In vivo CRISPR base editing for treatment of Huntington's disease.

Authors

Shraddha Shirguppe, Michael Gapinske, Devyani Swami, Kyrollos Shenouda, Angelo Miskalis, Nicholas Gosstola, Daniela Del Bosque Siller, Isabelle Guerra, Pankaj Acharya, Dana Joulani, Maddie G Szkwarek, Ananthan Nambiar, Abhishek Bhattacharjee, Anagha S Dangi, Norah Odle, Gabrielle E Nathan, Gianna Elias, Michelle Stilger, Jackson Winter, Wendy S Woods, Daphine Anand, Colin K W Lim, Sergei Maslov, Thomas Gaj, Pablo Perez-Pinera

Published in

Nature biomedical engineering. Jul 29, 2026. Epub Jul 29, 2026.

Abstract

Huntington's disease (HD) is a fatal neurodegenerative disorder caused by an expanded CAG repeat within exon 1 of the huntingtin (HTT) gene, resulting in a mutant protein that drives neuronal dysfunction and loss. A key event in the pathogenesis of HD is proteolytic cleavage of mutant HTT, which generates aggregation-prone N-terminal fragments that contribute to toxicity. Strategies that prevent this process thus hold therapeutic potential. Here we develop CRISPR base editors that generate proteolysis-resistant HTT isoforms by disrupting the splice acceptor of HTT exon 13, an exon that encodes critical proteolytic cleavage sites implicated in N-terminal fragment production. When delivered to the striatum of an HD rodent model, these editors reduced HTT fragment formation, decreased aggregation, improved functional deficits and attenuated brain atrophy. Collectively, these results demonstrate the potential of base editing and splice-site modulation to mitigate mutant HTT toxicity in HD.

PMID:
42527584
Bibliographic data and abstract were imported from PubMed on 30 Jul 2026.

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