siNA according to claim 60, wherein at least one phosphorothioate nucleoside linkage is located between the nucleotides at positions 2 and 3 from the 5' end of the first nucleotide sequence.

62. The siNA according to any one of the prior claims, wherein the antisense strand further comprises a TT sequence adjacent to the second nucleotide sequence.

63. The siNA according to any one of the prior claims, wherein the antisense chain further comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or more phosphorothioate nucleoside linkages.

64. (i) At least one phosphorothioate nucleoside linkage is located between the nucleotides at positions 1 and 2 from the 5' end of the second nucleotide sequence, (ii) At least one phosphorothioate nucleoside linkage is located between the nucleotides at positions 2 and 3 from the 5' end of the second nucleotide sequence, (iii) At least one phosphorothioate nucleoside linkage is located between the nucleotides at positions 1 and 2 from the 3' end of the second nucleotide sequence, and / or (iv) The siNA according to claim 63, wherein at least one phosphorothioate nucleoside linkage is located between nucleotides at positions 2 and 3 from the 3' end of the second nucleotide sequence.

65. (i) The first nucleotide from the 5' end of the first nucleotide sequence includes a 5' stabilizing end cap, (ii) The first nucleotide from the 5' end of the second nucleotide sequence includes a 5' stabilizing end cap, (iii) The first nucleotide from the 5' end of the first nucleotide sequence comprises a phosphorylation blocker and / or (iv) The siNA according to any one of the prior claims, wherein the first nucleotide from the 5' end of the second nucleotide sequence comprises a phosphorylation blocker.

66. The first nucleotide sequence or the second nucleotide sequence is 【Chemistry 1】 (In the formula, if R is alkyl, then R is H or alkyl (or AmNA(N-Me))), 【Chemistry 2】 The siNA according to any one of the prior claims, comprising at least one modified nucleotide selected from (wherein B is a nucleic acid base).

67. Short interfering nucleic acid (SINA) molecules, (a) Phosphorylation blockers of formula (IV): 【Transformation 3】 (In the formula, R １ However, it is a nucleic acid base, R ４ However, -OR ３０ or -NR ３１ R ３２ And, R ３０ is C １ to C ８ substituted or unsubstituted alkyl, and R ３１ and R ３２ However, when they combine with the nitrogen atoms they connect to, they form substituted or unsubstituted heterocyclic rings. (b) A short interfering nucleic acid (SINA) molecule containing a short interfering nucleic acid (SINA).

68. Short interfering nucleic acid (SINA) molecules, (a) 5' stabilizing end cap of formula (Ia): 【Chemistry 4】 (In the formula, R １ However, it is a nucleic acid base, aryl, heteroaryl, or H, R ２ but, 【Transformation 5】 -CH=CD-Z, -CD=CH-Z, -CD=CD-Z, -(CR ２１ R ２２ ) ｎ -Z, or -(C ２ ~C ６ alkenylene)-Z, where R ２０ is hydrogen, or R ２ and R ２０ together form a 3- to 7-membered carbocyclic ring substituted with -(CR ２１ R ２２ ) ｎ -Z or -(C ２ -C ６ alkenylene)-Z, n is 1, 2, 3, or 4, Z is -ONR ２３ R ２４ , -OP(O)OH(CH ２ ) ｍ CO ２ R ２３ , -OP(S)OH(CH ２ ) ｍ CO ２ R ２３ , -P(O)(OH) ２ , -P(O)(OH)(OCH ３ ), -P(O)(OH)(OCD ３ ), -SO ２ (CH ２ ) ｍ P(O)(OH) ２ , -SO ２ NR ２３ R ２５ , -NR ２３ R ２４ And, R ２１ and R ２２ However, independently, hydrogen or C １ ~C ６ It is alkyl, R ２１ and R ２２ However, together they form an oxo group, R ２３ However, hydrogen, or C １ ~C ６ It is alkyl, R ２４ However, -SO ２ R ２５ Or -C(O)R ２５ is, or R ２３ and R ２４ However, together with the nitrogen atoms they connect to, they form substituted or unsubstituted heterocyclic rings. R ２５ However, C １ ~C ６ It is alkyl, (where m is 1, 2, 3, or 4) (b) A short interfering nucleic acid (SINA) molecule containing a short interfering nucleic acid (SINA).

