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Last Updated: October 31, 2020

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Claims for Patent: 9,567,582

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Summary for Patent: 9,567,582
Title:RNA interference mediating small RNA molecules
Abstract: Double-stranded RNA (dsRNA) induces sequence-specific post-transcriptional gene silencing in many organisms by a process known as RNA interference (RNAi). Using a Drosophila in vitro system, we demonstrate that 19-23 nt short RNA fragments are the sequence-specific mediators of RNAi. The short interfering RNAs (siRNAs) are generated by an RNase III-like processing reaction from long dsRNA. Chemically synthesized siRNA duplexes with overhanging 3' ends mediate efficient target RNA cleavage in the lysate, and the cleavage site is located near the center of the region spanned by the guiding siRNA. Furthermore, we provide evidence that the direction of dsRNA processing determines whether sense or antisense target RNA can be cleaved by the produced siRNP complex.
Inventor(s): Tuschl; Thomas (Brooklyn, NY), Elbashir; Sayda Mahgoub (Cambridge, MA), Lendeckel; Winfried (Hohengandern, DE)
Assignee: MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN E.V. (Munich, DE) MASSACHUSETTS INSTITUTE OF TECHNOLOGY (Cambridge, MA) WHITEHEAD INSTITUTE OF BIOMEDICAL TECHNOLOGY (Cambridge, MA) UNIVERSITY OF MASSACHUSETTS (Boston, MA)
Application Number:14/476,465
Patent Claims: 1. An isolated double-stranded RNA molecule comprising a sense strand and an antisense strand, wherein: (i) each strand consists of 19-52 nucleotides; (ii) the RNA molecule comprises at least one 3'-overhang; (iii) the RNA molecule is non-enzymatically processed; and (iv) the RNA molecule is capable of target-specific RNA interference.

2. The RNA molecule of claim 1, wherein the 3'-overhang is from 1-5 nucleotides.

3. The RNA molecule of claim 1, wherein each strand has a length from 19-23.

4. The RNA molecule of claim 2, wherein the 3'-overhang is from 1-3 nucleotides.

5. The RNA molecule of claim 2, wherein the 3'-overhang is stabilized against degradation.

6. The RNA molecule of claim 1, which contains at least one modified nucleotide analogue.

7. The RNA molecule of claim 6, wherein the modified nucleotide analogue is selected from a sugar-modified ribonucleotide or a backbone modified ribonucleotide, or a combination thereof.

8. The RNA molecule according to claim 6, wherein the nucleotide analogue is a sugar-modified ribonucleotide, wherein the 2'-OH group is replaced by a group selected from H, OR, R, halo, SH, SR', NH.sub.2, NHR, N(R).sub.2 or CN, wherein R is C.sub.1-C.sub.6 alkyl, alkenyl or alkynyl and halo is F, Cl, Br or I.

9. The RNA molecule of claim 6, wherein the nucleotide analogue is a backbone-modified ribonucleotide containing a phosphorothioate group.

10. A pharmaceutical composition comprising at least one double-stranded RNA molecule of claim 1 and a pharmaceutical carrier.

11. The composition of claim 10 for diagnostic applications.

12. The composition of claim 10 for therapeutic applications.

13. The RNA molecule of claim 1, which comprises a single double stranded region.

14. The RNA molecule of claim 1, which comprises a single 3'-overhang.

15. The RNA molecule of claim 1, wherein the 3'-overhang is 2 nucleotides in length.

16. The RNA molecule of claim 1, wherein the double-stranded portion of the RNA molecule has an identity of at least 85 percent to a target mRNA molecule.

17. The RNA molecule of claim 1, wherein the double-stranded portion of the RNA molecule has an identity of 100 percent to a target mRNA molecule.

18. The RNA molecule of claim 1, wherein either the sense strand or the antisense strand is modified or blocked at the 3'-end.

19. The RNA molecule of claim 18, which is modified or blocked by a 3' extension of 17 to 20 nucleotides.

20. The RNA molecule of claim 1, which comprises a blunt 3'-end.

21. The RNA molecule of claim 1, wherein dsRNA processing originates at the 3'-end of the antisense strand of the RNA molecule.

22. The RNA molecule of claim 1, wherein the sense strand is 19-25 nucleotides in length.

23. The RNA molecule of claim 1, wherein the antisense strand is 19-25 nucleotides in length.

24. The RNA molecule of claim 1, wherein the antisense strand is complementary to a target mRNA molecule.

25. The RNA molecule of claim 1, wherein the sense strand is identical to a target mRNA molecule.

26. The RNA molecule of claim 6, wherein the at least one nucleotide analogue is a nucleotide lacking a 2'-hydroxyl in a sugar.

27. The RNA molecule of claim 6, wherein the at least one nucleotide analogue is located at one or more of the 5'-end, the 3'-end, the 3'-overhang, or all, of the double stranded RNA molecule.

28. The RNA molecule of claim 6, wherein the at least one nucleotide analogue is located at the 3'-end of the sense strand.

29. The RNA molecule of claim 1, wherein the 3'-overhang is in the antisense strand.

30. The RNA molecule of claim 1, wherein the 3'-overhang is in the sense strand.

31. An isolated double-stranded RNA molecule, comprising a double-stranded region consisting of 19-52 base pairs and a 3'-overhang, wherein the RNA molecule is non-enzymatically processed, and is capable of target-specific RNA interference.

32. The RNA molecule of claim 31, which comprises at least one nucleotide analogue.

33. The RNA molecule of claim 32, wherein the at least one nucleotide analogue is selected from a sugar- or a backbone-modified ribonucleotide, or a combination thereof.

34. The RNA molecule of claim 32, wherein the at least one nucleotide analogue is a sugar-modified ribonucleotide, wherein the 2'-OH group is replaced by a group selected from H, OR, R, halo, SH, SR, NH.sub.2, NHR, NR.sub.2 or CN, wherein R is C.sub.1-C.sub.6 alkyl, alkenyl or alkynyl and halo is F, Cl, Br or I.

35. The RNA molecule of claim 32, wherein the at least one nucleotide analogue is a backbone-modified ribonucleotide containing a phosphorothioate group.

36. The RNA molecule of claim 32, which comprises a single double stranded region.

37. The RNA molecule of claim 36, which comprises a single 3'-overhang.

38. The RNA molecule of claim 32, wherein the 3'-overhang is 1-5 nucleotides in length.

39. The RNA molecule of claim 32, wherein the 3'-overhang is 1-3 nucleotides in length.

40. The RNA molecule of claim 32, wherein the 3'-overhang is 2 nucleotides in length.

41. The RNA molecule of claim 32, wherein the double-stranded portion of the RNA molecule has an identity of at least 85 percent to a target mRNA molecule.

42. The RNA molecule of claim 32, wherein the double-stranded portion of the RNA molecule has an identity of 100 percent to a target mRNA molecule.

43. A composition comprising at least one RNA molecule of claim 32 and a pharmaceutical carrier.

44. The RNA molecule of claim 1, which mediates RNA interference of a mammalian RNA.

45. The RNA molecule of claim 32, which mediates RNA interference of a mammalian RNA.

46. The RNA molecule of claim 1, which mediates RNA interference of a human RNA.

47. The RNA molecule of claim 32, which mediates RNA interference of a human RNA.

48. The RNA molecule of claim 1, which mediates RNA interference of a plant RNA.

49. The RNA molecule of claim 32, which mediates RNA interference of a plant RNA.

50. The RNA molecule of claim 1, which mediates RNA interference of a target gene chosen from a pathogen-associated gene, a viral gene, a tumor-associated gene, or an autoimmune disease-associated gene.

51. The RNA molecule of claim 32, which mediates RNA interference of a target gene chosen from a pathogen-associated gene, a viral gene, a tumor-associated gene, or an autoimmune disease-associated gene.

52. The RNA molecule of claim 6, wherein the nucleotide analogue comprises a modified nucleobase or a non-naturally-occurring nucleobase.

53. The RNA molecule of claim 32, wherein the nucleotide analogue comprises a modified nucleobase or a non-naturally-occurring nucleobase.

54. An isolated double-stranded RNA molecule comprising a sense strand and an antisense strand, wherein: (i) each strand consists of 19-52 nucleotides; (ii) the RNA molecule comprises at least one 3'-overhang; (iii) the RNA molecule is synthetic; (iv) the RNA molecule comprises at least one nucleotide analogue; and (v) the RNA molecule is capable of target-specific RNA interference.

55. The RNA molecule of claim 54, wherein the RNA molecule is synthesized by chemical synthesis.

56. The RNA molecule of claim 54, wherein the RNA molecule is not prepared by enzymatic transcription.

57. The RNA molecule of claim 54, wherein the at least one nucleotide analogue is selected from a sugar- or a backbone-modified ribonucleotide, or a combination thereof.

58. The RNA molecule of claim 54, wherein the at least one nucleotide analogue is a sugar-modified ribonucleotide, wherein the 2'-OH group is replaced by a group selected from H, OR, R, halo, SH, SR, NH.sub.2, NHR, NR.sub.2 or CN, wherein R is C.sub.1-C.sub.6 alkyl, alkenyl or alkynyl and halo is F, Cl, Br or I.

59. The RNA molecule of claim 54, wherein the at least one nucleotide analogue is a backbone-modified ribonucleotide containing a phosphorothioate group.

60. The RNA molecule of claim 54, wherein the 3'-overhang is 1-5 nucleotides in length.

61. The RNA molecule of claim 54, which mediates RNA interference of a target gene chosen from a pathogen-associated gene, a viral gene, a tumor-associated gene, or an autoimmune disease-associated gene.

62. A pharmaceutical composition comprising at least one double-stranded RNA molecule of claim 54 and a pharmaceutical carrier.

63. The RNA molecule of claim 6, which is enzymatically processed after administration to a subject.

64. The RNA molecule of claim 32, which is enzymatically processed after administration to a subject.

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