Oligomeric compounds and methods

• US 9,738,895 B2
• Filed: 02/10/2015
• Issued: 08/22/2017
• Est. Priority Date: 10/24/2008
• Status: Active Grant

• Current Assignee: Ionis Pharmaceuticals, Inc.
• Original Assignee: Ionis Pharmaceuticals, Inc.
• Inventors: Swayze, Eric E., Bhat, Balkrishen, Lima, Walter F., Prakash, Thazha P., Kinberger, Garth A.
• Primary Examiner(s): Bowman, Amy
• Application Number:
  US14/618,853
• Publication Number:
  US 20150167006A1
• Time in Patent Office: 924 Days
• 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: C12N 15/1137 against enzymes viral enzymes C12N15/1131; receptors C12N15/1138
• CPC Class Codes: C12N 2310/11 Antisense
• CPC Class Codes: C12N 2310/14 interfering N.A.
• CPC Class Codes: C12N 2310/141 MicroRNAs, miRNAs
• CPC Class Codes: C12N 2310/31 of the backbone
• CPC Class Codes: C12N 2310/315 Phosphorothioates
• CPC Class Codes: C12N 2310/321 2'-O-R Modification
• CPC Class Codes: C12N 2310/351 Conjugate

Abstract

The present invention provides oligomeric compounds and uses thereof. In certain embodiments, such oligomeric compounds are useful as antisense compounds. Certain such antisense compounds are useful as RNase H antisense compounds or as RNAi compounds.

Claims

1. An oligomeric compound comprising an antisense oligonucleotide consisting of 16 to 30 linked nucleosides having the formula:

5′

-Q-(E)_w-(A)₂-(B)_x-(A)₂-(C)_y-(A)₃-D

wherein;

each A is a 2′

-OCH₃ modified nucleoside;

each E is, independently, a 2′

-F or a 2′

-OCH₃ modified nucleoside wherein at least the E that is linked to the adjacent 5′

-A is a 2′

-F modified nucleoside;

each B and C is a 2′

-F modified nucleoside;

D is H or 3′

-terminal group;

Q is a 5′

-phosphate stabilizing nucleoside comprising;

i) a 5′

-terminal modified phosphate; and

ii) a 2′

-substituent group selected from F, O—

(CH₂)₂—

O—

CH₃, and OCH₃;

w is from about 4 to about 10;

x is from about 2 to about 4; and

y is from about 3 to about 8.

2. The oligomeric compound of claim 1 wherein the 5′

-terminal modified phosphate is selected from a phosphonate, alkylphosphonate, substituted alkylphosphonate, aminoalkyl phosphonate, substituted aminoalkyl phosphonate, phosphorothioate, phosphoramidate, alkylphosphonothioate, substituted alkylphosphonothioate, phosphorodithioate, and thiophosphoramidate.

3. The oligomeric compound of claim 2 wherein the 5′

-terminal modified phosphate is selected from a phosphonate, alkylphosphonate and substituted alkylphosphonate.

4. The oligomeric compound of claim 1 wherein the 5′

-phosphate stabilizing nucleoside comprises a 5′

-substituent group selected from F and CH₃.

5. The oligomeric compound of claim 1 wherein the 2′

-substituent group is OCH₃.

6. The oligomeric compound of claim 1 wherein each E is a 2′

-F modified nucleoside.

7. The oligomeric compound of claim 1 wherein (E)_w comprises from 1 to 4,2′

-OH₃modified nucleosides.

8. The oligomeric compound of claim 1 wherein w is from 5 to 9, x is from 2 to 3 and y is from 4 to 7 and the sum of w, x and y is from 11 to 19.

9. The oligomeric compound of claim 8 wherein w is from 5 to 9, x is 2 and y is from 5 to 6.

10. The oligomeric compound of claim 1 wherein D is a 3′

-terminal group.

11. The oligomeric compound of claim 10 wherein the 3′

-terminal group comprises two linked 2′

-O—

(CH₂)₂—

OCH₃ modified nucleosides.

12. The oligomeric compound of claim 11 wherein the two linked 2′

-O—

(CH₂)₂—

OCH₃ modified nucleosides are non-hybridizing nucleosides.

13. The oligomeric compound of claim 1 comprising at least one 3′

-terminal group wherein said terminal group comprises a conjugate group.

14. The oligomeric compound of claim 1 wherein each internucleoside linking group linking said linked nucleosides is, independently, a phosphorothioate internucleoside linking group or a phosphodiester internucleoside linking group.

15. The oligomeric compound of claim 1 wherein each internucleoside linking group linking said linked nucleosides is a phosphorothioate internucleoside linking group.

16. The oligomeric compound of claim 1 wherein each internucleoside linking group between adjacent A groups is a phosphodiester internucleoside linking group.

17. The oligomeric compound of claim 1 wherein the oligomeric compound is an RNAi or microRNA compound.

18. A pharmaceutical composition comprising an oligomeric compound according to claim 1 and a pharmaceutically acceptable diluent or carrier.

19. A method of inhibiting gene expression comprising contacting one or more cells with an oligomeric compound of claim 1 wherein said oligomeric compound is complementary to a target RNA.

20. The method of claim 19, wherein the one or more cells are in vitro.

21. The method of claim 19, wherein the one or more cells are in an animal.