Modulation of Hepatitis B virus (HBV) expression
View Patent ↗Disclosed herein are antisense compounds and methods for decreasing HBV mRNA, DNA and protein expression. Such methods, compounds, and compositions are useful to treat, prevent, or ameliorate HBV-related diseases, disorders or conditions.
1. A compound, comprising a single-stranded modified oligonucleotide consisting of 20 linked nucleosides and having a nucleobase sequence consisting of the nucleobase sequences of SEQ ID NOs: 224, 226, and 807, wherein the modified oligonucleotide is at least 96% complementary over its entire length with a nucleic acid encoding hepatitis B virus (HBV) and at least one nucleoside of the modified oligonucleotide comprises a modified sugar.
2. The compound of claim 1 , wherein said modified oligonucleotide is at least 98% complementary to SEQ ID NO: 1.
3. The compound of claim 1 , wherein said modified oligonucleotide is 100% complementary to SEQ ID NO: 1.
4. The compound of claim 1 , wherein the modified oligonucleotide comprises at least one modified internucleoside linkage.
5. The compound of claim 4 , wherein each internucleoside linkage is a phosphorothioate internucleoside linkage.
6. The compound of claim 1 , wherein the at least one modified sugar is a bicyclic sugar.
7. The compound of claim 1 , wherein the at least one modified sugar comprises a 2′-O-methoxyethyl group.
8. The compound of claim 1 , wherein the at least one modified sugar comprises a 4′-CH(CH 3 )—O-2′ group.
9. The compound of claim 1 , wherein at least one nucleoside comprises a modified nucleobase.
10. The compound of claim 9 , wherein the modified nucleobase is a 5-methylcytosine.
11. The compound of claim 1 , wherein the modified oligonucleotide comprises:
a gap segment consisting of linked deoxynucleosides;
a 5′ wing segment consisting of linked nucleosides; and
a 3′ wing segment consisting of linked nucleosides;
wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment and wherein each nucleoside of each wing segment comprises a modified sugar.
12. The compound of claim 11 , wherein the gap segment consists of 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 linked nucleosides.
13. The compound of claim 11 , wherein the modified oligonucleotide comprises:
a gap segment consisting of ten linked deoxynucleosides;
a 5′ wing segment consisting of 1-5 linked nucleosides; and
a 3′ wing segment consisting of 1-5 linked nucleosides;
wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment, wherein each nucleoside of each wing segment comprises a 2′-O-methoxyethyl sugar; and wherein each internucleoside linkage is a phosphorothioate linkage.
14. A method of preventing, treating, ameliorating, or slowing progression of a HBV-related disease, disorder or condition in an animal comprising administering to the animal the compound of claim 1 , thereby preventing, treating, ameliorating, or slowing progression of a HBV-related disease, disorder or condition in the animal.
15. The method of claim 14 , wherein the animal is a human.
16. The method of claim 14 , wherein the disease, disorder or condition is jaundice, liver inflammation, liver fibrosis, inflammation, liver cirrhosis, liver failure, liver cancer, diffuse hepatocellular inflammatory disease, hemophagocytic syndrome, serum hepatitis, HBV viremia, or liver disease-related transplantation.
17. The method of claim 14 , wherein administering the compound of claim 1 reduces HBV antigen levels in the animal.
18. The method of claim 17 , wherein HBsAG levels are reduced.
19. The method of claim 17 , wherein HBeAG levels are reduced.
20. The compound of claim 1 , wherein the modified oligonucleotide consists of 20 linked nucleosides having the nucleobase sequence of SEQ ID NO: 224 and comprises:
a gap segment consisting of ten linked deoxynucleosides;
a 5′ wing segment consisting of 6 linked nucleosides; and
a 3′ wing segment consisting of 4 linked nucleosides;
wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment, wherein each nucleoside of each wing segment comprises a 2′-O-methoxyethyl sugar, wherein each internucleoside linkage of the modified oligonucleotide is a phosphorothioate linkage, and wherein each cytosine of the modified oligonucleotide is a 5-methylcytosine.
