RNA-Targeting CRISPR/CasRx System Relieves Disease Symptoms in Huntington's Disease Models

Huntington's disease (HD) is a devastating neurodegenerative disorder caused by the expansion of CAG repeats in the huntingtin (HTT) gene. Recent advances in gene editing technologies, such as CRISPR/CasRx, have opened new avenues for therapeutic interventions. In this study, we explored the efficacy of CRISPR/CasRx, which can specifically and accurately digest single-stranded RNA and down-regulate the expression of related genes, in targeting the HTT mRNA and its potential as a treatment strategy for HD. Our results showed that CRISPR/CasRx could significantly down-regulate HTT mRNA in different models, including human embryonic kidney (HEK) 293T cells, HD140Q-knockin (HD 140Q-KI) mice at various disease stages, and Huntingtin knockin (HD-KI) pigs, and lead to a subsequent decrease in the expression of mutant Huntingtin (mHTT) protein. Moreover, this intervention could significantly ameliorate the neurological symptoms in HD 140Q-KI mice and HD-KI pigs. These findings highlight the effectiveness of the RNA-targeting CRISPR/CasRx as a potential therapeutic strategy for HD. Furthermore, the success of this approach provides valuable insights and novel avenues for the treatment of other genetic disorders caused by gene mutations.