Modified iRNA agents

• US 8,344,125 B2
• Filed: 11/16/2009
• Issued: 01/01/2013
• Est. Priority Date: 04/17/2003
• Status: Active Grant

• Current Assignee: Alnylam Pharmaceuticals Incorporated
• Original Assignee: Alnylam Pharmaceuticals Incorporated
• Inventors: Manoharan, Muthiah, Rajeev, Kallanthottathil G.
• Primary Examiner(s): VIVLEMORE, TRACY ANN
• Application Number:
  US12/619,382
• Publication Number:
  US 20100179309A1
• Time in Patent Office: 1,142 Days
• Field of Search: None
• US Class Current: 536/24.5
• CPC Class Codes: A61K 47/55 the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
• CPC Class Codes: A61K 47/554 the modifying agent being a steroid plant sterol, glycyrrhetic acid, enoxolone or bile acid
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: C07H 21/02 with ribosyl as saccharide radical
• CPC Class Codes: C12N 15/111 General methods applicable to biologically active non-coding nucleic acids
• 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 2310/11 Antisense
• CPC Class Codes: C12N 2310/14 interfering N.A.
• CPC Class Codes: C12N 2310/315 Phosphorothioates
• CPC Class Codes: C12N 2310/321 2'-O-R Modification
• CPC Class Codes: C12N 2310/323 modified ring structure
• CPC Class Codes: C12N 2310/344 Position-specific modifications, e.g. on every purine, at the 3'-end
• CPC Class Codes: C12N 2310/3515 Lipophilic moiety, e.g. cholesterol
• CPC Class Codes: C12N 2320/32 Special delivery means, e.g. tissue-specific
• CPC Class Codes: C12N 2320/51 modulating the chemical stability, e.g. nuclease-resistance
• CPC Class Codes: C12N 2330/30 chemically synthesised

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The invention relates to iRNA agents, which preferably include a monomer in which the ribose moiety has been replaced by a moiety other than ribose.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 carbohydrate; or a steroid, e.g., cholesterol, which is optionally substituted with at least one carbohydrate. 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 (I) is incorporated into at least one of said strands:

2. The compound of claim 1, wherein R³ is OR^a.

3. The compound of claim 2, wherein

4. The compound of claim 2, wherein A is O.

5. The compound of claim 2, wherein A is S.

6. The compound of claim 1, wherein R³ is OR^b.

7. The compound of claim 2, wherein R⁷ is (CH₂)₅NHR^d or (CH₂)₅NHC(O)R^d.

8. The compound of claim 2, wherein R^d is chosen from the group of a galactose radical, an N-acetylgalactose radical, or a mannose radical.

9. The compound of claim 1, wherein R⁹ is OR^a.

10. The iRNA agent of claim 9, wherein

11. The iRNA agent of claim 1, wherein R⁹ is OR^b.

16. The iRNA agent of claim 1, wherein X is N(CO)R⁷.

17. The iRNA agent of claim 16, wherein R⁷ is a C₃-C₈ alkyl substituted with NHC(O)R^d.

18. The iRNA agent of claim 17, wherein R^d is chosen from the group of a galactose radical, an N-acetylgalactose radical, or a mannose radical.

19. The iRNA agent of claim 1, wherein A is O in each occurrence.

20. The iRNA agent of claim 1, wherein A is S in at least one occurrence.

12. An iRNA agent comprising a first strand and a second strand, wherein at least one subunit having a formula (I′

) is incorporated into at least one of said strands;

13. The iRNA agent of claim 12, wherein R⁹ is OR^a.

14. The iRNA agent of claim 12, wherein R⁹ is OR^b.

15. The iRNA agent of claim 12, wherein