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Somatic CAG expansion in Huntington's disease is dependent on the MLH3 endonuclease domain, which can be excluded via MLH3 splice redirection to suppress expansion

By Jennie C. L. Roy, Antonia Vitalo, Marissa A. Andrew, Eduarda Mota-Silva, Marina Kovalenko, Zoe Burch, Anh M. Nhu, Paula Elaine Cohen, Ed Grabczyk, Vanessa C Wheeler, Ricardo Mouro Pinto

Posted 27 Oct 2020
bioRxiv DOI: 10.1101/2020.10.26.356238

Somatic expansion of the CAG repeat tract that causes Huntington's disease (HD) is thought to contribute to the rate of disease pathogenesis. Therefore, factors influencing repeat expansion are potential therapeutic targets. Genes in the DNA mismatch repair pathway are critical drivers of somatic expansion in HD mouse models. Here, we have tested, using genetic and pharmacological approaches, the role of the endonuclease domain of the mismatch repair protein MLH3 in somatic CAG expansion in HD mice and patient cells. A point mutation in the MLH3 endonuclease domain completely eliminated CAG expansion in the brain and peripheral tissues of a HD knock-in mouse model ( Htt Q111). To test whether the MLH3 endonuclease could be manipulated pharmacologically, we delivered splice switching oligonucleotides in mice to redirect Mlh3 splicing to exclude the endonuclease domain. Splice redirection to an isoform lacking the endonuclease domain was associated with reduced CAG expansion. Finally, CAG expansion in HD patient-derived primary fibroblasts was also significantly reduced by redirecting MLH3 splicing to the endogenous endonuclease domain-lacking isoform. These data indicate the potential of targeting the MLH3 endonuclease domain to slow somatic CAG repeat expansion in HD, a therapeutic strategy that may be applicable across multiple repeat expansion disorders. ### Competing Interest Statement V.C.W. is a scientific advisory board member of Triplet Therapeutics, a company developing new therapeutic approaches to address triplet repeat disorders such Huntington's disease and Myotonic Dystrophy, and of LoQus23 Therapeutics, and has provided paid consulting services to Alnylam and Acadia Pharmaceuticals. Her financial interests in Triplet Therapeutics were reviewed and are managed by Massachusetts General Hospital and Partners HealthCare in accordance with their conflict of interest policies. R.M.P. and V.C.W have received sponsored research funding from Pfizer unrelated to the content of this manuscript. E.G. is a named inventor on a patent related to this work (US10669542B2).

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