Methods and compositions for modulating alpha-1-antitrypsin expression
Disclosed herein are methods for decreasing AIAT mRNA and protein expression and treating, ameliorating, preventing, slowing progression, or stopping progression of fibrosis. Disclosed herein are methods for decreasing AIAT mRNA and protein expression and treating, ameliorating, preventing, slowing progression, or stopping progression of liver disease, such as, AIATD associated liver disease, and pulmonary disease, such as, AIATD associated pulmonary disease in an individual in need thereof. Methods for inhibiting AIAT mRNA and protein expression can also be used as a prophylactic treatment to prevent individuals at risk for developing a liver disease, such as, AIATD associated liver disease and pulmonary disease, such as, AIATD associated pulmonary disease.
1. A compound comprising a modified oligonucleotide consisting of 17 to 30 linked nucleosides and comprising a nucleobase sequence comprising a portion of at least 17 contiguous nucleobases complementary to an equal length portion of nucleobases 1421-1498 of SEQ ID NO: 1, wherein the nucleobase sequence of the modified oligonucleotide is at least 90% complementary to SEQ ID NO: 1, wherein the modified oligonucleotide comprises one or more regions of alternating sugar modifications wherein the nucleosides alternate between nucleosides having a 2′-OMe modification and nucleotides having a 2′-F sugar modification, and wherein the oligonucleotide comprises phosphorothioate internucleoside linkages located within 3 nucleosides of the 3′-end of the oligonucleotide.
2. The compound of claim 1 , wherein the nucleobase sequence comprises at least 18 contiguous nucleobases complementary to an equal length portion of nucleobases 1421-1498 of SEQ ID NO: 1.
3. The compound of claim 1 , wherein the nucleobase sequence comprises at least 19 contiguous nucleobases complementary to an equal length portion of nucleobases 1421-1498 of SEQ ID NO: 1.
4. The compound of claim 1 , wherein the nucleobase sequence comprises at least 20 contiguous nucleobases complementary to an equal length portion of nucleobases 1421-1498 of SEQ ID NO: 1.
5. The compound of claim 1 , wherein the modified oligonucleotide consists of 18 to 24 linked nucleosides.
6. The compound of claim 1 , wherein the nucleobase sequence of the modified oligonucleotide is at least 95% complementary to SEQ ID NO: 1.
7. The compound of claim 1 , wherein the nucleobase sequence of the modified oligonucleotide is 100% complementary to SEQ ID NO: 1.
8. The compound of claim 1 , consisting of a single-stranded modified oligonucleotide.
9. The compound of claim 1 , wherein the modified oligonucleotide is an RNA oligonucleotide.
10. The compound of claim 9 , wherein the compound comprises a double-stranded RNA oligonucleotide, wherein one strand of the double-stranded RNA oligonucleotide is the RNA oligonucleotide comprising a nucleobase sequence comprising a portion of at least 17 contiguous nucleobases complementary to an equal length portion of nucleobases 1421-1498 of SEQ ID NO: 1.
11. A method of treating an alpha-1-antitrypsin deficiency (A1ATD)-associated liver disease in an animal comprising administering to the animal the compound of claim 1 , thereby treating the A1ATD associated liver disease in the animal.
12. A method of reducing liver fibrosis in an animal comprising administering to the animal the compound of claim 1 , thereby reducing liver fibrosis in the animal.
13. A method of treating an A1ATD associated liver disease in an animal comprising administering to the animal the compound of claim 10 , thereby treating the A1ATD associated liver disease in the animal.
14. A method of reducing liver fibrosis in an animal comprising administering to the animal the compound of claim 10 , thereby reducing liver fibrosis in the animal.