I007 Developing RNA-targeting oral small molecules to treat repeat expansion disorders

<h3>Background</h3> Genetic analysis has identified several genes including MSH3, PMS1, PMS2, MLH1 that repair as well as drive aberrant expansion of repeat sequences in the genome. These genes have been implicated in Huntington’s disease (HD) and other neurological disorders including SCA1, DM1, FRAXA, and in vivo disease models provide evidence for a mechanistic role in driving somatic repeat expansion. We have developed a target and lead discovery platform that enables the identification of orally bioavailable small molecules that predictably and selectively reduce the expression levels of target genes in a precise and tunable manner. <h3>Aims</h3> We describe the identification, development and optimization of PMS1 RNA-targeting small molecules to modify the onset and progression of repeat expansion disorders (REDs) by targeting their root genetic cause, trinucleotide DNA instability. <h3>Methods/Techniques</h3> CAG length of the Huntingtin gene was measured analytically and differences in somatic instability were quantified following chronic treatment of cells with PMS1 RNA-targeting small molecules. <h3>Results/Outcome</h3> We demonstrate as a proof-of-concept that reduction of PMS1 levels slows the expansion of CAG repeats over time both in artificial expansion systems as well as patient derived cells. Target engagement and a favorable pharmacokinetic profile was also achieved in monkeys in vivo with RGT compounds. <h3>Conclusions</h3> Our novel platform has enabled the identification and development of RNA-targeting small molecules that selectively target PMS1. Reduction of PMS1 levels slows the expansion of CAG repeats and reduces somatic instability in various models of HD.