Splice modulators target PMS1 to reduce somatic expansion of the Huntington’s disease-associated CAG repeat

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 and James F. Gusella ()
Additional contact information
Zachariah L. McLean: Massachusetts General Hospital
Dadi Gao: Massachusetts General Hospital
Kevin Correia: Massachusetts General Hospital
Jennie C. L. Roy: Massachusetts General Hospital
Shota Shibata: Massachusetts General Hospital
Iris N. Farnum: Massachusetts General Hospital
Zoe Valdepenas-Mellor: Massachusetts General Hospital
Marina Kovalenko: Massachusetts General Hospital
Manasa Rapuru: Massachusetts General Hospital
Elisabetta Morini: Massachusetts General Hospital
Jayla Ruliera: Massachusetts General Hospital
Tammy Gillis: Massachusetts General Hospital
Diane Lucente: Massachusetts General Hospital
Benjamin P. Kleinstiver: Massachusetts General Hospital
Jong-Min Lee: Massachusetts General Hospital
Marcy E. MacDonald: Massachusetts General Hospital
Vanessa C. Wheeler: Massachusetts General Hospital
Ricardo Mouro Pinto: Massachusetts General Hospital
James F. Gusella: Massachusetts General Hospital

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract 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. Targeted CRISPR-Cas9 editing shows this effect is not due to huntingtin lowering, pointing instead to pseudoexon inclusion in PMS1. Homozygous but not heterozygous inactivation of PMS1 also reduces CAG repeat expansion, supporting PMS1 as a genetic modifier of HD and a potential target for therapeutic intervention. Although splice modulation provides one strategy, genome-wide transcriptomics also emphasize consideration of cell-type specific effects and polymorphic variation at both target and off-target sites.

Date: 2024
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DOI: 10.1038/s41467-024-47485-0

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