Methods and compositions for the specific inhibition of alpha-1 antitrypsin by double-stranded RNA
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.
1. A nucleic acid for reducing expression of α-1 antitrypsin mRNA comprising an oligonucleotide strand, wherein said oligonucleotide strand consists of 21 nucleotides, wherein one or more of said 21 nucleotides are modified nucleotides, and wherein said oligonucleotide strand is 100% complementary to SEQ ID NO: 1908.
2. The nucleic acid of claim 1 , wherein said modified nucleotides are selected from: a 2′-O-methyl nucleotide; a 2′-fluoro nucleotide;
and a 2′-O-methyl nucleotide and a 2′-fluoro nucleotide.
3. The nucleic acid of claim 2 , wherein said oligonucleotide strand comprises one or more phosphorothioate linkages.
4. The nucleic acid of claim 3 , wherein said oligonucleotide strand comprises a 3′-terminus having one or more phosphorothioate linkages.
5. The nucleic acid of claim 1 , wherein said nucleic acid is a short interfering RNA (siRNA).
6. The nucleic acid of claim 1 , wherein each of said 21 nucleotides is a modified nucleotide.
7. The nucleic acid of claim 1 , wherein said oligonucleotide strand comprises one or more modifications patterns.
8. The nucleic acid of claim 2 , wherein said nucleic acid comprises a double stranded nucleic acid (dsNA), wherein said oligonucleotide strand is a second oligonucleotide strand, wherein said dsNA further comprises a first oligonucleotide strand having a nucleotide sequence consisting of 21 nucleotides, wherein said first and second oligonucleotide strands form a duplex region of 21 base pairs, and wherein said nucleotide sequence of said first oligonucleotide strand consists of SEQ ID NO: 1908.
9. The nucleic acid of claim 8 , wherein said first and second oligonucleotide strands are separate nucleic acid molecules.
10. The nucleic acid of claim 8 , wherein said first or said second oligonucleotide strand comprises one or more phosphorothioate linkages or each of said first and second oligonucleotide strands comprises one or more phosphorothioate linkages.
11. The nucleic acid of claim 10 , wherein each of said first and second oligonucleotide strands comprises a 3′ terminus, and wherein said first oligonucleotide strand comprises a phosphorothioate linkage at said 3′ terminus or said second oligonucleotide strand comprises a phosphorothioate linkage at said 3′-terminus or each of said first and second oligonucleotide strands comprises a phosphorothioate linkage at said 3′-terminus.
12. The nucleic acid of claim 8 , comprising a targeting ligand attached to said first oligonucleotide strand, said second oligonucleotide strand, or both.
13. The nucleic acid of claim 12 , wherein said targeting ligand comprises a GalNAc moiety or a tri-antennary GalNAc moiety.
14. The nucleic acid of claim 8 , wherein said first or second oligonucleotide strand comprises one or more inverted abasic residues or each of said first and second oligonucleotide strands comprises one or more inverted abasic residues.
15. The nucleic acid of claim 8 , wherein said dsNA is a short interfering RNA (siRNA).
16. The nucleic acid of claim 8 , wherein a 3′-terminus of said first oligonucleotide strand and a 5′-terminus of said second oligonucleotide strand form a blunt end.
17. The nucleic acid of claim 8 , wherein termini of said first and second oligonucleotide strands each form a blunt end.
18. A pharmaceutical composition comprising said nucleic acid of claim 1 and a pharmaceutically acceptable carrier.
19. A pharmaceutical composition comprising said dsNA of claim 8 and a pharmaceutically acceptable carrier.