69. Short interfering nucleic acid (SINA) molecules, (a) 5' stabilizing end cap of formula (Ib): 【Transformation 6】 (In the formula, R １ However, it is a nucleic acid base, aryl, heteroaryl, or H, R ２ but, 【Transformation 7】 -CH=CD-Z, -CD=CH-Z, -CD=CD-Z, -(CR ２１ R ２２ ) ｎ -Z, or -(C) ２ ~C ６ Alkenylene)-Z, R ２０ However, is it hydrogen, or R ２ and R ２０ But together, - (CR ２１ R ２２ ) ｎ -Z or -(C) ２ -C ６ It forms a 3- to 7-membered carbocyclic ring substituted with alkenylene-Z, n is 1, 2, 3, or 4, Z is -ONR ２３ R ２４ , -OP(O)OH(CH ２ ) ｍ CO ２ R ２３ , -OP(S)OH(CH ２ ) ｍ CO ２ R ２３ , -P(O)(OH) ２ , -P(O)(OH)(OCH ３ ), -P(O)(OH)(OCD ３ ), -SO ２ (CH ２ ) ｍ P(O)(OH) ２ , -SO ２ NR ２３ R ２５ , -NR ２３ R ２４ And, R ２１ and R ２２ However, independently, hydrogen or C １ ~C ６ It is alkyl, R ２１ and R ２２ However, together they form an oxo group, R ２３ However, hydrogen, or C １ ~C ６ It is alkyl, R ２４ However, -SO ２ R ２５ Or -C(O)R ２５ is, or R ２３ and R ２４ However, together with the nitrogen atoms they connect to, they form substituted or unsubstituted heterocyclic rings. R ２５ However, C １ ~C ６ It is alkyl, (where m is 1, 2, 3, or 4) (b) A short interfering nucleic acid (SINA) molecule containing a short interfering nucleic acid (SINA).

70. Short interfering nucleic acid (SINA) molecules, (a) 5' stabilizing end cap selected from the group consisting of formulas (1) to (15), formulas (9X) to (12X), and formulas (9Y) to (12Y): 【Transformation 8】 【change】 (In the formula, R １ However, (which is a nucleic acid base, aryl, heteroaryl, or H), (b) A short interfering nucleic acid (SINA) molecule containing a short interfering nucleic acid (SINA).

71. Short interfering nucleic acid (SINA) molecules, A 5' stabilizing end cap selected from the group consisting of formulas (1A) to (15A), formulas (9B) to (12B), formulas (9AX) to (12AX), formulas (9AY) to (12AY), formulas (9BX) to (12BX), and formulas (9BY) to (12BY): 【Chemistry 9】 【change】 Furthermore (b) A short interfering nucleic acid (SINA) molecule containing a short interfering nucleic acid (SINA).

72. The siNA molecule according to any one of claims 67 to 71, wherein the siNA comprises the sense chain according to any one of claims 1 to 66.

73. The siNA molecule according to any one of claims 67 to 72, wherein the siNA comprises the antisense chain according to any one of claims 1 to 66.

74. Short interfering nucleic acid (SINA) molecules, (a) A sense strand comprising a first nucleotide sequence which is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the RNA corresponding to the target gene, wherein the first nucleotide sequence comprises any one of the nucleotide sequences SEQ ID NOs: 1-56, 103-158, and 205-260, (b) A short interfering nucleic acid (SINA) molecule comprising an antisense strand comprising a second nucleotide sequence that is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% complementary to the RNA corresponding to the target gene, wherein the second nucleotide sequence comprises one of the nucleotide sequences SEQ ID NOs. 57-102, 159-204, and 261-306.

75. Interfering nucleic acid (SINA) molecules, (a) A sense strand containing one nucleotide sequence from sequence numbers 307-362 and 415-444, (b) A short interfering nucleic acid (SINA) molecule comprising an antisense strand containing one of the nucleotide sequences of sequence numbers 363-409, 445-533, and 536-539.

76. The siNA according to any one of claims 1 to 66 and 68 to 75, wherein the siNA further comprises a phosphorylation blocker.

