Compositions and methods for inhibiting gene expression of alpha-1 antitrypsin
View Patent ↗The invention relates to a RNA interference triggers for inhibiting the expression of an AAT gene through the mechanism of RNA interference. The invention also relates to a pharmaceutical composition comprising the AAT RNAi trigger together with an excipient capable of improving delivery of the RNAi trigger to a liver cell in vivo. Delivery of the AAT RNAi trigger to liver cells in vivo provides for inhibition of AAT gene expression and treatment of alpha 1-antitrypsin deficiency and associated diseases.
1. An RNA interference (RNAi) trigger molecule capable of inhibiting the expression of an alpha-1 antitrypsin gene, wherein the RNAi trigger molecule comprises a sense strand sequence and an antisense strand sequence, wherein the sense strand sequence and the antisense strand sequence form a sequence pair of SEQ ID NOs: 16/28 or a sequence meroduplex of SEQ ID NOs: 16/29/44.
2. The RNAi trigger molecule of claim 1 , wherein the sense strand or antisense strand contains one or more modified nucleotide or nucleotide mimics.
3. The RNAi trigger molecule of claim 2 , wherein the sense strand sequence and an antisense strand sequence form a sequence pair of SEQ ID NOs: 53/67.
4. The RNAi trigger molecule of claim 2 , wherein the sense strand sequence and an antisense strand sequence form a sequence meroduplex of SEQ ID NOs: 53/68/84.
5. The RNAi trigger molecule of claim 2 , wherein the modified nucleotide is selected from the group consisting of: a 2′-O-methyl modified nucleotide, a nucleotide comprising a 5′-phosphorothioate group, a 2′-deoxy-2′-fluoro modified nucleotide, a 2′-deoxy-modified nucleotide, a locked nucleotide, an abasic nucleotide, a deoxythymidine, an inverted deoxythymidine, a 2′-amino-modified nucleotide, a 2′-alkyl-modified nucleotide, a morpholino nucleotide, a phosphorothioate linked nucleotide, and a non-natural base comprising nucleotide.
6. A pharmaceutical composition comprising the RNAi trigger molecule of claim 1 and a MLP delivery polymer.
7. A method for inhibiting the expression of an AAT gene in a cell, a tissue, or an organism, the method comprising introducing into a cell, tissue, or organism the RNAi trigger molecule of claim 1 .
8. The method of claim 7 , wherein inhibiting expression of the AAT gene in an organism treats, prevents, or manages a pathological condition or disease caused by alpha-1 antitrypsin deficiency.
9. The method claim 8 , wherein the pathological condition and disease caused by alpha-1 antitrypsin deficiency is selected from the group consisting of: chronic hepatitis, cirrhosis, hepatocellular carcinoma, and fulminant hepatic failure.
10. The RNAi trigger molecule of claim 1 , wherein a targeting moiety is conjugated to the 5′ end of the sense strand.
11. The RNAi trigger molecule of claim 10 , wherein the targeting moiety comprises a cholesteryl group or an N-acetyl-galactosamine.
12. The RNAi trigger molecule of claim 10 wherein the targeting moiety comprises a cholesterol-triethylene glycol group.