21. The compound of claim 1 , wherein the modified oligonucleotide consists of 20 linked nucleosides having the nucleobase sequence of SEQ ID NO: 226 and comprises:
a gap segment consisting of ten linked deoxynucleosides;
a 5′ wing segment consisting of 5 linked nucleosides; and
a 3′ wing segment consisting of 5 linked nucleosides;
wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment, wherein each nucleoside of each wing segment comprises a 2′-O-methoxyethyl sugar, wherein each internucleoside linkage of the modified oligonucleotide is a phosphorothioate linkage, and wherein each cytosine of the modified oligonucleotide is a 5-methylcytosine.
22. The compound of claim 1 , wherein the modified oligonucleotide consists of 20 linked nucleosides having the nucleobase sequence of SEQ ID NO: 807 and comprises:
a gap segment consisting of ten linked deoxynucleosides;
a 5′ wing segment consisting of 6 linked nucleosides; and
a 3′ wing segment consisting of 4 linked nucleosides;
wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment, wherein each nucleoside of each wing segment comprises a 2′-O-methoxyethyl sugar, wherein each internucleoside linkage of the modified oligonucleotide is a phosphorothioate linkage, and wherein each cytosine of the modified oligonucleotide is a 5-methylcytosine.
23. A method of preventing, treating, ameliorating, or slowing progression of a HBV-related disease, disorder or condition in an animal comprising administering to the animal the compound of claim 20 , thereby preventing, treating, ameliorating, or slowing progression of a HBV-related disease, disorder or condition in the animal.
24. The method of claim 23 , wherein the disease, disorder or condition is jaundice, liver inflammation, liver fibrosis, inflammation, liver cirrhosis, liver failure, liver cancer, diffuse hepatocellular inflammatory disease, hemophagocytic syndrome, serum hepatitis, HBV viremia, or liver disease-related transplantation.
25. The method of claim 23 , wherein administering the compound of claim 20 reduces HBV antigen levels in the animal.
26. The method of claim 25 , wherein HBsAG levels are reduced.
27. The method of claim 25 , wherein HBeAG levels are reduced.
28. A method of preventing, treating, ameliorating, or slowing progression of a HBV-related disease, disorder or condition in an animal comprising administering to the animal the compound of claim 21 , thereby preventing, treating, ameliorating, or slowing progression of a HBV-related disease, disorder or condition in the animal.
29. The method of claim 28 , wherein the disease, disorder or condition is jaundice, liver inflammation, liver fibrosis, inflammation, liver cirrhosis, liver failure, liver cancer, diffuse hepatocellular inflammatory disease, hemophagocytic syndrome, serum hepatitis, HBV viremia, or liver disease-related transplantation.
30. The method of claim 28 , wherein administering the compound of claim 21 reduces HBV antigen levels in the animal.
31. The method of claim 30 , wherein HBsAG levels are reduced.
32. The method of claim 30 , wherein HBeAG levels are reduced.
33. A method of preventing, treating, ameliorating, or slowing progression of a HBV-related disease, disorder or condition in an animal comprising administering to the animal the compound of claim 22 , thereby preventing, treating, ameliorating, or slowing progression of a HBV-related disease, disorder or condition in the animal.
34. The method of claim 33 , wherein the disease, disorder or condition is jaundice, liver inflammation, liver fibrosis, inflammation, liver cirrhosis, liver failure, liver cancer, diffuse hepatocellular inflammatory disease, hemophagocytic syndrome, serum hepatitis, HBV viremia, or liver disease-related transplantation.
35. The method of claim 33 , wherein administering the compound of claim 22 reduces HBV antigen levels in the animal.
36. The method of claim 35 , wherein HBsAG levels are reduced.
37. The method of claim 35 , wherein HBeAG levels are reduced.