77. The phosphorylation blocker has the structure of formula (IV): 【Chemistry 10】 It has, in the formula, R １ However, it is a nucleic acid base, R ４ However, -OR ３０ or -NR ３１ R ３２ And R ３０ However, C １ ~C ８ It is a substituted or unsubstituted alkyl group. R ３１ and R ３２ The siNA according to any one of claims 10, 65, and 76, wherein they, together with the nitrogen atoms to which they are connected, form a substituted or unsubstituted heterocyclic ring.

78. R ４ However, -OCH ３ or -N(CH ２ CH ２ ) ２ The siNA according to claim 67 or 77, wherein O.

79. The siNA according to any one of claims 10, 65, 67, and 76-78, wherein (i) the phosphorylation blocker is connected to the 5' end of the sense chain, (ii) the phosphorylation blocker is connected to the 3' end of the sense chain, (iii) the phosphorylation blocker is connected to the 5' end of the antisense chain, or (iv) the phosphorylation blocker is connected to the 3' end of the antisense chain.

80. (i) The phosphorylation blocker is attached to the 5' end of the sense chain via one or more linkers independently selected from phosphodiester linkers, phosphorothioate linkers, and phosphorodithioate linkers. (ii) The phosphorylation blocker is attached to the 3' end of the sense chain via one or more linkers independently selected from phosphodiester linkers, phosphorothioate linkers, and phosphorodithioate linkers. (iii) The phosphorylation blocker is attached to the 5' end of the antisense chain via one or more linkers independently selected from phosphodiester linkers, phosphorothioate linkers, and phosphorodithioate linkers, or (iv) The siNA according to claim 78, wherein the phosphorylation blocker is connected to the 3' end of the antisense chain via one or more linkers independently selected from a phosphodiester linker, a phosphorothioate linker, and a phosphorodithioate linker.

81. The siNA according to any one of the prior claims, wherein the siNA further comprises galactosamine.

82. The galactosamine mentioned above is N-acetylgalactosamine (GalNAc) of formula (VII): 【Chemistry 11】 The siNA according to claim 10 or 81, wherein each n is independently 1 or 2 in the formula.

83. The galactosamine is N-acetylgalactosamine (GalNAc) of formula (VI): 【Chemistry 12】 And in the formula, m is 1, 2, 3, 4, or 5. Each n is independently either 1 or 2. p is 0 or 1, Each R is independently H, Each Y is independently selected from -O-P(=O)(SH)-, -O-P(=O)(O)-, -O-P(=O)(OH)-, and -O-P(S)S-. Z is H, or a second protecting group. Either L is a linker, or L and Y together are a linker. The siNA according to claim 10 or 81, wherein A is H, OH, a third protecting group, an activating group, or an oligonucleotide.

84. (i) Is A an oligonucleotide? Or (ii) A is one to two oligonucleotides, according to claim 83.

85. The siNA according to claim 84, wherein the oligonucleotide is dTdT.

86. The siNA according to any one of claims 10, 84, and 85, wherein the galactosamine is connected to (i) the 3' end of the sense chain, (ii) the 5' end of the sense chain, (iii) the 3' end of the antisense chain, or (iv) the 5' end of the antisense chain.

87. The aforementioned galactosamine, (i) The 3' end of the sense chain via one or more linkers independently selected from a phosphodiester linker, a phosphorothioate linker, or a phosphorodithioate linker, (ii) The 5' end of the sense chain via one or more linkers independently selected from a phosphodiester linker, a phosphorothioate linker, or a phosphorodithioate linker, (iii) The 3' end of the atnisense strand via one or more linkers independently selected from a phosphodiester linker, a phosphorothioate linker, or a phosphorodithioate linker, (iv) The siNA according to claim 86, connected to the 5' end of the atonisense chain via one or more linkers independently selected from a phosphodiester linker, a phosphorothioate linker, or a phosphorodithioate linker.

88. The siNA according to any one of claims 1 to 67 and 70 to 87, wherein the siNA further comprises a 5' stabilizing end cap.

89. The siNA according to any one of claims 10, 65, and 88, wherein the 5'-stabilizing end cap is a 5'-vinylphosphonate or a deuterated 5'-vinylphosphonate.

