Lowering mutant huntingtin by small molecules relieves Huntington's disease symptoms and progression

ABSTRACT: Huntington's disease (HD) is an incurable inherited disorder caused by a repeated expansion of glutamines in the huntingtin gene (Htt). The mutant protein causes neuronal degeneration leading to severe motor and psychological symptoms. Selective downregulation of the mutant Htt gene product is considered the most promising therapeutic approach for HD. We report the identification of small molecule inhibitors of Spt5- Pol II, SPI-24 and SPI-77, which selectively lower mutant Htt mRNA and protein levels in HD cells. In the BACHD mouse model, their direct delivery to the striatum diminished mutant Htt levels, ameliorated mitochondrial dysfunction, restored BDNF expression, and improved motor and anxiety-like phenotypes. Pharmacokinetic studies revealed that these SPIs pass the blood-brain-bar

SUBMITTER: Anat Bahat 

PROVIDER: S-SCDT-10_1038-S44321-023-00020-Y | biostudies-other |

REPOSITORIES: biostudies-other