RNA-Targeting CRISPR/CasRx System Relieves Disease Symptoms in Huntington's Disease Models. Sus scrofa,Mus musculus

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.

亨廷顿舞蹈症（Huntington's disease, HD）是一种由亨廷顿（HTT）基因内CAG重复序列扩增引发的毁灭性神经退行性疾病。近年来，CRISPR/CasRx等基因编辑技术的进展为治疗干预开辟了全新途径。本研究探究了可特异性精准消化单链RNA并下调相关基因表达的CRISPR/CasRx系统靶向HTT mRNA的效果，及其作为HD治疗策略的潜力。研究结果显示，CRISPR/CasRx可在多种模型中显著下调HTT mRNA的表达水平，这些模型包括人胚肾（HEK）293T细胞、不同疾病阶段的HD140Q敲入（HD140Q-KI）小鼠以及亨廷顿敲入（HD-KI）猪，并随之降低突变型亨廷顿（mHTT）蛋白的表达量。此外，该干预手段可显著改善HD140Q-KI小鼠与HD-KI猪的神经功能症状。上述研究结果凸显了靶向RNA的CRISPR/CasRx系统作为HD潜在治疗策略的有效性。此外，该技术方案的成功为其他由基因突变引发的遗传性疾病的治疗提供了宝贵思路与全新方向。