90. The 5' stabilizing end cap has the structure of formula (Ia): 【Chemistry 13】 It has, in the formula, R １ However, it is a nucleic acid base, aryl, heteroaryl, or H, R ２ but, 【Chemistry 14】 -CH=CD-Z, -CD=CH-Z, -CD=CD-Z, -(CR ２１ R ２２ ) ｎ -Z, or -(C) ２ ~C ６ Alkenylene)-Z, R ２０ However, is it hydrogen, or R ２ and R ２０ But together, - (CR ２１ R ２２ ) ｎ -Z or -(C) ２ -C ６ It forms a 3- to 7-membered carbocyclic ring substituted with alkenylene-Z, n is 1, 2, 3, or 4, Z is -ONR ２３ R ２４ , -OP(O)OH(CH ２ ) ｍ CO ２ R ２３ , -OP(S)OH(CH ２ ) ｍ CO ２ R ２３ , -P(O)(OH) ２ , -P(O)(OH)(OCH ３ ), -P(O)(OH)(OCD ３ ), -SO ２ (CH ２ ) ｍ P(O)(OH) ２ , -SO ２ NR ２３ R ２５ , -NR ２３ R ２４ , or -NR ２３ SO ２ R ２４ And, R ２１ and R ２２ Either of these independently, hydrogen or C １ ~C ６ Alkyl or R ２１ and R ２２ However, together they form an oxo group, R ２３ However, hydrogen, or C １ ~C ６ It is alkyl, R ２４ However, -SO ２ R ２５ Or -C(O)R ２５ is, or R ２３ and R ２４ However, together with the nitrogen atoms they connect to, they form substituted or unsubstituted heterocyclic rings. R ２５ However, C １ ~C ６ It is alkyl, The SINA according to any one of claims 10, 65, and 88, wherein m is 1, 2, 3, or 4.

91. The 5' stabilizing end cap has the structure of formula (Ib): 【Chemistry 15】 It has, in the formula, R １ However, it is a nucleic acid base, aryl, heteroaryl, or H, R ２ but, 【Chemistry 16】 -CH=CD-Z, -CD=CH-Z, -CD=CD-Z, -(CR ２１ R ２２ ) ｎ -Z, or -(C) ２ ~C ６ Alkenylene)-Z, R ２０ However, is it hydrogen, or R ２ and R ２０ But together, - (CR ２１ R ２２ ) ｎ -Z or -(C) ２ -C ６ It forms a 3- to 7-membered carbocyclic ring substituted with alkenylene-Z, n is 1, 2, 3, or 4, Z is -ONR ２３ R ２４ , -OP(O)OH(CH ２ ) ｍ CO ２ R ２３ , -OP(S)OH(CH ２ ) ｍ CO ２ R ２３ , -P(O)(OH) ２ , -P(O)(OH)(OCH ３ ), -P(O)(OH)(OCD ３ ), -SO ２ (CH ２ ) ｍ P(O)(OH) ２ , -SO ２ NR ２３ R ２５ , -NR ２３ R ２４ , or -NR ２３ SO ２ R ２４ And, R ２１ and R ２２ Either of these independently, hydrogen or C １ ~C ６ Alkyl or R ２１ and R ２２ However, together they form an oxo group, R ２３ However, hydrogen, or C １ ~C ６ It is alkyl, R ２４ However, -SO ２ R ２５ Or -C(O)R ２５ is, or R ２３ and R ２４ However, together with the nitrogen atoms they connect to, they form substituted or unsubstituted heterocyclic rings. R ２５ However, C １ ~C ６ It is alkyl, The SINA according to claim 65 or 88, wherein m is 1, 2, 3, or 4.

92. R １ The siNA according to claim 90 or 91, wherein the siNA is an aryl.

93. The siNA according to claim 92, wherein the aryl is phenyl.

94. The siNA according to any one of claims 10, 65, and 88, wherein the 5' stabilizing end cap is selected from the group consisting of formulas (1) to (15), formulas (9X) to (12X), and formulas (9Y) to (12Y). 【Chemistry 17】 【change】 (In the formula, R １ (However, it is a nucleic acid base, aryl, heteroaryl, or H.)

