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Last Updated: November 28, 2020

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Claims for Patent: 7,838,657

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Summary for Patent: 7,838,657
Title:Spinal muscular atrophy (SMA) treatment via targeting of SMN2 splice site inhibitory sequences
Abstract: The present invention is directed to methods and compositions capable of blocking the inhibitory effect of a newly-identified intronic inhibitory sequence element, named ISS-N1 (for "intronic splicing silencer"), located in the SMN2 gene. The compositions and methods of the instant invention include oligonucleotide reagents (e.g., oligoribonucleotides) that effectively target the SMN2 ISS-N1 site in the SMN2 pre-mRNA, thereby modulating the splicing of SMN2 pre-mRNA to include exon 7 in the processed transcript. The ISS-N1 blocking agents of the invention cause elevated expression of SMN protein, thus compensating for the loss of SMN protein expression commonly observed in subjects with spinal muscular atrophy (SMA).
Inventor(s): Singh; Ravindra N. (Shrewsbury, MA), Singh; Natalia N. (Shrewsbury, MA), Singh; Nirmal K. (Temple, TX), Androphy; Elliot J. (Natick, MA)
Assignee: University of Massachusetts (Boston, MA)
Application Number:11/295,725
Patent Claims: 1. An oligonucleotide of 15 to 40 linked nucleotides or modified nucleotides in length, which oligonucleotide comprises a sequence: at least 80% complementary to intron 7 of the SMN2 gene over the entire length of the oligonucleotide; and at least 85% complementary to the sequence 5'-CCAGCAUUAUGAAAG-3' (SEQ ID NO: 3); wherein the oligonucleotide comprises at least one modified nucleotide.

2. The oligonucleotide of claim 1, which is at least 90% complementary to the sequence 5'-CCAGCAUUAUGAAAG-3' (SEQ ID NO: 3).

3. The oligonucleotide of claim 1 which is 100% complementary to the sequence 5'-CCAGCAUUAUGAAAG-3' (SEQ ID NO: 3).

4. The oligonucleotide of claim 1 comprising the sequence 5'-CUUUCAUAAUGCUGG-3' (SEQ ID NO: 4).

5. The oligonucleotide of claim 1, which oligonucleotide comprises at least one modified nucleotide which comprises a modified sugar moiety.

6. The oligonucleotide of claim 1, which oligonucleotide comprises at least one 2'-deoxy ribonucleotide.

7. The oligonucleotide of claim 6, wherein the at least one 2'-deoxy ribonucleotide is 2'-deoxy adenosine or 2'-deoxy guanosine.

8. The oligonucleotide of claim 1, wherein the oligonucleotide comprises at least one modified nucleotide comprising a modified sugar moiety which is modified at the 2'-position.

9. The oligonucleotide of claim 8, wherein the modified sugar moiety comprises a 2-substituent selected from the group consisting of: H, OR, R, halo, SH, SR, NH.sub.2, NHR, NR.sub.2, and ON, where R is a C.sub.1-C.sub.6 alkyl, alkenyl, or alkynyl and halo is F, Cl, Br or I.

10. The oligonucleotide of claim 8, wherein the modified sugar moiety comprises a 2' OCH.sub.3.

11. The oligonucleotide of claim 1, wherein the oligonucleotide comprises at least one modified nucleotide selected from the group consisting of 2'-fluoro-cytidine, 2'-fluoro-uridine, 2'-fluoro-adenosine, 2'-fluoro-guanosine, 2'-amino-cytidine, 2'-amino-uridine, 2'-amino-adenosine, 2'-amino-guanosine and 2'-amino-butyryl-pyrene-uridine.

12. The oligonucleotide of claim 1, wherein the oligonucleotide comprises at least one modified nucleotide selected from the group consisting of 5-bromo-uridine, 5-iodo-uridine, 5-methyl-cytidine, ribo-thymidine, 2-aminopurine, 5-fluoro-cytidine, and 5-fluoro-uridine, 2,6-diaminopurine, 4-thio-uridine, and 5-amino-allyl-uridine.

13. The oligonucleotide of claim 1, wherein the oligonucleotide comprises at least one modified linkage.

14. The oligonucleotide of claim 13, wherein the at least one modified linkage is a phosphorothioate linkage.

15. The oligonucleotide of claim 13, wherein each linkage of the oligonucleotide is a phosphorothioate linkage.

16. The oligonucleotide of claim 1, wherein the modified nucleotide is a locked nucleic acid (LNA) nucleotide.

17. The oligonucleotide of claim 1, comprising at least one bicyclic nucleotide.

18. The oligonucleotide of claim 1, wherein each nucleotide of the oligonucleotide is a modified nucleotide.

19. The oligonucleotide of claim 1, wherein each nucleotide of the oligonucleotide comprises a modified sugar moiety.

20. The oligonucleotide of claim 1, wherein each nucleotide of the oligonucleotide is a modified nucleotide and each modified nucleotide comprises the same modification.

21. The oligonucleotide of claim 20, wherein each nucleotide of the oligonucleotide comprises a bicyclic nucleotide.

22. The oligonucleotide of claim 1, wherein each nucleotide of the oligonucleotide comprises a modified sugar moiety which is modified at the 2'-position.

