Polycyclic sugar surrogate-containing oligomeric compounds and compositions for use in gene modulation

• US 8,124,745 B2
• Filed: 05/05/2010
• Issued: 02/28/2012
• Est. Priority Date: 11/05/2002
• Status: Expired due to Term

• Current Assignee: Ionis Pharmaceuticals, Inc.
• Original Assignee: ISIS Pharmaceuticals Incorporated
• Inventors: Allerson, Charles, Bhat, Balkrishen, Swayze, Eric E., Prakash, Thazha P.
• Primary Examiner(s): ANGELL, JON E
• Application Number:
  US12/774,566
• Publication Number:
  US 20100216982A1
• Time in Patent Office: 664 Days
• Field of Search: 536/22.1, 536/24.5
• US Class Current: 536/22.1
• 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
• CPC Class Codes: C07H 21/04 with deoxyribosyl 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 2310/14 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 2310/323 modified ring structure
• CPC Class Codes: C12N 2310/343 having patterns, e.g. ==--==--==--
• CPC Class Codes: C12N 2310/3521 Methyl
• CPC Class Codes: C12N 2310/3533 Halogen
• CPC Class Codes: C12N 2320/51 modulating the chemical stability, e.g. nuclease-resistance

Abstract

Compositions comprising first and second oligomers are provided wherein at least a portion of the first oligomer is capable of hybridizing with at least a portion of the second oligomer, at least a portion of the first oligomer is complementary to and capable of hybridizing to a selected target nucleic acid, and at least one of the first or second oligomers includes a modification comprising a polycyclic sugar surrogate. Oligomer/protein compositions are also provided comprising an oligomer complementary to and capable of hybridizing to a selected target nucleic acid and at least one protein comprising at least a portion of an RNA-induced silencing complex (RISC), wherein at least one nucleoside of the oligomer has a polycyclic sugar surrogate modification.

Claims

1. A bicyclic nucleoside having the formula:

2. The bicyclic nucleoside of claim 1 wherein R is H.

3. The bicyclic nucleoside of claim 1 wherein R is methyl.

4. The bicyclic nucleoside of claim 1, wherein T₁ is a protected hydroxyl.

5. The bicyclic nucleoside of claim 1, wherein T₁ is a dimethoxytrityl protected hydroxyl.

6. The bicyclic nucleoside of claim 1, wherein T₂ is diisopropylamino cyanoethoxy phosphoramidite.

7. The bicyclic nucleoside of claim 1, wherein T₁ is dimethoxytrityl protected hydroxyl and T2 is diisopropylamino cyanoethoxy phosphoramidite.

8. The bicyclic nucleoside of claim 1 having the configuration:

9. An oligomeric compound comprising at least one bicyclic nucleoside having the formula:

10. The oligomeric compound of claim 9 wherein for each bicyclic nucleoside having said formula R is H.

11. The oligomeric compound of claim 9 wherein for each bicyclic nucleoside having said formula R is methyl.

12. The oligomeric compound of claim 9 wherein each internucleoside linking group is, independently, phosphodiester, phosphorothioate, chiral phosphorothioate, phosphorodithioate, phosphotriester, aminoalkylphosphotriester, methyl and other alkyl phosphonate, chiral phosphonate, phosphinate, phosphoramidate, thionophosphoramidate, thionoalkylphosphonate, thionoalkylphosphotriester, selenophosphate, boranophosphate or methylene(methylimino).

13. The oligomeric compound of claim 9 wherein each internucleoside linking group is, independently, a phosphodiester or a phosphorothioate.

14. The oligomeric compound of claim 9 wherein the configuration of each bicyclic nucleoside having said formula is:

15. The oligomeric compound of claim 9 further comprising at least one nucleoside having the formula:

16. The oligomeric compound of claim 15 comprising a plurality of nucleosides having said formula wherein each J is, independently, H, hydroxyl, protected hydroxyl or a sugar substituent group.

17. The oligomeric compound of claim 9 comprising from about 10 to about 40 nucleosides and or bicyclic nucleosides.

18. The oligomeric compound of claim 9 comprising from about 18 to about 30 nucleosides and or bicyclic nucleosides.

19. The oligomeric compound of claim 9 comprising from about 21 to about 24 nucleosides and or bicyclic nucleosides.

20. The oligomeric compound of claim 9 comprising from about 15 to about 30 nucleosides and or bicyclic nucleosides.