METHODS OF USING OLIGOMERIC COMPOUNDS COMPRISING 2'-SUBSTITUTED NUCLEOSIDES

• US 20120059045A1
• Filed: 10/23/2009
• Published: 03/08/2012
• Est. Priority Date: 10/24/2008
• Status: Abandoned Application

• Current Assignee: ISIS Pharmaceuticals Incorporated
• Original Assignee: ISIS Pharmaceuticals Incorporated
• Inventors: Prakash, Thazha P., Siwkowski, Andrew M., Swayze, Eric E., Bhat, Balkrishen
• Application Number:
  US13/125,560
• Publication Number:
  US 20120059045A1
• Time in Patent Office: Days
• US Class Current: 514/44.A
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: C07H 19/10 with the saccharide radical esterified by phosphoric or polyphosphoric acids
• CPC Class Codes: C07H 21/00 Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids

Abstract

The present disclosure provides oligomeric compounds comprising at least one 2′-fluoroethoxy modified nucleoside of formula I and methods of using these oligomeric compounds. The methods provided herein include contacting a cell or administering to an animal at least one of the oligomeric compounds. In certain embodiments, the oligomeric compounds hybridize to a portion of a target RNA resulting in loss of normal function of the target RNA.

Claims

1. A method comprising contacting a cell with an oligomeric compound, wherein said oligomeric compound comprises at least one 2′

-fluoroethoxy modified nucleoside having formula I;

2. The method of claim 1 wherein R₁ and R₂ are each H for each of said 2′

-fluoroethoxy modified nucleosides of formula I.

3. The method of claim 1 wherein one of R₁ and R₂ is F for each of said 2′

-fluoroethoxy modified nucleosides of formula I.

4. The method of claim 1 wherein R₁ and R₂ are each F for each of said 2′

-fluoroethoxy modified nucleosides of formula I.

5. The method of claim 1 wherein each Bx is, independently, an optionally protected uracil, thymine, cytosine, 5-methylcytosine, adenine or guanine.

6. The method of any claim 1 wherein said oligomeric compound further comprises a 5′

or 3′

-terminal group.

7. The method of claim 1 wherein each linked monomeric subunit that is not a β

-D-2′

-deoxyribonucleoside or a 2′

-fluoroethoxy modified nucleoside of formula I is a modified nucleoside wherein each modified nucleoside is, independently, a bicyclic modified nucleoside, a 2′

-modified nucleoside, a 4′

-thio modified nucleoside or a 4′

-thio-2′

-modified nucleoside.

11. The method of claim 1 wherein said oligomeric compound comprises a gapped oligomeric compound comprising two external regions separated by an internal region wherein each external region independently comprises from 1 to 5 contiguous 2′

-fluoroethoxy modified nucleosides having formula I and the internal region comprises from 6 to about 23 contiguous monomeric subunits independently selected from nucleosides and modified nucleosides.

13. The method of claim 11 wherein essentially each monomeric subunit in the internal region is a β

-D-2′

-deoxyribonucleoside.

15. The method of claim 11 wherein each external region comprises from 1 to 3 2′

-fluoroethoxy modified nucleosides having formula I and the internal region comprises from about 10 to about 14 β

-D-2′

-deoxyribonucleosides.

21. The method of claim 15 wherein each external region comprises 2 2′

-fluoroethoxy modified nucleosides having formula I and the internal region comprises 10 β

-D-2′

-deoxyribonucleosides.

23. The method of any claim 1 wherein said oligomeric compound comprises a 5′

-terminal 2′

-fluoroethoxy modified nucleoside having formula I wherein T₁ is a phosphate group.

26. The method of claim 1 wherein each internucleoside linking group is, independently, a phosphodiester or a phosphorothioate.

28. The method of claim 1 wherein said oligomeric compound comprises from 8 to about 18 linked monomeric subunits.

30. The method of claim 1 wherein said oligomeric compound comprises from 10 to about 14 linked monomeric subunits.

32. The method of claim 1 wherein said oligomeric compound comprises from 18 to about 21 linked monomeric subunits.

33. The method of claim 1 wherein said oligomeric compound comprises from 19 to about 20 linked monomeric subunits.

34. The method of claim 1 wherein said cell is in an animal.

35. The method of claim 1 wherein said cell is in a human.

36. The method of claim 1 wherein said target RNA is selected from mRNA, pre-mRNA and micro RNA.

38. The method of claim 36 wherein said target RNA is human mRNA.

39. The method of claim 1 wherein said target RNA is cleaved thereby inhibiting its function.

40. The method of claim 1 further comprising evaluating the antisense activity of said oligomeric compound on said cell.

41. The method of claim 40 wherein said evaluating comprises detecting the levels of target RNA.

42. The method of claim 40 wherein said evaluating comprises detecting the levels of a protein.

43. The method of claim 40 wherein said evaluating comprises detection of one or more phenotypic effects.

87. The method of claim 7 wherein each linked monomeric subunit that is not a 2′

-fluoroethoxy modified nucleoside of formula I is a modified nucleoside.

8-10. -10. (canceled)

12. (canceled)

14. (canceled)

16-20. -20. (canceled)

22. (canceled)

24-25. -25. (canceled)

27. (canceled)

29. (canceled)

31. (canceled)

37. (canceled)

44-86. -86. (canceled)