OLIGOMERIC COMPOUNDS AND METHODS

• US 20150167006A1
• Filed: 02/10/2015
• Published: 06/18/2015
• Est. Priority Date: 10/24/2008
• Status: Active Grant

• Current Assignee: Ionis Pharmaceuticals, Inc.
• Original Assignee: ISIS Pharmaceuticals Incorporated
• Inventors: Swayze, Eric E., Lima, Walter F., Prakash, Thazha P., Kinberger, Garth A., Bhat, Balrkishen
• Granted Patent: US 9,738,895 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• 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: 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 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 H, a 5′

-phosphate stabilizing nucleoside or a 5′

-terminal group;

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 Q is a 5′

-phosphate stabilizing nucleoside comprising;

i) a 5′

-terminal modified phosphate;

or

ii) a 5′

-terminal unmodified phosphate and a modified sugar moiety comprising a 5′

-modification;

or

iii) a 5′

-terminal modified phosphate and a modified sugar moiety comprising a 5′

-modification.

3. The oligomeric compound of claim 2 comprising a 5′

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

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

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

5. The oligomeric compound of claim 2 comprising a modified sugar moiety comprising a 5′

-modification wherein the 5′

-modification is a 5′

-substituent group selected from F and CH₃.

6. The oligomeric compound of claim 5 comprising a sugar moiety comprising a 5′

-modification wherein the sugar moiety comprising a 5′

-modification further comprises a 2′

-modification selected from halogen, allyl, amino, azido, thio, O-allyl, O—

C₁-C₁₀ alkyl, O—

C₁-C₁₀ substituted alkyl, OCF₃, O—

(CH₂)₂—

O—

CH₃, O(CH₂)₂SCH₃, O—

(CH₂)₂—

O—

N(R_m)(R_n), O—

CH₂—

C(═

O)—

N(R_m)(R_n), where each R_m and R_n is, independently, H or substituted or unsubstituted C₁-C₁₀ alkyl, O[(CH₂)_nO]_mCH₃, O(CH₂)₁NH₂, O(CH₂)₁CH₃, O(CH₂)_nONH₂, OCH₂C(═

O)N(H)CH₃, O(CH₂)_nON[(CH₂)_nCH₃]₂, where n and m are from 1 to about 10;

C₁ to C₁₀ alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aralkyl, O-alkaryl or O-aralkyl, SH, SCH₃, OCN, Cl, Br, CN, CF₃, OCF₃, SOCH₃, SO₂CH₃, ONO₂, NO₂, N₃, NH₂, heterocycloalkyl, heterocycloalkaryl, aminoalkylamino, polyalkylamino and substituted silyl.

7. The oligomeric compound of claim 6 wherein the 2′

-modification is selected from F, O—

(CH₂)₂—

O—

CH₃, and OCH₃.

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

-phosphate stabilizing nucleoside comprises a 5′

-terminal modified phosphate and a modified sugar moiety comprising a 5′

-modification.

9. The oligomeric compound of claim 1 wherein Q is a 5′

-terminal group comprising a modified nucleoside comprising a 5′

-phosphate group.

10. The oligomeric compound of claim 9 wherein the modified nucleoside is a 2′

-F, 2′

-OCH₃ or 2′

-O—

(CH₂)₂—

O—

CH₃ modified nucleoside.

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

-F modified nucleoside.

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

-OCH₃ modified nucleosides.

13. 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.

14. The oligomeric compound of claim 13 wherein w is from 5 to 9, x is 2 and y is from 5 to 6.

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

-terminal group.

16. The oligomeric compound of claim 15 wherein the 3′

-terminal group comprises two linked 2′

-O—

(CH₂)₂—

OCH₃ modified nucleosides.

17. The oligomeric compound of claim 16 wherein the two linked 2′

-O—

(CH₂)₂—

OCH₃ modified nucleosides are non-hybridizing nucleosides.

18. The oligomeric compound of claim 1 comprising at least one 5′

-terminal group or 3′

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

19. The oligomeric compound of claim 1 wherein D is H.

20. 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.

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

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

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

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

25. 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.

26. The method of claim 25, wherein the one or more cells are in vitro.

27. The method of claim 25, wherein the one or more cells are in an animal.