95. The siNA according to any one of claims 10, 65, and 88, wherein the 5' stabilizing end cap is selected from the group consisting of formulas (1A) to (15A), formulas (9B) to (12B), formulas (9AX) to (12AX), formulas (9AY) to (12AY), formulas (9BX) to (12BX), and formulas (9BY) to (12BY). [Chemistry 18] 【change】

96. The 5' stabilizing end cap has the structure of formula (Ic): 【Chemistry 19】 It has, in the formula, R １ However, it is a nucleic acid base, aryl, heteroaryl, or H, R ２ but, 【Chemistry 20】 -CH=CD-Z, -CD=CH-Z, -CD=CD-Z, -(CR ２１ R ２２ ) ｎ -Z, or -(C) ２ ~C ６ Alkenylene)-Z, R ２０ However, is it hydrogen, or R ２ and R ２０ But together, - (CR ２１ R ２２ ) ｎ -Z or -(C) ２ -C ６ It forms a 3- to 7-membered carbocyclic ring substituted with alkenylene-Z, n is 1, 2, 3, or 4, Z is -ONR ２３ R ２４ , -OP(O)OH(CH ２ ) ｍ CO ２ R ２３ , -OP(S)OH(CH ２ ) ｍ CO ２ R ２３ , -P(O)(OH) ２ , -P(O)(OH)(OCH ３ ), -P(O)(OH)(OCD ３ ), -SO ２ (CH ２ ) ｍ P(O)(OH) ２ , -SO ２ NR ２３ R ２５ , -NR ２３ R ２４ , or -NR ２３ SO ２ R ２４ And, R ２１ and R ２２ Either of these independently, hydrogen or C １ ~C ６ Alkyl or R ２１ and R ２２ However, together they form an oxo group, R ２３ However, hydrogen, or C １ ~C ６ It is alkyl, R ２４ However, -SO ２ R ２５ Or -C(O)R ２５ is, or R ２３ and R ２４ However, together with the nitrogen atoms they connect to, they form substituted or unsubstituted heterocyclic rings. R ２５ However, C １ ~C ６ It is alkyl, The SINA according to claim 65 or 88, wherein m is 1, 2, 3, or 4.

97. R １ However, the siNA according to claim 96 is an aryl.

98. The siNA according to claim 97, wherein the aryl is phenyl.

99. The siNA according to any one of claims 10, 65, and 88, wherein the 5' stabilizing end cap is selected from the group consisting of formulas (21) to (35). 【Chemistry 21】 (In the formula, R １ (However, it is a nucleic acid base, aryl, heteroaryl, or H.)

100. The siNA according to any one of claims 10, 65, and 88, wherein the 5' stabilizing end cap is selected from the group consisting of formulas (21A) to (35A), formulas (29B) to (32B), formulas (29AX) to (32AX), formulas (29AY) to (32AY), formulas (29BX) to (32BX), and formulas (29BY) to (32BY). 【Chemistry 22】 【change】 (In the formula, R １ (However, it is a nucleic acid base, aryl, heteroaryl, or H.)

101. The antisense strand, sense strand, first nucleotide sequence, and / or second nucleotide sequence are 【Chemistry 23】 The siNA according to any one of claims 1 to 100, comprising at least one thermally destabilized nucleotide selected from.

102. The siNA according to any one of claims 10, 65, and 88-101, wherein the 5' stabilizing end cap is connected to (i) the 5' end of the antisense chain, or (ii) the 5' end of the sense chain.

103. The aforementioned 5' stabilizing end cap, (i) via one or more linkers independently selected from a phosphodiester linker, a phosphorothioate linker, or a phosphorodithioate linker, the 5' end of the antisense chain, (ii) The siNA according to claim 102, wherein the sense chain is connected to the 5' end via one or more linkers independently selected from a phosphodiester linker, a phosphorothioate linker, or a phosphorodithioate linker.

104. (i) Whether the target gene is a viral gene, (ii) The target gene is a gene, and is of DNA virus origin, (iii) Whether the target gene is derived from a double-stranded DNA (dsDNA) virus, (iv) Whether the target gene is derived from hepadnavirus, (v) Whether the target gene is a gene derived from hepatitis B virus (HBV), (vi) The target gene is a gene derived from any one of HBV genotypes A to J, or (vii) The siNA according to any one of the prior claims, wherein the target gene is selected from the S gene or X gene of HBV.

