SPI-24

SPI-24 is a small molecule inhibitor of the interaction between the transcription elongation factor Spt5 and RNA polymerase II (Pol II). Developed by researchers at the Weizmann Institute of Science and Bar-Ilan University, it was identified through high-throughput screening for compounds that selectively target the transcription of expanded-repeat genes. SPI-24 specifically inhibits the expression of mutant *Huntingtin* (mHtt) without affecting wild-type *Htt* or other essential Spt4/Spt5-mediated activities. Preclinical studies in the BACHD mouse model of Huntington's disease demonstrated that SPI-24 can cross the blood-brain barrier and, when administered orally or subcutaneously, significantly delays disease progression, improves motor and anxiety-like phenotypes, and restores mitochondrial function and BDNF expression. It is being explored as a therapeutic candidate for Huntington's disease and other repeat expansion diseases (REDs), including SCA36, amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD).