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Last Updated: March 29, 2024

Details for Patent: 8,742,092


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Title:RNA sequence-specific mediators of RNA interference
Abstract: The present invention relates to a Drosophila in vitro system which was used to demonstrate that dsRNA is processed to RNA segments 21-23 nucleotides (nt) in length. Furthermore, when these 21-23 nt fragments are purified and added back to Drosophila extracts, they mediate RNA interference in the absence of long dsRNA. Thus, these 21-23 nt fragments are the sequence-specific mediators of RNA degradation. A molecular signal, which may be their specific length, must be present in these 21-23 nt fragments to recruit cellular factors involved in RNAi. This present invention encompasses these 21-23 nt fragments and their use for specifically inactivating gene function. The use of these fragments (or chemically synthesized oligonucleotides of the same or similar nature) enables the targeting of specific mRNAs for degradation in mammalian cells, where the use of long dsRNAs to elicit RNAi is usually not practical, presumably because of the deleterious effects of the interferon response. This specific targeting of a particular gene function is useful in functional genomic and therapeutic applications.
Inventor(s): Tuschl; Thomas (Brooklyn, NY), Sharp; Phillip A. (Newton, MA), Zamore; Phillip D. (Northborough, MA), Bartel; David P. (Brookline, MA)
Assignee: University of Massachusetts (Boston, MA) Whitehead Institute for Biomedical Research (Cambridge, MA) Massachusetts Institute of Technology (Cambridge, MA) Max-Planck-Gesellschaft zur Forderung der Wissenschaften E.V. (Munich, DE)
Filing Date:Oct 04, 2010
Application Number:12/897,756
Claims:1. A pharmaceutical composition comprising: an isolated double-stranded RNA molecule of from 21 to 23 nucleotides, comprising two separate RNA strands which are not covalently linked, that is perfectly complementary to a cellular mRNA and mediates RNA interference of the mRNA; and an appropriate carrier.

2. A pharmaceutical composition comprising: an isolated double-stranded RNA molecule of from 21 to 23 nucleotides, which is chemically synthesized in the form of two separate RNA strands which are not covalently linked, that is perfectly complementary to a cellular mRNA and mediates RNA interference of the mRNA; and an appropriate carrier.

3. A composition comprising an isolated, chemically synthesized double-stranded RNA molecule of 21 or 23 nucleotides, comprising two separate RNA strands which are not covalently linked, that is perfectly complementary to a mammalian cellular mRNA and mediates RNA interference by directing cleavage of the mRNA to which it corresponds, wherein cleavage is directed within the region of sequence correspondence with the isolated RNA molecule.

4. A pharmaceutical composition comprising: an isolated double-stranded RNA molecule of 21 or 23 nucleotides, in the form of two separate RNA strands which are not covalently linked, that is perfectly complementary to an mRNA and mediates RNA interference of the mRNA, wherein the isolated RNA molecule comprises one or more of a non-naturally occurring nucleotide, or a deoxyribonucleotide, or a non-standard nucleotide; and an appropriate carrier.

5. The pharmaceutical composition of claim 1, wherein a strand of the isolated RNA molecule is 21 nucleotides in length.

6. The pharmaceutical composition of claim 1, wherein a strand of the isolated RNA molecule is 22 nucleotides in length.

7. The pharmaceutical composition of claim 1, wherein a strand of the isolated RNA molecule is 23 nucleotides in length.

8. The pharmaceutical composition of claim 1, wherein the cellular mRNA is a human mRNA.

9. The pharmaceutical composition of claim 1, wherein the isolated RNA molecule comprises a terminal 3' hydroxyl group.

10. The composition of claim 3, further comprising an appropriate carrier, wherein the composition is a pharmaceutical composition.

11. A pharmaceutical composition comprising: an isolated double-stranded RNA molecule of 21 or 23 nucleotides, comprising two separate RNA strands which are not covalently linked, said RNA molecule comprising an RNA strand that is perfectly complementary to an mRNA to mediate RNA interference of the mRNA, wherein the mRNA encodes a protein whose presence in a human is associated with a disease or an undesirable condition; and an appropriate carrier.

12. The composition of claim 11, wherein the isolated RNA molecule is chemically synthesized.

13. The composition of claim 11, wherein the RNA molecule comprises one or more of a non-naturally occurring nucleotide, or a deoxyribonucleotide, or a non-standard nucleotide.

