Lipophilic conjugated iRNA agents

• US 7,851,615 B2
• Filed: 08/03/2007
• Issued: 12/14/2010
• Est. Priority Date: 04/17/2003
• Status: Active Grant

• Current Assignee: Alnylam Pharmaceuticals Incorporated
• Original Assignee: Alnylam Pharmaceuticals Incorporated
• Inventors: Manoharan, Muthiah, Rajeev, Kallanthottahil G.
• Primary Examiner(s): VIVLEMORE, TRACY ANN
• Application Number:
  US11/833,934
• Publication Number:
  US 20080108801A1
• Time in Patent Office: 1,229 Days
• Field of Search: None
• US Class Current: 536/24.5
• CPC Class Codes: C12N 15/113 Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing when used in plants C12N15/8218
• CPC Class Codes: C12N 2310/14 interfering N.A.
• CPC Class Codes: C12N 2310/321 2'-O-R Modification
• CPC Class Codes: C12N 2310/322 2'-R Modification
• CPC Class Codes: C12N 2310/3515 Lipophilic moiety, e.g. cholesterol
• CPC Class Codes: C12N 2310/3521 Methyl
• CPC Class Codes: C12N 2310/3533 Halogen

Abstract

The invention relates to iRNA agents, which preferably include a monomer in which the ribose moiety has been replaced by a moiety other than ribose. The inclusion of such a monomer can allow for modulation of a property of the iRNA agent into which it is incorporated, e.g., by using the non-ribose moiety as a point to which a ligand or other entity, e.g., a lipophilic moiety is directly, or indirectly, tethered. The invention also relates to methods of making and using such modified iRNA agents.

Claims

1. An iRNA agent comprising a first strand and a second strand, wherein at least one subunit having a formula (II) is incorporated into at least one of said strands, and at least one of said strands leads to the cleavage of a complementary target sequence via a RISC dependent mechanism:

2. The compound of claim 1, wherein R¹ is CH₂OR^b and R⁹ is OH.

3. The compound of claim 2, wherein R¹ and R⁹ are trans.

4. The compound of claim 3, wherein A is O.

5. The compound of claim 3, wherein A is S.

6. The compound of claim 1, wherein R⁷ is (CH₂)₅NHR^d or (CH₂)₅NHC(O)R^d.

7. The compound of claim 1, wherein R^d is lithocholic-oleyl, lauroyl, docosanoyl, stearoyl, palmitoyl, myristoyl, oleoyl, linoleoyl or dodecanoyl.

8. The compound of claim 1, wherein R^d is lauroyl.

9. The compound of claim 1, wherein R^d is dodecanoyl.

10. The compound of claim 1, wherein R^d is stearoyl.

11. The compound of claim 1, wherein R^d is palmitoyl.

12. The compound of claim 1, wherein R^d is myristoyl.

13. The compound of claim 1, wherein R^d is oleoyl.

14. The compound of claim 1, wherein R^d is linoleoyl.

15. The compound of claim 1, wherein R^d is lithocholic-oleyl.

16. The compound of claim 1, wherein R^d is docosanoyl.

17. The compound of claim 1, wherein R^d is PEG.

18. The compound of claim 1, wherein R^d is PEG-5K.

19. The compound of claim 1, wherein R^d is PEG-20K.

20. The compound of claim 1, wherein R^d is PEG-40K.

21. An iRNA agent comprising a first strand and a second strand, wherein at least one subunit having a formula (II) is incorporated into at least one of said strands, and at least one of said strands leads to the cleavage of a complementary target sequence via a RISC dependent mechanism:

22. The compound of claim 21, wherein R¹ is CH₂OR^b and R⁹ is OH.

23. The compound of claim 21, wherein R⁷ is (CH₂)₅NHR^d or (CH₂)₅NHC(O)R^d.

24. The compound of claim 21, wherein R^d is lithocholic-oleyl, lauroyl, docosanoyl, stearoyl, palmitoyl, myristoyl, oleoyl, linoleoyl or dodecanoyl.

25. The compound of claim 21, wherein R^d is PEG, PEG-5K, PEG-20K, or PEG-40K.