105. (i) The second nucleotide sequence is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% complementary to 15 to 30 nucleotides in the 200 to 720 or 1100 to 1700 positions of SEQ ID NO: 410 (ii) The second nucleotide sequence is at least approximately 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% complementary to 15 to 30 nucleotides in positions 200-280, 300-445, 460-510, 650-720, 1170-1220, 1250-1300, or 1550-1630 of SEQ ID NO: 410 (iii) The second nucleotide sequence is at least approximately 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% complementary to 15 to 30 nucleotides at positions 200-230, 250-280, 300-330, 370-400, 405-445, 460-500, 670-700, 1180-1210, 1260-1295, 1520-1550, or 1570-1610 of SEQ ID NO: 410 (iv) The second nucleotide sequence is at least approximately 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% complementary to 15 to 30 nucleotides starting at positions 203, 206, 254, 305, 375, 409, 412, 415, 416, 419, 462, 466, 467, 674, 676, 1182, 1262, 1263, 1268, 1526, 1577, 1578, 1580, 1581, 1583, or 1584 of SEQ ID NO: 410 (v) The first nucleotide sequence is identical by at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% to 15 to 30 nucleotides in positions 200-720 or 1100-1700 of SEQ ID NO: 410, (vi) The first nucleotide sequence is identical by at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% to 15 to 30 nucleotides in positions 200-280, 300-445, 460-510, 650-720, 1170-1220, 1250-1300, or 1550-1630 of SEQ ID NO: 410, (vii) The first nucleotide sequence is identical by at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% to 15 to 30 nucleotides in positions 200–230, 250–280, 300–330, 370–400, 405–445, 460–500, 670–700, 1180–1210, 1260–1295, 1520–1550, or 1570–1610 of SEQ ID NO: 410, and / or (viiii) The siNA according to any one of claims 1 to 104, wherein the first nucleotide sequence is identical by at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% to 15 to 30 nucleotides starting at positions 203, 206, 254, 305, 375, 409, 412, 415, 416, 419, 462, 466, 467, 674, 676, 1182, 1262, 1263, 1268, 1526, 1577, 1578, 1580, 1581, 1583, or 1584 of SEQ ID NO:

410.

106. (i) The first nucleotide sequence comprises any one of the nucleotide sequences of sequence numbers 1 to 56, 103 to 158 and 205 to 260, (ii) The second nucleotide sequence comprises any one of the nucleotide sequences from SEQ ID NOs. 57-102, 159-204, and 261-306, and (iii) the sense strand comprises any one of the nucleotide sequences from SEQ ID NOs. 307-362 and 415-444, and / or (iv) The SINA according to any one of the prior claims, wherein the antisense strand comprises one nucleotide sequence from SEQ ID NOs. 363-409, 445-533, and 536-539.

107. (i) At least one end of the siNA is a blunt end, (ii) At least one end of the siNA includes an overhang, and the overhang includes at least one nucleotide, or (iii) The siNA according to any one of the prior claims, wherein both ends of the siNA include an overhang, and the overhang includes at least one nucleotide.

108. The SINA according to any one of the prior claims, wherein the SINA is selected from ds-SINA-001 to ds-SINA-0178.

109. At least one 2'-fluoronucleotide or 2'-O-methylnucleotide is a 2'-fluoro or 2'-O-methyl nucleotide mime of formula (V). 【Chemistry 24】 And in the formula, R １ However, independently, they are nucleic acid bases, aryls, heteroaryls, or H, and Q １ and Q ２ However, independently, it is either S or O. R ５ However, independently, -OCD ３ -F, or -OCH ３ And, R ６ and R ７ However, the siNA according to any one of the prior claims is independently H, D, or CD3.

110. The 2'-fluoro or 2'-O-methyl nucleotide mimetic is a nucleotide mimetic of formula (16) to formula (20), 【Chemistry 25】 (In the formula, R １ However, it is a nucleic acid base, R ２ However, independently, F or -OCH ３ The SINA according to claim 109.

111. The siNA according to any one of the prior claims, wherein at least one 2'-fluoronucleotide is a 2'-fluoronucleotide mime.

112. (i) At least one, two, three, four, five or more 2'-fluoronucleotides on the antisense strand or the second nucleotide sequence are 2'-fluoronucleotide mimes, (ii) The nucleotides at positions 2, 5, 6, 8, 10, 14, 16 and / or 17 from the 5' end of the antisense strand or the second nucleotide sequence are 2'-fluoronucleotide mimes. (iii) At least one, two, three, four, five or more 2'-fluoronucleotides on the sense strand or the first nucleotide sequence are 2'-fluoronucleotide mimes and / or (iv) The siNA according to claim 111, wherein the nucleotides at positions 3, 5, 7, 8, 9, 10, 11, 12, 14, and / or 17 from the 5' end of the sense strand or the first nucleotide sequence are 2'-fluoronucleotide mimes.

