Clustered Regularly Interspaced Short Palindromic Repeats-Based Genome Surgery for the Treatment of Autosomal Dominant Retinitis Pigmentosa

色素性视网膜炎 遗传增强 视网膜电图 基因 医学 突变 遗传学 眼科 生物 视网膜
作者
Yi‐Ting Tsai,W. D. Wu,Ting-Ting Lee,Wei-Pu Wu,Christine L. Xu,Karen Sophia Park,Xuan Cui,Sally Justus,Chyuan‐Sheng Lin,Ruben Jauregui,Pei-Yin Su,Stephen H. Tsang
出处
期刊:Ophthalmology [Elsevier BV]
卷期号:125 (9): 1421-1430 被引量:101
标识
DOI:10.1016/j.ophtha.2018.04.001
摘要

To develop a universal gene therapy to overcome the genetic heterogeneity in retinitis pigmentosa (RP) resulting from mutations in rhodopsin (RHO).Experimental study for a combination gene therapy that uses both gene ablation and gene replacement.This study included 2 kinds of human RHO mutation knock-in mouse models: RhoP23H and RhoD190N. In total, 23 RhoP23H/P23H, 43 RhoP23H/+, and 31 RhoD190N/+ mice were used for analysis.This study involved gene therapy using dual adeno-associated viruses (AAVs) that (1) destroy expression of the endogenous Rho gene in a mutation-independent manner via an improved clustered regularly interspaced short palindromic repeats-based gene deletion and (2) enable expression of wild-type protein via exogenous cDNA.Electroretinographic and histologic analysis.The thickness of the outer nuclear layer (ONL) after the subretinal injection of combination ablate-and-replace gene therapy was approximately 17% to 36% more than the ONL thickness resulting from gene replacement-only therapy at 3 months after AAV injection. Furthermore, electroretinography results demonstrated that the a and b waves of both RhoP23H and RhoD190N disease models were preserved more significantly using ablate-and-replace gene therapy (P < 0.001), but not by gene replacement monotherapy.As a proof of concept, our results suggest that the ablate-and-replace strategy can ameliorate disease progression as measured by photoreceptor structure and function for both of the human mutation knock-in models. These results demonstrate the potency of the ablate-and-replace strategy to treat RP caused by different Rho mutations. Furthermore, because ablate-and-replace treatment is mutation independent, this strategy may be used to treat a wide array of dominant diseases in ophthalmology and other fields. Clinical trials using ablate-and-replace gene therapy would allow researchers to determine if this strategy provides any benefits for patients with diseases of interest.
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