Treatment of autosomal dominant retinitis pigmentosa caused by RHO-P23H mutation with high-fidelity Cas13X in mice

作者：Zixiang Yan, Yuqin Yao, Luyao Li, Lingqiong Cai, Haiwei Zhang, Shenghai Zhang, Qingquan Xiao, Xing Wang, Erwei Zuo, Chunlong Xu, Jihong Wu, Hui Yang · 发表于：Molecular Therapy — Nucleic Acids · 年份：2023 · DOI：10.1016/j.omtn.2023.08.002 · 被引用次数：22 · 研究领域：CRISPR and Genetic Engineering、Retinal Development and Disorders、Advanced biosensing and bioanalysis techniques

Mutations in Rhodopsin (RHO) gene commonly cause autosomal dominant retinitis pigmentosa (adRP) without effective therapeutic treatment so far. Compared with genomic DNA-targeting CRISPR-Cas9 system, Cas13 edits RNA for therapeutic applications, avoiding the risk of causing permanent changes in the genome. In particular, a compact and high-fidelity Cas13X (hfCas13X) recently has been developed to degrade targeted RNA with minimal collateral effects and could also be packaged in a single adeno-associated virus for efficient in vivo delivery. In this study, we engineered single-guide RNA for hfCas13X to specifically knock down human mutant Rhodopsin transcripts RHO-P23H with minimal effect on wild-type transcripts. Moreover, treatment with hfCas13X alleviated the adRP progression in both RHO-P23H overexpression-induced and humanized hRHO P23H/WT mouse models. Our study indicates the potential of hfCas13X in treating adRP caused by RHO mutations and other genetic diseases.