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

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 expression 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-barrier. 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 mutant Htt levels by small molecules can be an effective therapeutic strategy for HD. Spt5-Pol II complex inhibitors (SPIs) were previously identified to selectively inhibit transcription of mutant huntingtin mRNA, without affecting wild-type huntingtin in striatal cells. Here, two novel and improved SPI analogs were identified.Administration of SPI-24 and SPI-77 to BACHD mice, a well-established mouse model of Huntington's disease, either directly to the brain striatum or by subcutaneous or oral delivery, significantly reduced the expression level of mutant Htt mRNA in the striatum. Pharmacokinetics experiments along with oral delivery or subcutaneous injection confirm that both SPIs can pass the BBB and lower mutant Htt expression in the striatum. Lowering mutant Htt level by SPI administration resulted in significant improvements in motor coordination, anxiety symptoms, and when administered to early-stage BACHD mice, slowed down the progressive deterioration of the disease. Short or prolonged SPI-24 treatments did not cause changes in global gene expression or notable side effects. Targeting the transcription elongation complex required for mutant huntingtin expression with small molecules ameliorated motor and psychological symptoms in a mouse model of Huntington's disease.