Modulation of mTORCI activity and autophagy via CIB2-RHEB interaction
Provided herein are compositions and methods for down-regulating mTORC1 signaling in a subject, comprising administering to the subject an effective amount of one or more compositions that promote increased levels or activity of CIB2 or a biologically active fragment or variant thereof in the subject.
1 . A method for treating a disease, condition or disorder by down-regulating mTORC1 signaling in a subject, comprising administering to the subject an effective amount of one or more compositions that increase activity of CIB2 or a biologically active fragment or variant thereof in the subject, wherein the subject is in need of treatment for the disease, condition, or disorder selected from the group consisting of macular degeneration and age-related macular degeneration, thereby downregulating mTORC1 signaling in the subject.
2 . The method of claim 1 , wherein the disease, condition, or disorder is age-related macular degeneration.
3 . The method of claim 1 , wherein the method increases canonical and non-canonical autophagy and/or phagolysosomal digestion in cells.
4 . The method of claim 3 wherein the cells comprise retinal pigment epithelium.
5 . The method of claim 1 , wherein the one or more compositions comprise a nucleic acid comprising a sequence encoding CIB2 or a biologically active fragment or variant thereof.
6 . The method of claim 5 , wherein the nucleic acid is provided by a viral vector.
7 . The method of claim 6 , wherein the viral vector comprises an adeno-associated (AAV) donor vector.
8 . The method of claim 1 , wherein the one or more compositions comprise at least one non-naturally occurring nuclease, wherein the nuclease cleaves a sequence in a genome of a cell in the subject, such that the CIB2 or a biologically active fragment or variant thereof is integrated into the genome of the cell in the subject.
9 . The method of claim 8 , wherein the nuclease is administered as a nucleic acid and is expressed by the cell.
10 . The method of claim 9 , wherein the nuclease is administered as a polypeptide.
11 . The method of claim 8 , wherein the vector is administered prior to or after the administration of the at least one nuclease.
12 . The method of claim 8 , wherein the vector is administered together with the at least one nuclease.
13 . The method of claim 8 , wherein the at least one nuclease is selected from the group consisting of a zinc finger nuclease (ZFN), a TALE nuclease (TALEN), a CRISPR/Cas nuclease system and combinations thereof.
14 . The method of claim 1 , wherein the one or more compositions comprise a polypeptide comprising CIB2 or a biologically active fragment or variant thereof.
15 . The method of claim 14 , wherein the one or more compositions comprise an agent that facilitates uptake of the polypeptide into cells.
16 . The method of claim 15 , wherein the agent comprises one or more cationic peptides, amphipathic molecules, lipid-based carriers or combinations thereof.
17 . The method of claim 15 , wherein the polypeptide is associated with a protein transduction domain.
18 . The method of claim 17 , wherein the polypeptide is a fusion protein comprising the protein transduction domain.
19 . The method of claim 1 , wherein the method further comprises administering an effective amount of an additional therapeutic agent.
20 . The method of claim 5 , wherein the one or more compositions comprise a nucleic acid comprising a sequence encoding CIB2.