RNA-based therapies in animal models of Leber congenital amaurosis causing blindness  

作　　者：Xia Wang Xianghong Shan Kevin Gregory-Evans Cheryl Y.Gregory-Evans 

机构地区：[1]Department of Ophthalmology and Visual Sciences,University of British Columbia,Vancouver BC V5Z 3N9,Canada

出　　处：《Precision Clinical Medicine》2020年第2期113-126,共14页精准临床医学（英文）

基　　金：This work was supported by Fighting Blindness Canada(grant No.20R23299).

摘　　要：Leber congenital amaurosis(LCA)is a severe,genetically heterogeneous recessive eye disease in which∼35%of genemutations are in-frame nonsensemutations coding for loss-of-function premature termination codons(PTCs)inmRNA.Nonsense suppression therapy allows read-through of PTCs leading to production of full-length protein.A limitation of nonsense suppression is that nonsense-mediated decay(NMD)degrades PTC-containing RNA transcripts.The purpose of this study was to determine whether inhibition of NMD could improve nonsense suppression efficacy in vivo.Using a high-throughput approach in the recessive cep290 zebrafish model of LCA(cep290;Q1223X),we first tested the NMD inhibitor Amlexanox in combination with the nonsense suppression drug Ataluren.We observed reduced retinal cell death and improved visual function.With these positive data,we next investigated whether this strategy was also applicable across species in two mammalianmodels:Rd12(rpe65;R44X)and Rd3(rd3;R107X)mouse models of LCA.In the Rd12 model,cell death was reduced,RPE65 protein was produced,and in vivo visual function testing was improved.We establish for the first time that the mechanism of action of Amlexanox in Rd12 retina was through reduced UPF1 phosphorylation.In the Rd3 model,however,no beneficial effect was observed with Ataluren alone or in combination with Amlexanox.This variation in response establishes that some forms of nonsensemutation LCA can be targeted by RNA therapies,but that this needs to be verified for each genotype.The implementation of precision medicine by identifying better responders to specific drugs is essential for development of validated retinal therapies.

关 键 词：precision medicine Ataluren AMLEXANOX nonsense suppression RPE65 CEP290 RD3 

分 类 号：R73[医药卫生—肿瘤]