Yan Zixiang, Yao Yuqin, Li Luyao, Cai Lingqiong, Zhang Haiwei, Zhang Shenghai, Xiao Qingquan, Wang Xing, Zuo Erwei, Xu Chunlong, Wu Jihong, Yang Hui
Shenzhen Branch, Guangdong Laboratory for Lingnan Modern Agriculture, Key Laboratory of Synthetic Biology, Ministry of Agriculture and Rural Affairs, Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen 518000, China.
HuidaGene Therapeutics Co., Ltd., Shanghai 200131, China.
Mol Ther Nucleic Acids. 2023 Aug 7;33:750-761. doi: 10.1016/j.omtn.2023.08.002. eCollection 2023 Sep 12.
Mutations in (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 delivery. In this study, we engineered single-guide RNA for hfCas13X to specifically knock down human mutant 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 mouse models. Our study indicates the potential of hfCas13X in treating adRP caused by RHO mutations and other genetic diseases.
视紫红质（RHO）基因突变通常会导致常染色体显性遗传性视网膜色素变性（adRP），迄今为止尚无有效的治疗方法。与靶向基因组DNA的CRISPR-Cas9系统相比，Cas13编辑RNA用于治疗应用，避免了在基因组中引起永久性变化的风险。特别是，最近开发了一种紧凑且高保真的Cas13X（hfCas13X），以最小的附带效应降解靶向RNA，并且还可以包装在单个腺相关病毒中以实现高效递送。在本研究中，我们设计了用于hfCas13X的单向导RNA，以特异性敲低人类突变RHO转录本RHO-P23H，同时对野生型转录本的影响最小。此外，用hfCas13X处理可减轻RHO-P23H过表达诱导的和人源化hRHO小鼠模型中的adRP进展。我们的研究表明hfCas13X在治疗由RHO突变引起的adRP和其他遗传疾病方面具有潜力。
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