Selective reduction of the deleterious activity of extended tri-nucleotide repeat containing genes
Aspects of the invention include methods of selectively reducing the deleterious activity of mutant extended trinucleotide repeat containing genes in a cell, as well as compositions used in such methods. The deleterious activity (e.g., toxicity and/or dis-functionality of products encoded thereby) of a mutant extended trinucleotide repeat containing gene may be selectively reduced in a variety of different ways, e.g., by selectively decreasing SPT4 mediated transcriptional activity, by enhancing functionality of proteins encoded thereby, etc. Aspects of the invention further include assays for identifying agents that find use in methods of the invention, e.g. as summarized above. Methods and compositions of the invention find use in a variety of different applications, including the prevention or treatment of disease conditions associated with the presence of genes containing mutant extended trinucleotide repeats, such as Huntington's Disease (HD).
1. A method of selectively reducing the deleterious activity in a cell of a target gene comprising a mutant extended trinucleotide repeat domain, the method comprising:
providing in the cell an effective amount of an agent that selectively reduces transcription of the mutant extended trinucleotide repeat domain of the target gene in the cell to selectively reduce the deleterious activity of the target gene in the cell, wherein the agent is a SPT4 protein inhibitory agent.
2. The method according to claim 1 , wherein the agent modulates the activity of a protein encoded by the gene comprising mutant extended trinucleotide repeat domain.
3. The method according to claim 2 , wherein deleterious impact of the gene is toxicity of the protein and the agent reduces the toxicity of the protein in the cell.
4. The method according to claim 2 , wherein the deleterious impact of the gene is loss of function of the protein and the agent enhances functionality of the protein in the cell.
5. The method according to claim 2 , wherein the agent selectively modulates deleterious activity of the protein encoded by the gene following expression.
6. The method according to claim 2 , wherein the agent modulates expression of the protein from the gene.
7. The method according to claim 1 , wherein the mutant trinucleotide repeat domain is present in a coding region of the gene.
8. The method according to claim 1 , wherein the SPT4 protein inhibitory agent inhibits SUPT4H.
9. The method according to claim 1 , wherein the cell is in vitro or in vivo.
10. The method according to claim 6 , wherein the agent selectively reduces transcription of the gene to enhance functionality of the protein in the cell.
11. The method according to claim 6 , wherein the agent selectively reduces transcription of the gene to reduce toxicity of the protein in the cell.
12. The method according to claim 1 , wherein the method is a method of modifying progression in a subject of a disease arising from a gene containing a mutant extended trinucleotide repeat domain.
13. The method of claim 1 , wherein the agent reduces aggregation of proteins encoded by the mutant extended trinucleotide repeat domain of the target gene in the cell.
14. The method of claim 1 , wherein the agent reduces transcriptional processivity through the mutant extended trinucleotide repeat domain of the target gene.