23. The oligonucleotide of claim 22, wherein the modified sugar moiety comprises a 2' substituent selected from the group consisting of: H, OR, R, halo, SH, SR, NH.sub.2, NHR, NR.sub.2, and ON, where R is a C.sub.1-C.sub.6 alkyl, alkenyl, or alkynyl and halo is F, Cl, Br or I.

24. The oligonucleotide of claim 22, wherein each modified sugar moiety comprises a 2' OCH.sub.3.

25. The oligonucleotide of claim 1, which is 20 nucleotides or more in length.

26. A composition comprising the oligonucleotide of claim 1 and a pharmaceutically acceptable carrier.

27. An oligonucleotide of 15 to 40 nucleotides or modified nucleotides in length, wherein the oligonucleotide comprises a sequence: 100% complementary to intron 7 of the SMN2 gene over the entire length of the oligonucleotide; and 100% complementary to the sequence 5'-CCAGCAUUAUGAAAG-3' (SEQ ID NO:3), wherein the oligonucleotide comprises a at least one modified nucleotide comprising a modified sugar moiety.

28. The oligonucleotide of claim 27, which oligonucleotide comprises at least one 2'-deoxy ribonucleotide.

29. The oligonucleotide of claim 28, wherein the at least one 2'-deoxy ribonucleotide is 2'-deoxy adenosine or 2'-deoxy guanosine.

30. The oligonucleotide of claim 27, wherein the oligonucleotide comprises at least one modified nucleotide comprising a modified sugar moiety which is modified at the 2' position.

31. The oligonucleotide of claim 30, wherein the modified sugar moiety comprises a 2'-substituent selected from the group consisting of: H, OR, R, halo, SH, SR, NH.sub.2, NHR, NR.sub.2, and ON, where R is a C.sub.1-C.sub.6 alkyl, alkenyl, or alkynyl and halo is F, Cl, Br or I.

32. The oligonucleotide of claim 30, wherein the modified sugar moiety comprises a 2' OCH.sub.3.

33. The oligonucleotide of claim 27, wherein the modified nucleotide is selected from the group consisting of 2'-fluoro-cytidine, 2'-fluoro-uridine, 2'-fluoro-adenosine, 2'-fluoro-guanosine, 2'-amino-cytidine, 2'-amino-uridine, 2'-amino-adenosine, 2'-amino-guanosine and 2'-amino-butyryl-pyrene-uridine.

34. The oligonucleotide of claim 27, wherein the modified nucleotide is selected from the group consisting of 5-bromo-uridine, 5-iodo-uridine, 5-methyl-cytidine, ribo-thymidine, 2-aminopurine, 5-fluoro-cytidine, and 5-fluoro-uridine, 2,6-diaminopurine, 4-thio-uridine, and 5-amino-allyl-uridine.

35. The oligonucleotide of claim 27, wherein the oligonucleotide comprises at least one modified linkage.

36. The oligonucleotide of claim 27, wherein the at least one modified linkage is a phosphorothioate linkage.

37. The oligonucleotide of claim 35, wherein each linkage is a phosphorothioate linkage.

38. The oligonucleotide of claim 27, which oligonucleotide comprises a locked nucleic acid (LNA) nucleotide.

39. The oligonucleotide of claim 27, comprising at least one bicyclic nucleotide.

40. The oligonucleotide of claim 27, wherein each nucleotide of the oligonucleotide is a modified nucleotide.

41. The oligonucleotide of claim 27, wherein each nucleotide of the oligonucleotide comprises a modified sugar moiety.

42. The oligonucleotide of claim 27, wherein each nucleotide of the oligonucleotide is a modified nucleotide and each modified nucleotide comprises the same modification.

43. The oligonucleotide of claim 27, wherein each nucleotide of the oligonucleotide comprises a bicyclic nucleotide.

44. The oligonucleotide of claim 27, wherein each nucleotide of the oligonucleotide comprises a modified sugar moiety modified at the 2'-position.

45. The oligonucleotide of claim 44, wherein the modified sugar moiety comprises a 2' substituent selected from the group consisting of: H, OR, R, halo, SH, SR, NH.sub.2, NHR, NR.sub.2, and ON, where R is a C.sub.1-C.sub.6 alkyl, alkenyl, or alkynyl and halo is F, Cl, Br or I.

46. The oligonucleotide of claim 44, wherein each modified sugar moiety comprises a 2' OCH.sub.3.

47. The oligonucleotide of claim 27, which is 20 nucleotides or more in length.

48. A composition comprising the oligonucleotide of claim 27 and a pharmaceutically acceptable carrier.

49. The oligonucleotide of claim 1, which comprises the complement of the nucleotide sequence CCAGCAUUAUGAAAGUGAAU, set forth as nucleotides 10-29 of SEQ ID NO:103.

50. The oligonucleotide of claim 48, which consists of the complement of the nucleotide sequence CCAGCAUUAUGAAAGUGAAU, set forth as nucleotides 10-29 of SEQ ID NO:103.

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