Targeting microRNAs for metabolic disorders
Described herein are compounds comprising modified oligonucleotides that are complementary to miR-103 and/or miR-107 and methods of treating diseases and disorders using the compounds.
1. A method of treating fatty liver disease comprising administering to the subject a therapeutically effective amount of a compound comprising the structure (II):
wherein X is a phosphodiester linkage; each N of N m is a deoxyadenosine (A); m is 2; Y is a phosphodiester linkage; and MO is 5′-C S A S A S U S G S C S U S G S C S A S AAC S A S A S U S G S C S U S G S C S A S - 3′ (SEQ ID NO: 7), wherein each nucleoside followed by a subscript “S” is a S-cEt nucleoside, each nucleoside not followed by a subscript is a deoxynucleoside, and each internucleoside linkage between two S-cEt nucleosides is a phosphorothioate linkage, and the remaining internucleoside linkages are phosphodiester linkages; and wherein Y is linked to the 3′ terminus of MO; and wherein the fatty liver disease is selected from non-alcoholic fatty liver disease (NAFLD), alcoholic fatty liver disease, alcoholic steatohepatitis, and non-alcoholic steatohepatitis (NASH).
2. The method of claim 1 , wherein the subject has a metabolic disorder selected from among pre-diabetes, diabetes, metabolic syndrome, obesity, diabetic dyslipidemia, hyperlipidemia, hypertension, hypertriglyceridemia, hyperfattyacidemia, hypercholesterolemia, and hyperinsulinemia.
3. The method of claim 2 , wherein the fatty liver disease is non-alcoholic fatty liver disease and the diabetes is type 2 diabetes.
4. The method of claim 2 , wherein the fatty liver disease is non-alcoholic steatohepatitis and the diabetes is type 2 diabetes.
5. The method of claim 2 , wherein the metabolic disorder is pre-diabetes and the fatty liver disease is non-alcoholic fatty liver disease.
6. The method of claim 2 , wherein the metabolic disorder is pre-diabetes and the fatty liver disease is non-alcoholic steatohepatitis.
7. The method of claim 1 , wherein the compound is comprised in an aqueous composition.
8. The method of claim 3 , wherein the compound is comprised in an aqueous composition.
9. The method of claim 4 , wherein the compound is comprised in an aqueous composition.
10. The method of claim 5 , wherein the compound is comprised in an aqueous composition.
11. The method of claim 6 , wherein the compound is comprised in an aqueous composition.
12. A method of treating fatty liver disease comprising administering to the subject a therapeutically effective amount of a compound having the structure:
and wherein the fatty liver disease is selected from non-alcoholic fatty liver disease (NAFLD), alcoholic fatty liver disease, alcoholic steatohepatitis, and non-alcoholic steatohepatitis (NASH).
13. The method of claim 12 , wherein the subject has a metabolic disorder selected from among pre-diabetes, diabetes, metabolic syndrome, obesity, diabetic dyslipidemia, hyperlipidemia, hypertension, hypertriglyceridemia, hyperfattyacidemia, hypercholesterolemia, and hyperinsulinemia.
14. The method of claim 13 , wherein the fatty liver disease is non-alcoholic fatty liver disease and the diabetes is type 2 diabetes.
15. The method of claim 13 , wherein the fatty liver disease is non-alcoholic steatohepatitis and the diabetes is type 2 diabetes.
16. The method of claim 13 , wherein the metabolic disorder is pre-diabetes and the fatty liver disease is non-alcoholic fatty liver disease.
17. The method of claim 13 , wherein the metabolic disorder is pre-diabetes and the fatty liver disease is non-alcoholic steatohepatitis.
18. The method of claim 12 , wherein the compound is comprised in an aqueous composition.
19. The method of claim 14 , wherein the compound is comprised in an aqueous composition.
20. The method of claim 15 , wherein the compound is comprised in an aqueous composition.
21. The method of claim 16 , wherein the compound is comprised in an aqueous composition.
22. The method of claim 17 , wherein the compound is comprised in an aqueous composition.