113. (i) at least 1, 2, 3, 4, 5, 6 or more 2'-fluoronucleotide mimics are present in the f4P nucleotide 【Chemistry 26】 And, (ii) 10, 9, 8, 7, 6, 5, 4, 3 or 2 or fewer 2'-fluoronucleotide mimics, f4P nucleotide 【Chemistry 27】 And, (iii) 1, 2, 3, 4, 5, 6 or more 2'-fluoronucleotide mimics, f2P nucleotide 【Chemistry 28】 And, (iv) 10, 9, 8, 7, 6, 5, 4, 3, or 2 or fewer 2'-fluoronucleotide mimics, f2P nucleotide 【Chemistry 29】 And, (v) 1, 2, 3, 4, 5, 6 or more 2'-fluoronucleotide mimetic units are present in the fX nucleotide. 【Transformation 30】 and / or (vi) 10, 9, 8, 7, 6, 5, 4, 3 or 2 or fewer 2'-fluoronucleotide mimics, fX nucleotide 【Chemistry 31】 The siNA according to claim 111 or 112.

114. (i) The first nucleotide from the 5' end of the antisense strand or the second nucleotide sequence is a d2vd3 nucleotide 【Chemistry 32】 and / or (ii) The first nucleotide from the 3' end of the antisense strand or the second nucleotide sequence is a d2vd3 nucleotide 【Transformation 33】 The SINA described in any one of the prior claims.

115. A composition, (I) (a ) siNA according to any one of claims 1 to 114, and (b) a pharmaceutically acceptable excipient, (II) Two, three, four, five, six, seven, eight, nine, ten or more siNAs as described in any one of claims 1 to 114, or (III) A composition comprising (a) two, three, four, five, six, seven, eight, nine, ten or more siNAs as described in any one of claims 1 to 114, and (b) a pharmaceutically acceptable excipient.

116. (i) at least 1, 2, 3, 4, 5 or more siNAs target the HBV S gene, and / or (ii) The composition according to claim 115, wherein at least one, two, three, four, five or more siNAs target the HBV X gene.

117. (i) Additional HBV treatment drugs, (ii) Additional HBV therapeutic agents selected from nucleotide analogs, nucleoside analogs, capsid assembly modulators (CAMs), recombinant interferons, entry inhibitors, small molecule immunomodulators, and oligonucleotide therapies. (iii) Additional siNA, (iv) Additional SINA selected from any of ds-SINA-001 to ds-SINA-0178, (v) Oligonucleotide therapy selected from antisense oligonucleotides (ASOs), NAPs, or STOPs. (vi) an ASO selected from ASO1 or ASO2, and / or (vii) HBV STOPS (trademark) ALG-010133, HBV CAM ALG-000184, ASO1, Recombinant Interferon Alpha 2b, IFN-a, PEG-IFN-a-2a, Lamivudine, Terbivudine, Adefovir Dipivoxil, Klevudine, Entecavir, Tenofovir Alafenamide, Tenofovir Disoproxil, NVR3-778, BAY41-4109, JNJ-632, JNJ-3989 (ARO-HBV), RG6004, GSK3228836, RE The composition according to claim 115 or 116, further comprising an additional HBV therapeutic agent selected from P-2139, REP-2165, AB-729, VIR-2218, RG6346 (DCR-HBVS), JNJ-6379, GLS4, ABI-HO731, JNJ-440, NZ-4, RG7907, EDP-514, AB-423, AB-506, ABI-H03733, and ABI-H2158.

118. Use of siNA according to any one of claims 1 to 114, or a composition according to any one of claims 115 to 117, in the manufacture of a pharmaceutical product for treating a disease.

119. (i) Whether the disease is a viral disease, (ii) The disease is caused by a DNA virus, (iii) The disease is caused by double-stranded DNA (dsDNA virus), (iv) The disease is caused by the hepadnavirus, (v) The disease is caused by hepatitis B virus (HBV), or (vi) The use according to claim 118, wherein the disease is caused by any one HBV genotype A to J.

