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 single stranded modified oligonucleotide consisting of 20 to 30 linked nucleosides and having a nucleobase sequence comprising any of the nucleobase sequences of SEQ ID NOs: 321-331, 333, 352-362, 365-375, 378, 379, 433, 491-497, 511-513, 515, 605-629, 632-634, 650-666, 700-708, 742-746, 770, 771, 774-777, 811, 918,919, 924-926, 928, 947, 948, 950-956, 971, 972, 974-982, 995, 997-1004, 1055-1063, 1067-1105, 1119-1132, 1145, 1147-1161, 1180-1185, 1188-1205, 1207-1223, 1236-1241, 1255-1258, 1271, or 1272, 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.
2. The single stranded modified oligonucleotide of claim 1 , wherein said modified oligonucleotide is 100% complementary to SEQ ID NO: 1.
3. The single stranded modified oligonucleotide of claim 1 , wherein at least one internucleoside linkage is a modified internucleoside linkage.
4. The compound of claim 3 , wherein each internucleoside linkage is a phosphorothioate internucleoside linkage.
5. The single stranded modified oligonucleotide of claim 1 , wherein at least one modified sugar is a bicyclic sugar.
6. The single stranded modified oligonucleotide of claim 1 , wherein at least one modified sugar comprises a 2′-O-methoxyethyl group.
7. The single stranded modified oligonucleotide of claim 1 , wherein the modified sugar comprises a 2′-O(CH 2 ) 2 —OCH 3 group.
8. The single stranded modified oligonucleotide of claim 1 , wherein the modified sugar comprises a 4′-CH(CH 3 )—O-2′ group.
9. The single stranded modified oligonucleotide of claim 1 , wherein at least one nucleoside comprises a modified nucleobase.
10. The single stranded modified oligonucleotide of claim 9 , wherein the modified nucleobase is a 5-methylcytosine.
11. The single stranded modified oligonucleotide of claim 1 , wherein the gap segment consists of 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 linked nucleosides.
12. The single stranded modified oligonucleotide of claim 1 , wherein the modified oligonucleotide comprises:
a gap segment consisting of ten linked deoxynucleosides;
a 5′ wing segment consisting of five linked nucleosides; and
a 3′ wing segment consisting of five 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.
13. A composition comprising the single stranded modified oligonucleotide of claim 1 or salt thereof and at least one of a pharmaceutically acceptable carrier or diluent.
14. A method of preventing, treating, ameliorating, or slowing progression of a HBV-related disease, disorder or condition in an animal comprising administering the single stranded modified oligonucleotide of claim 1 to the animal, thereby preventing, treating, ameliorating, or slowing progression of the HBV-related disease, disorder or condition.
15. The method of claim 14 , wherein the disease, disorder or condition is liver disease.
16. The method of claim 14 , wherein the disease, disorder or condition is jaundice, liver inflammation, liver fibrosis, inflammation, liver cirrhosis, liver failure, diffuse hepatocellular inflammatory disease, hemophagocytic syndrome, serum hepatitis, HBV viremia, or liver disease-related transplantation.
17. The method of claim 14 , wherein administering the single stranded modified oligonucleotide of claim 1 to the animal reduces 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 method of claim 17 , wherein the animal is human.
21. The single stranded modified oligonucleotide of claim 12 , wherein the modified sugar comprises a 2′-O-methoxyethyl group.