I009 Branaplam decreases mutant HTT and improves the molecular fingerprint in Huntington’s disease patient neurons

<h3></h3> Huntington’s disease (HD) is a neurodegenerative condition caused by poly-Q expansion in the Huntingtin (HTT) protein. In this study, we report increased levels of mutant HTT (mHTT) in cells derived from HD patients, including fibroblasts and induced pluripotent stem cell (iPSC)-derived cortical neurons, utilizing mesoscale discovery (MSD) HTT assays. The fibroblasts and cortical neurons from HD patients exhibit abnormal alternative splicing, a characteristic molecular feature of HD. Branaplam, a splicing modulator that had been under clinical investigation for HD, reduced total HTT (tHTT) and mHTT levels in fibroblasts, iPSCs, cortical progenitors, and neurons in a dose-dependent manner, with an IC50 consistently below 10 nM. Branaplam enhances the inclusion of previously unannotated novel exons, including a 115 bp frameshift-inducing exon in the HTT transcript. This exon is induced by Branaplam treatment in both control and HD patient cells, significantly reducing HTT RNA and protein levels. Notably, Branaplam corrects the aberrant alternative splicing seen in HD patients‘ fibroblasts and cortical neurons. These results¹ underscore the potential of splicing modulators in treating CAG repeat disorders and elucidate their molecular impacts in patient-derived cellular models. <h3>Reference</h3> Krach F, Stemick J, Boerstler T, Weiss A, Lingos I, Reischl S, Meixner H, Ploetz S, Farrell M, Hehr U, Kohl Z, Winner B, Winkler J. An alternative splicing modulator decreases mutant HTT and improves the molecular fingerprint in Huntington’s disease patient neurons. <i>Nat Commun</i>. 2022 Nov 10;<b>13</b>(1):6797.