120. (i) Additional HBV therapeutic agents in the manufacture of the pharmaceutical product, (ii) Additional HBV therapeutic agents selected from nucleotide analogs, nucleoside analogs, capsid assembly modulators (CAMs), recombinant interferons, entry inhibitors, small molecule immunomodulators, and oligonucleotide therapies. (iii) Additional siNA, (iv) Additional SINA selected from any of ds-SINA-001 to ds-SINA-0178, (v) Oligonucleotide therapy selected from antisense oligonucleotides (ASOs), NAPs, or STOPs, (vi) ASOs selected from ASO1 or ASO2, and / or (vii) HBV STOPS (trademark) ALG-010133, HBV CAM ALG-000184, ASO1, Recombinant Interferon Alpha 2b, IFN-a, PEG-IFN-a-2a, Lamivudine, Terbivudine, Adefovir Dipivoxil, Klevudine, Entecavir, Tenofovir Alafenamide, Tenofovir Disoproxil, NVR3-778, BAY41-4109, JNJ-632, JNJ-3989 (ARO-HBV), RG6004, GSK3228836, R The use according to claim 118 or 119, further comprising an additional HBV therapeutic agent selected from EP-2139, REP-2165, AB-729, VIR-2218, RG6346 (DCR-HBVS), JNJ-6379, GLS4, ABI-HO731, JNJ-440, NZ-4, RG7907, EDP-514, AB-423, AB-506, ABI-H03733, and ABI-H2158.

121. (i) Whether the disease is a liver disease, (ii) Whether the disease is non-alcoholic fatty liver disease (NAFLD) or hepatocellular carcinoma (HCC), (iii) The use according to claim 118, wherein the disease is non-alcoholic steatohepatitis (NASH).

122. The use according to claim 118 or 121, further comprising a drug for treating liver disease in the manufacture of the aforementioned pharmaceutical product.

123. (i) The liver disease treatment agent is selected from peroxisome proliferator-activated receptor (PPAR) agonists, farnesoid X receptor (FXR) agonists, lipid modifiers, and incretin therapies, (ii) The liver disease treatment agent is a PPAR agonist, selected from a PPAR α agonist, a dual PPAR α / δ agonist, a PPAR γ agonist, and a dual PPAR α / γ agonist, or (iii) The use according to claim 122, wherein the liver disease treatment agent is selected from fibrates, elafibranol, thiazolidinedione (TZD), pioglitazone, saroglitazal, obetichol asis (OCA), alamcol, glucagon-like peptide 1 (GLP-1) receptor agonists, dipeptidyl peptidase 4 (DPP-4) inhibitors, exenatide, liraglutide sitagliptin, and vildagliptin.

124. siNA according to any one of claims 1 to 114, for use as a pharmaceutical.

125. A composition according to any one of claims 115 to 117 for use as a pharmaceutical.

126. A siNA according to any one of claims 1 to 114, for use in the treatment of a disease.

127. (i) Whether the disease is a viral disease, (ii) The disease is caused by a DNA virus, (iii) The disease is caused by double-stranded DNA (dsDNA virus), (iv) The disease is caused by the hepadnavirus, (v) Whether the disease is caused by hepatitis B virus (HBV), (vi) The disease is caused by any one of the HBV genotypes A to J, (vii) Whether the aforementioned disease is a liver disease, (viiii) Whether the disease is non-alcoholic fatty liver disease (NAFLD) or hepatocellular carcinoma (HCC), (ix) The siNA according to claim 126, wherein the disease is non-alcoholic steatohepatitis (NASH).

128. A composition according to any one of claims 115 to 117 for use in the treatment of a disease.

129. (i) Whether the disease is a viral disease, (ii) The disease is caused by a DNA virus, (iii) The disease is caused by double-stranded DNA (dsDNA virus), (iv) The disease is caused by the hepadnavirus, (v) Whether the disease is caused by hepatitis B virus (HBV), (vi) The disease is caused by any one of the HBV genotypes A to J, (vii) Whether the aforementioned disease is a liver disease, (viiii) Whether the disease is non-alcoholic fatty liver disease (NAFLD) or hepatocellular carcinoma (HCC), (ix) The composition according to claim 128, wherein the disease is non-alcoholic steatohepatitis (NASH).

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