Abstract
AbstractHuntington’s disease (HD) is an incurable inherited disorder caused by repeat expansion in the huntingtin gene (Htt). The mutant protein causes neuronal degeneration leading to severe motor and psychological abnormalities. Selective downregulation of the mutantHttexpression is considered the leading therapeutic approach for HD. We report the identification of novel small molecule inhibitors of Spt5-Pol II, SPI-24 and SPI-77, which selectively lower mutantHttmRNA and protein levels in HD cells. In the BACHD mouse model, their direct delivery to the striatum diminished mutantHttlevels, ameliorated mitochondrial dysfunction, restored BDNF expression and improved motor and anxious-like phenotypes. Pharmacokinetic studies revealed that these SPIs pass the blood-brain-barrier and prolonged subcutaneous injection or oral administration to early-stage mice significantly delayed disease deterioration. SPI-24 long-term treatment had no side effects or global changes in gene expression. Thus, lowering mutantHttlevels by small molecules can be an effective therapeutic strategy for HD.
Publisher
Cold Spring Harbor Laboratory