I002 Small molecule PMS1 regulators to treat repeat expansion diseases: Huntington’s disease (HD) and beyond

<h3></h3> The PMS1 gene is a key component of the DNA mismatch repair pathway, implicated in the pathological somatic trinucleotide repeat expansion observed in Huntington’s Disease (HD) and other trinucleotide repeat expansion disorders such as DM1, FXS, and FRDA. Genome-wide association studies (GWAS) have identified PMS1, along with other genes in the mismatch repair pathway as genetic modifiers impacting the age of onset in HD. Functional studies, including the genetic knockout of PMS1 in HD mouse models, which stalled repeat expansion, further reinforce the gene’s important role in the progression of somatic repeat expansions. To date, there has been a lack of successful strategies for directly targeting the PMS1 protein with small molecule inhibitors. Leveraging the integrative RNA-targeting small molecule discovery platform from Rgenta Therapeutics, we have pioneered the development of first-in-class oral small molecules. These molecules are designed to modulate PMS1 pre-mRNA splicing, curtailing the production of the aberrant PMS1 protein, thereby potentially preventing, or decelerating the onset of somatic repeat expansion diseases. Our leading compounds have demonstrated the ability to decrease PMS1 RNA and protein levels in human cell lines and in animal models. Significantly, these molecules exhibit promising pharmacological efficacy in inhibiting repeat expansions in disease models and possess favorable pharmacokinetic profiles that facilitate crossing the blood-brain barrier. We will provide an update to our progress of oral small molecule splice modulators and discuss their potential in treating the underlying causes of repeat expansion diseases.