14. A pharmaceutical composition comprising: an isolated double-stranded RNA molecule of from 21 to 23 nucleotides, comprising two separate RNA strands which are not covalently linked, said RNA molecule comprising an RNA strand that is perfectly complementary to an mRNA to mediate RNA interference of the mRNA, wherein the double-stranded RNA molecule reduces expression of the mRNA and the mRNA encodes a protein whose presence in a human is associated with a disease or an undesirable condition; and an appropriate carrier.

15. The composition of claim 14, wherein the isolated RNA is chemically synthesized.

16. The composition of claim 14, wherein the RNA molecule comprises one or more of a non-naturally occurring nucleotide, or a deoxyribonucleotide, or a non-standard nucleotide.

17. A composition comprising an isolated double-stranded RNA molecule of 21 or 23 nucleotides in length, comprising two RNA strands which are not covalently linked, wherein the RNA molecule comprises an RNA strand that is perfectly complementary to an mRNA to mediate RNA interference.

18. The composition of claim 17, wherein the double-stranded RNA molecule is chemically synthesized.

19. The composition of claim 17, wherein the double-stranded RNA molecule comprises one or more non-naturally occurring nucleotides.

20. The composition of claim 17, wherein the double-stranded RNA molecule comprises one or more non-standard nucleotides.

21. The composition of claim 17, wherein the double-stranded RNA molecule comprises one or more deoxyribonucleotides.

22. The composition of claim 17, wherein the double-stranded RNA molecule comprises a terminal 3' hydroxyl group.

23. The composition of claim 17, wherein each RNA strand of the double-stranded RNA molecule comprises a terminal 3' hydroxyl group.

24. The composition of claim 17, wherein the mRNA is a cellular mRNA.

25. The composition of claim 17, wherein the mRNA is a mammalian mRNA.

26. The composition of claim 17, wherein the mRNA is a human mRNA.

27. The composition of claim 17, wherein the mRNA encodes a protein that is associated with a disease or an undesirable condition.

28. The composition of claim 17, wherein the mRNA is a viral mRNA.

29. The composition of claim 17, wherein a strand of the double-stranded RNA molecule is 21 nucleotides in length.

30. The composition of claim 17, wherein a strand of the double-stranded RNA molecule is 23 nucleotides in length.

31. The composition of claim 17, further comprising an appropriate carrier.

32. A composition comprising an isolated, chemically synthesized double-stranded RNA molecule of from 21 to 23 nucleotides in length, in the form of two RNA strands which are not covalently linked, wherein: (i) the double-stranded RNA molecule comprises a strand that is perfectly complementary to an mRNA to mediate RNA interference; and (ii) the double-stranded RNA molecule comprises one or more non-naturally occurring nucleotides, wherein the mRNA encodes a cellular protein or a viral protein.

33. The composition of claim 32, wherein the double-stranded RNA molecule comprises a terminal 3' hydroxyl group.

34. The composition of claim 32, wherein a strand of the double-stranded RNA molecule is 21 nucleotides in length.

35. The composition of claim 32, wherein a strand of the double-stranded RNA molecule is 22 nucleotides in length.

36. The composition of claim 32, wherein a strand of the double-stranded RNA molecule is 23 nucleotides in length.

37. The composition of claim 32, wherein the mRNA is a cellular mRNA.

38. The composition of claim 32, wherein the mRNA is a mammalian mRNA.

39. The composition of claim 32, wherein the mRNA is a human mRNA.

40. The composition of claim 32, wherein the mRNA encodes a protein that is associated with a disease or an undesirable condition.

41. The composition of claim 32, wherein the mRNA is a viral mRNA.

42. The composition of claim 32, further comprising an appropriate carrier.

43. The pharmaceutical composition of claim 1, wherein the mRNA is a mammalian mRNA.

44. The pharmaceutical composition of claim 2, wherein the mRNA is a mammalian mRNA.

45. The composition of claim 17, wherein the mRNA is an oncogene mRNA.

46. The composition of claim 32, wherein the mRNA is an oncogene mRNA.

47. The composition of claim 17, wherein both strands of the double-stranded RNA molecule are 21 nucleotides in length.

48. The composition of claim 17, wherein both strands of the double-stranded RNA molecule are 23 nucleotides in length.

49. The composition of claim 32, wherein both strands of the double-stranded RNA molecule are 21 nucleotides in length.

50. The composition of claim 32, wherein both strands of the double-stranded RNA molecule are 22 nucleotides in length.

51. The composition of claim 32, wherein both strands of the double-stranded RNA molecule are 23 nucleotides in length.

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