Oligomeric compounds and compositions for use in modulation of small non-coding RNAs
Compounds, compositions and methods are provided for modulating the expression and function of small non-coding RNAs. The compositions comprise oligomeric compounds, targeted to small non-coding RNAs. Methods of using these compounds for modulation of small non-coding RNAs as well as downstream targets of these RNAs and for diagnosis and treatment of disease associated with small non-coding RNAs are also provided.
1. A method of treating or preventing a disease or disorder associated with a microRNA comprising:
contacting an animal having or predisposed to the disorder with a therapeutically effective amount of compound comprising an oligomeric compound consisting of 15 to 30 monomeric subunits,
wherein the oligomeric compound is at least 90% complementary to the microRNA, and at least one monomeric subunit is a modified nucleoside;
and thereby treating or preventing the disease or disorder;
wherein the disease or disorder is diabetes or hypertension, and the oligomeric compound reduces one or more markers of insulin response.
2. A method of modulating one or more phenotypic outcomes comprising:
contacting a cell with a compound comprising an oligomeric compound consisting of 15 to 30 monomeric subunits,
wherein the oligomeric compound is at least 90% complementary to a microRNA, and
wherein at least one monomeric subunit is a modified nucleoside;
and thereby modulating one or more phenotypic outcomes;
wherein the one or more phenotypic outcomes is insulin response, and wherein the method further comprises detecting the modulation by a change in one or more markers of insulin response.
3. The method of claim 2 wherein the one or more markers of insulin response is selected from insulin-like growth factor binding protein-1 (IGFBP-1) expression, cytosolic PEPCK (PEPCK-C) expression, and follistatin expression.
4. The method of claim 1 wherein the microRNA is a let-7 homolog.
5. The method of claim 4 , wherein the oligomeric compound is at least 95% complementary to a let-7homolog.
6. The method of claim 4 , wherein the oligomeric compound is 100% complementary to a let-7homolog.
7. The method of claim 4 , wherein the oligomeric compound is 100% complementary to at least an 8-nucleobase portion of let-7homolog.
8. The method of claim 1 , wherein the oligomeric compound consists of an oligonucleotide.
9. The method of claim 1 , wherein at least one monomeric subunit comprises a modified sugar moiety.
10. The method of claim 9 , wherein the modified sugar moiety is selected from a 2′-F sugar moiety, a 2′-O-methyl sugar moiety, a 2′-O-methoxyethyl sugar moiety, and a bicyclic sugar moiety.
11. The method of claim 1 wherein the oligomeric compound comprises at least one modified internucleoside linkage.
12. The method of claim 11 wherein the modified internucleoside linkage is a phosphorothioate linkage.
13. The method of claim 2 , wherein the oligomeric compound consists of an oligonucleotide.
14. The method of claim 2 , wherein at least one monomeric subunit comprises a modified sugar moiety.
15. The method of claim 14 , wherein the modified sugar moiety is selected from a 2′-F sugar moiety, a 2′-O-methyl sugar moiety, a 2′-O-methoxyethyl sugar moiety, and a bicyclic sugar moiety.
16. The method of claim 1 wherein the oligomeric compound comprises at least one modified internucleoside linkage.
17. The method of claim 16 wherein the modified internucleoside linkage is a phosphorothioate linkage.