Methods and compositions for the specific inhibition of alpha-1 antitrypsin by double-stranded RNA

Patent metadata

Field	Value
Publication number	US-10370655-B2
Application number	US-201615247201-A
Country	US
Kind code	B2
Filing date	Aug 25, 2016
Priority date	Jul 3, 2013
Publication date	Aug 6, 2019
Grant date	Aug 6, 2019

Abstract

This invention relates to compounds, compositions, and methods useful for reducing α-1 antitrypsin target RNA and protein levels via use of dsRNAs, e.g., Dicer substrate siRNA (DsiRNA) agents.

First claim

We claim:

1. A nucleic acid comprising an oligonucleotide strand consisting of 22 nucleotides in length, wherein said oligonucleotide strand has a region that is perfectly complementary to a contiguous sequence of α-1 antitrypsin mRNA consisting of 20 nucleotides in length, which contiguous sequence comprises a target α-1 antitrypsin mRNA sequence as set forth in SEQ ID NO: 1547, and wherein the nucleic acid comprises one or more modified nucleotides.

2. A mammalian cell containing the nucleic acid of claim 1 .

3. A pharmaceutical composition comprising the nucleic acid of claim 1 and a pharmaceutically acceptable carrier.

4. A kit comprising the nucleic acid of claim 1 and instructions for its use.

5. The nucleic acid of claim 1 , further comprising one or more phosphorothioate linkages.

6. A double stranded nucleic acid (dsNA) comprising a sense strand and an antisense strand, wherein the antisense strand is 22 nucleotides in length, wherein the antisense strand has a region that is perfectly complementary to a contiguous sequence of α-1 antitrypsin mRNA consisting of 20 nucleotides in length, which contiguous sequence comprises a target α-1 antitrypsin mRNA sequence as set forth in SEQ ID NO: 1547, and wherein the dsNA comprises one or more modified nucleotides.

7. The dsNA of claim 6 , wherein the sense strand and antisense strand form a duplex such that the antisense strand comprises a two nucleotide overhang at its 3′ end.

8. The dsNA of claim 6 , wherein the dsNA comprises a duplex of 20 to 25 base pairs in length.

9. The dsNA of claim 7 , wherein the sense strand is 25 to 53 nucleotides in length.

10. The dsNA of claim 7 , wherein the sense strand is 36 nucleotides in length.

11. The dsNA of claim 7 , wherein the 3′ terminus of the sense strand and the 5′ terminus of the antisense strand form a blunt end.

12. The dsNA of claim 6 , wherein the sense strand comprises a tetraloop at its 3′ end.

13. The dsNA of claim 10 , wherein the sense strand comprises a tetraloop at its 3′ end.

14. The dsNA of claim 13 , wherein the tetraloop comprises a single stranded loop having a sequence of GAAA.

15. The dsNA of claim 6 , wherein the dsNA comprises at least one phosphorothioate linkage.

16. The dsNA of claim 14 , wherein the dsNA comprises at least one phosphorothioate linkage.

17. The dsNA of claim 6 , wherein the one or more modified nucleotides contains a 2′ modification.

18. The dsNA of claim 17 , wherein the one or more modified nucleotides are selected from a 2′-O-methyl nucleotide and a 2′-fluoro nucleotide.

19. The dsNA of claim 18 , wherein the dsNA comprises at least one 2′-fluoro nucleotide and at least one 2′-O-methyl nucleotide.

20. The dsNA of claim 6 , wherein the dsNA is attached to a moiety selected from the group consisting of a GalNAc moiety, a cholesterol moiety, and a cholesterol targeting ligand.

21. The dsNA of claim 18 , wherein the dsNA is attached to a GalNAc moiety.

22. A pharmaceutical composition comprising the dsNA of claim 21 and a pharmaceutically acceptable carrier.

Assignees

• Dicerna Pharmaceuticals Inc

Inventors

• Brown Bob D
• Dudek Henryk T

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P1/16

  for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics · CPC title

• C12N2310/343

  having patterns, e.g. ==--==--==-- · CPC title

• C12N2310/321

  2'-O-R Modification · CPC title

• C12N2310/14

  interfering nucleic acids [NA] · CPC title