An RNA-targeting CRISPR-Cas13d system alleviates disease-related phenotypes in Huntington's disease models.

ABSTRACT: Huntington's disease (HD) is a fatal, dominantly inherited neurodegenerative disorder caused by CAG trinucleotide expansion in exon 1 of the huntingtin (HTT) gene. Since the reduction of pathogenic mutant HTT messenger RNA is therapeutic, we developed a mutant allele-sensitive CAG^EX RNA-targeting CRISPR-Cas13d system (Cas13d-CAG^EX) that eliminates toxic CAG^EX RNA in fibroblasts derived from patients with HD and induced pluripotent stem cell-derived neurons. We show that intrastriatal delivery of Cas13d-CAG^EX via an adeno-associated viral vector selectively reduces mutant HTT mRNA and protein levels in the striatum of heterozygous zQ175 mice, a model of HD. This also led to improved motor coordination, attenuated striatal atrophy and reduction of

SUBMITTER: Morelli KH 

PROVIDER: S-EPMC9829537 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature