Antisense modulation of GCGR expression
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 17 to 30 linked nucleosides in length and having a nucleobase sequence comprising the sequence of SEQ ID NOs: 17, 31, 81, 82 or 85, wherein said modified oligonucleotide is complementary to SEQ ID NO: 2, and wherein said modified oligonucleotide comprises at least one modified internucleoside linkage.
2. The compound of claim 1 , wherein the compound is single-stranded.
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 the at least one 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′—CH 2 —N(R)—O—2′ bridge wherein R is, independently, H, C 1 -Cl 12 alkyl, or a protecting group.
9. The compound of claim 7 , wherein each of the at least one bicyclic sugar comprises a 4′—CH(CH 3 )—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. A method comprising administering to an animal the compound of claim 1 .
14. The method of claim 13 , wherein administering the compound prevents, treats, ameliorates, or slows progression of a metabolic disease or condition.
15. The method of claim 14 , wherein the disease or condition is diabetes.
16. The method of claim 14 , wherein the disease or condition is Type 2 diabetes.
17. The method of claim 14 wherein administering the compound decreases glucose levels in the animal.
18. The method of claim 17 , wherein the animal is human.
19. The compound of claim 1 wherein said modified oligonucleotide has the nucleobase sequence consisting of SEQ ID NO: 81 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.
20. The compound of claim 1 wherein said modified oligonucleotide has the nucleobase sequence consisting of SEQ ID NO: 17 and comprises:
a gap segment consisting of ten linked deoxynucleosides;
a 5′ wing segment consisting of five linked nucleosides;
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, 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. The compound of claim 1 wherein said modified oligonucleotide has the nucleobase sequence consisting of SEQ ID NO: 82 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.
22. The compound of claim 1 wherein said modified oligonucleotide has the nucleobase sequence consisting of SEQ ID NO: 31 and comprises:
a gap segment consisting of ten linked deoxynucleosides;
a 5′ wing segment consisting of five linked nucleosides;
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, 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.
23. The compound of claim 1 wherein said modified oligonucleotide has the nucleobase sequence consisting of SEQ ID NO: 85 and comprises:
a gap segment consisting of ten linked deoxynucleosides;
a 5′ wing segment consisting of five linked nucleosides;
a 3′ wing segment consisting of six 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.
24. The compound of claim 1 , comprising said modified oligonucleotide and a conjugate group.