Zachariah L McLean, Dadi Gao, Kevin Correia, Jennie C L Roy, Shota Shibata, Iris N Farnum, Zoe Valdepenas-Mellor, Marina Kovalenko, Manasa Rapuru, Elisabetta Morini, Jayla Ruliera, Tammy Gillis, Diane Lucente, Benjamin P Kleinstiver, Jong-Min Lee, Marcy E MacDonald, Vanessa C Wheeler, Ricardo Mouro Pinto, James F Gusella
Huntington's disease (HD) is a dominant neurological disorder caused by an expanded HTT exon 1 CAG repeat that lengthens huntingtin's polyglutamine tract. Lowering mutant huntingtin has been proposed for treating HD, but genetic modifiers implicate somatic CAG repeat expansion as the driver of onset. We find that branaplam and risdiplam, small molecule splice modulators that lower huntingtin by promoting HTT pseudoexon inclusion, also decrease expansion of an unstable HTT exon 1 CAG repeat in an engineered cell model...
April 12, 2024: Nature Communications