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

作者：Yan, Zixiang; Yao, Yuqin; Li, Luyao; Cai, Lingqiong; Zhang, Haiwei; Zhang, Shenghai; Xiao, Qingquan; Wang, Xing; Zuo, Erwei^*; Xu, Chunlong^*; Wu, Jihong^*; Yang, Hui^*

来源：Molecular Therapy-Nucleic Acids, 2023, 33: 750-761.

DOI：10.1016/j.omtn.2023.08.002

• RETINAL FUNCTION
• RHODOPSIN GENE
• PIG MODEL
• ALLELE

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 hRHOP23H/WT mouse models. Our study indicates the potential of hfCas13X in treating adRP caused by RHO mutations and other genetic diseases.

• 单位
  中国医学科学院; 复旦大学; 中国科学院