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In vivo CRISPR base editing for treatment of Huntington’s disease

ABSTRACT: Huntington's disease (HD) is an inherited and ultimately fatal neurodegenerative disorder caused by an expanded polyglutamine-encoding CAG repeat within exon 1 of the huntingtin (HTT) gene, which produces a mutant protein that destroys striatal and cortical neurons. A potentially critical event in the pathogenesis of HD is the proteolytic cleavage of the mutant HTT protein, which leads to fragments of the N-terminal domain of the protein that form toxic aggregates. Given the role that proteolysis of the mutant HTT protein plays in HD, strategies for preventing this process hold potential for treating the disorder. By screening >1401 CRISPR base editors targeting splice elements in the HTT gene, we identify platforms capable of producing HTT protein isoforms resistant to proteolysis via the disruption of the splice acceptor sequence for exon 13. When delivered to the striatum of an HD rodent model, these base editors induced efficient exon skipping and decreased the formation of the HTT protein fragments, which in turn reduced HTT protein aggregation, improved functional deficits and attenuated striatal and cortical atrophy. Collectively, these results illustrate the potential for CRISPR base editing to decrease the toxicity of the mutant HTT protein for HD.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE272134 | GEO | 2024/07/12

REPOSITORIES: GEO

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