I008 Lowering mutant Huntingtin by small molecules relieves Huntington’s disease symptoms and slows down its progression in mice

<h3></h3> Spt4/Spt5 complex is a transcription elongation factor specifically required for the transcription of expanded-repeat genes involved in inherited neurodegenerative diseases, particularly Huntington’s disease (HD), SCA36, and ALS/FTD. The requirement of Spt4/Spt5 for selective transcription of 3 distinct expanded repeat genes places Spt4/Spt5 as an attractive target for drugs against these and potentially other repeat expansion diseases (REDs). Using a high throughput drug screen, we identified small molecules that inhibit Spt5-Pol II interaction, called SPIs. Several SPIs display a selective inhibitory effect on the mutant Huntingtin gene without affecting the WT Htt gene or other Spt4/Spt5 activities. Using SAR-by-catalog and chemical synthesis, we identified two potent analogs that inhibit Htt mutant gene in the low µM to nM range: SPI-24 and SPI-77. 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 anxious-like phenotypes. Pharmacokinetic studies revealed that these SPIs pass the blood-brain barrier. Prolonged subcutaneous or oral administrations to early-stage BACHD 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 SPIs can be an effective therapeutic strategy. SPIs are superior over other Htt lowering approaches with respect to mutant Htt selectivity, delivery methods, and potential for expansion into additional REDs.