LIPID FORMULATED SINGLE STRANDED RNA

• US 20130156845A1
• Filed: 04/29/2011
• Published: 06/20/2013
• Est. Priority Date: 04/29/2010
• Status: Abandoned Application

• Current Assignee: Alnylam Pharmaceuticals Incorporated
• Original Assignee: Alnylam Pharmaceuticals Incorporated, ISIS Pharmaceuticals Incorporated (Ionis Pharmaceuticals, Inc.)
• Inventors: Manoharan, Muthiah, Elbashir, Sayda, Rajeev, Kallanthottathil G., Prakash, Thazha P., Swayze, Eric E., Lima, Walter F.
• Application Number:
  US13/643,940
• Publication Number:
  US 20130156845A1
• Time in Patent Office: Days
• US Class Current: 424/450
• CPC Class Codes: A61K 31/7088 Compounds having three or more nucleosides or nucleotides
• CPC Class Codes: A61K 9/1272 with substantial amounts of non-phosphatidyl, i.e. non-acylglycerophosphate, surfactants as bilayer-forming substances, e.g. cationic lipids with cholesterol as the only non-phosphatidyl surfactant A61K9/127; lipids as modifying agent A61K47/543
• CPC Class Codes: A61K 9/1275 Lipoproteins; Chylomicrons; Artificial HDL, LDL, VLDL, protein-free species thereof; Precursors thereof
• CPC Class Codes: C12N 15/111 General methods applicable to biologically active non-coding nucleic acids
• CPC Class Codes: C12N 15/88 using microencapsulation, e.g. using amphiphile liposome vesicle
• CPC Class Codes: C12N 2310/11 Antisense
• CPC Class Codes: C12N 2320/32 Special delivery means, e.g. tissue-specific

Abstract

The present invention provides compositions comprising a nucleic acid lipid particle and an oligomeric compound and uses thereof. In certain embodiments, such compositions are useful as antisense compounds. Certain such antisense compounds are useful as RNase H antisense compounds or as RNAi compounds.

Claims

1. A composition comprising a nucleic acid lipid particle comprising a single stranded RNA, wherein the nucleic acid lipid particle comprises a lipid formulation comprising 45-65 mol % of a cationic lipid, 5 mol % to about 10 mol %, of a non-cationic lipid, 25-40 mol % of a sterol, and 0.5-5 mol % of a PEG or PEG-modified lipid.

2. The composition of claim 1, wherein the cationic lipid comprises formula A wherein formula A is

3. The composition of claim 2, wherein the cationic lipid comprises 2,2-Dilinoleyl-4-dimethylaminoethyl-[1,3]-dioxolane.

4. The composition of claim 2, wherein the cationic lipid comprises 2,2-Dilinoleyl-4-dimethylaminoethyl-[1,3]-dioxolane, the non-cationic lipid comprises DSPC, the sterol comprises cholesterol and the PEG lipid comprises PEG-DMG.

5. The composition of claim 4, wherein the cationic lipid comprises 2,2-Dilinoleyl-4-dimethylaminoethyl-[1,3]-dioxolane and the formulation is selected from the group consisting of:

6. The composition of claim 1, wherein the single stranded RNA comprising a nucleoside having Formula I:

7. The composition of claim 1, wherein the single stranded RNA comprising a nucleoside having Formula II:

8. The composition of claim 1, wherein the single stranded RNA comprising a nucleoside having Formula III:

9. The composition of claim 8 wherein R₁ is selected from halogen, O-alkyl, O-haloalkyl, O-alkoxy.

10. The composition of claim 8 wherein R₁ is F.

11. The oligomeric compound of claim 8 wherein R₁ is O—

C₂-C₄ alkyl or haloalkyl.

12. The oligomeric compound of claim 8 wherein R₁ is OCH₃.

13. The oligomeric compound of claim 8 wherein R₁ is O(CH₂)₂OCH₃.

14. The oligomeric compound of claim 8 wherein R₁ is FCH₂CH₄.

15. The oligomeric compound of claim 8 wherein R₁ is (CH₂)₂[O(CH₂)₂]_tOCH₃, where t is from 1-3.

16. The oligomeric compound of claim 8 wherein R₁ is selected from, trifluoroalkoxy, azido, aminooxy, S-alkyl, N(J₄)-alkyl, O-alkenyl, S-alkenyl, N(J₄)-alkenyl, O-alkynyl, S-alkynyl, N(J₄)-alkynyl, and X₂—

V.

17. The oligomeric compound of claim 8 wherein R₁ is X₂—

V.

18. The oligomeric compound of claim 17 wherein V is (CH₂)₂F.

19. The oligomeric compound of claim 17 wherein V is CH₂CONH(CH₂)_i—

S—

R₄

20. The oligomeric compound of claim 17 wherein V is CH₂CONH[(CH₂)_k1—

N(H)]_k2—

(CH₂)_k1NH₂.

21. The oligomeric compound of claim 17 wherein V is CH₂CONH—

(CH₂)₃—

N(H)—

(CH₂)₄—

N(H)—

(CH₂)₃NH₂.

22. The oligomeric compound of claim 17 wherein V is CH₂CONH(CH₂)_JNR₅R₆.

23. The oligomeric compound of claim 22 wherein R₅ is methyl and R₆ is methyl.

24. The oligomeric compound of claim 8, wherein X₂ is O.

25. The oligomeric compound of claim 8, wherein X₂ is S.

26. The oligomeric compound of claim 8, wherein X₂ is CR₇R₈.

27. The oligomeric compound of claim 8, wherein at least one of q₁ and q₂ is C₁-C₆ alkyl or substituted C₁-C₆ alkyl.

28. The oligomeric compound of claim 27 wherein at least one of q₁ and q₂ is C₁-C₆ alkyl.

29. The oligomeric compound of claim 6, wherein the phosphorus moiety is P(Y_a)(Y_b)(Y_c), where Y_a is O or S, and each Y_b and Y_c is, independently, selected from OH, SH, alkyl, alkoxy, substituted C₁-C₆ alkyl and substituted C₁-C₆ alkoxy.

30. The oligomeric compound of claim 29 wherein Y_a is O and Y_b and Y_c are each OH.

31. The composition of claim 1, further comprising a lipoprotein.

32. The composition of claim 1, further comprising apolipoprotein E (ApoE).