Antisense modulation of GCGR expression
View Patent ↗Provided herein are methods, compounds, and compositions for reducing expression of GCGR mRNA and protein in an animal. Such methods, compounds, and compositions are useful to treat, prevent, delay, or ameliorate metabolic disease, for example, diabetes, or a symptom thereof.
1. A compound comprising a modified oligonucleotide consisting of 12 to 30 linked nucleosides and having a nucleobase sequence comprising at least an 8 nucleobase portion of SEQ ID NO: 11, wherein said modified oligonucleotide is at least 96% complementary to SEQ ID NO: 2 as measured over the entirety of the nucleobase sequence of the modified oligonucleotide, and wherein the oligonucleotide comprises at least one modified internucleoside linkage.
2. The compound of claim 1 , consisting of a single-stranded modified oligonucleotide.
3. The compound of claim 1 , wherein said modified oligonucleotide is at least 98% complementary to SEQ ID NO: 2.
4. The compound of claim 1 , wherein said modified oligonucleotide is 100% complementary to SEQ ID NO: 2.
5. The compound of claim 1 , wherein each modified internucleoside linkage is a phosphorothioate internucleoside linkage.
6. The compound of claim 1 , wherein at least one nucleoside of the modified oligonucleotide comprises a modified sugar.
7. The compound of claim 6 , wherein the at least one modified sugar is a bicyclic sugar.
8. The compound of claim 7 , wherein each of the at least one bicyclic sugar comprises a 4′-CH2-N(R)—O-2′ bridge wherein R is, independently, H, C1-C12 alkyl, or a protecting group.
9. The compound of claim 7 , wherein each of the at least one bicyclic sugar comprises a 4′-CH(CH3)-O-2′ bridge.
10. The compound of claim 6 , wherein at least one modified sugar comprises a 2′-O-methoxyethyl group.
11. The compound of claim 1 , wherein at least one nucleoside comprises a modified nucleobase.
12. The compound of claim 11 , wherein the modified nucleobase is a 5-methylcytosine.
13. 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.
14. The compound of claim 13 wherein the modified oligonucleotide comprises:
a gap segment consisting of ten linked deoxynucleosides;
a 5′ wing segment consisting of three linked nucleosides; and
a 3′ wing segment consisting of four 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.
15. The compound of claim 13 , wherein the modified oligonucleotide comprises:
a gap segment consisting of ten linked deoxynucleosides;
a 5′ wing segment consisting of three linked nucleosides; and
a 3′ wing segment consisting of four 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 modified sugar; and wherein each internucleoside linkage is a phosphorothioate linkage.
16. The compound of claim 1 , wherein the modified oligonucleotide consists of 17 linked nucleosides.
17. The compound of claim 13 , wherein the modified oligonucleotide consists of 17 linked nucleosides.
18. The compound of claim 1 , wherein said modified oligonucleotide consists of 17 to 25 linked nucleosides.
19. The compound of claim 1 , wherein said modified oligonucleotide consists of a nucleobase sequence of SEQ ID NO: 11.
20. The compound of claim 1 , wherein said modified oligonucleotide consists of the nucleobase sequence of SEQ ID NO: 11 and comprises:
a gap segment consisting of ten linked deoxynucleosides;
a 5′ wing segment consisting of three linked nucleosides;
a 3′ wing segment consisting of four 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 modified sugar, wherein each internucleoside linkage of said modified oligonucleotide is a phosphorothioate linkage, and wherein each cytosine residue of said modified oligonucleotide is a 5-methylcytosine.
21. A composition comprising the compound of claim 1 or salt thereof and at least one of a pharmaceutically acceptable carrier or diluent.
22. A method comprising administering to an animal the compound of claim 1 .
23. The method of claim 22 , wherein administering the compound treats, ameliorates, or slows progression of a metabolic disease or condition.
24. The method of claim 23 , wherein the disease or condition is diabetes.
25. The method of claim 23 , wherein the disease or condition is Type 2 diabetes.
26. The method of claim 24 , wherein administering the compound decreases blood glucose levels in the animal.
27. The method of claim 26 , wherein the animal is human.
28. The method of claim 26 , wherein the blood glucose levels are plasma glucose levels or serum glucose levels.
29. The compound of claim 1 , wherein the compound consists of a single-stranded modified oligonucleotide consisting of the nucleobase sequence of SEQ ID NO: 11 and comprises:
a gap segment consisting often linked deoxynucleosides;
a 5′ wing segment consisting of three linked nucleosides;
a 3′ wing segment consisting of four 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 modified sugar, wherein each internucleoside linkage of said modified oligonucleotide is a phosphorothioate linkage, and wherein each cytosine residue of said modified oligonucleotide is a 5-methylcytosine.
30. The compound of claim 1 , comprising said modified oligonucleotide and a conjugate, wherein said modified oligonucleotide consists of the nucleobase sequence of SEQ ID NO: 11 and comprises:
a gap segment consisting often linked deoxynucleosides;
a 5′ wing segment consisting of three linked nucleosides;
a 3′ wing segment consisting of four 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 modified sugar, wherein each internucleoside linkage of said modified oligonucleotide is a phosphorothioate linkage, and wherein each cytosine residue of said modified oligonucleotide is a 5-methylcytosine.
31. The compound of claim 30 , wherein the compound consists of the modified oligonucleotide and a conjugate, wherein the modified oligonucleotide is single-stranded.
32. A method comprising administering to an animal the compound of claim 29 , wherein administering treats, ameliorates, or slows progression of diabetes.
33. A composition comprising the compound of claim 29 or salt thereof and at least one of a pharmaceutically acceptable carrier or diluent.