Differential Proteomics and Functional Research following Gene Therapy in a Mouse Model of Leber Congenital Amaurosis

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From: PLoS ONE(Vol. 7, Issue 8)
Publisher: Public Library of Science
Document Type: Report
Length: 9,377 words
Lexile Measure: 1540L

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Author(s): Qinxiang Zheng 1 , Yueping Ren 1 , Radouil Tzekov 2 , Yuanping Zhang 3 , Bo Chen 4 , Jiangping Hou 1 , Chunhui Zhao 1 , Jiali Zhu 1 , Ying Zhang 1 , Xufeng Dai 1 , Shan Ma 5 , Jia Li 5 , Jijing Pang 1 , 6 , Jia Qu 1 , * , Wensheng Li 1 , 7 , *


Leber congenital amaurosis (LCA) is an inherited retinal degenerative disorder characterized by severe loss of vision at early age. Affecting around 1 in 80,000 of the population, comprising 5% of the total inherited retinal degenerative diseases, LCA is the major cause leading to binocular blindness in children (10%~20%) [1], [2]. Besides visual impairment from infancy, LCA is also typically characterized by nystagmus, sluggish or no pupillary responses and, low or even non-recordable electroretinogram (ERG) amplitude. LCA is regarded as an autosomal recessive disease, although some autosomal dominant cases were also reported [3], [4]. LCA has been linked to at least fifteen genes, which are AIPL1 , CRB1 , CRX , GUCY2D , LRAT , TULP1 , RPE65 , RPGRIP1 ,CEP290 , RDH12 , LCA5 , TULP1 , RD3 , IMPDH1 and SPATA7 (RetNet:http://www.sph.uth.tmc.edu) [5]. About 16% of all LCA cases are caused by mutations of RPE65 gene [6], which is mainly expressed in retinal pigment epithelium (RPE) [7]. RPE65 is an isomerohydrolase in the canonical retinoid visual cycle, which is the enzymatic pathway that regenerates photoreceptor chromophore 11- cis -retinal after it is bleached in the process of light perception [8]. Studies in knockout mice (RPE65 -/- ) demonstrated that the lack of RPE65 protein does not allow a physiological recovery of 11-cis -retinal and rods and cones degenerate quickly after birth, probably because of the constitutive opsin signaling [9], while administration of 9- cis or 11-cis -retinal could partially restore both rod and cone function [10]. To date, the most successful example of experimental gene therapy for an ocular disease is the gene delivery of RPE65 gene in LCA mice and patients [11]. rAAV-vector-mediated RPE65 gene replacement has rescued morphological, biochemical and electrophysiological abnormalities present in murine models with RPE65 deficiency [12], [13]. More importantly, several groups have reported rescue of vision after rAAV-vector-mediated gene replacement in the Swedish Briard dog, a spontaneous RPE65 -null model [14]-[17], where stable vision improvement has been maintained over 8 years after a single rAAV vector administration [18], [19]. These results, in addition to the absence of side effects after rAAV vector subretinal delivery in non-human primates [20], have paved the way to ongoing clinical trials using rAAV2/2 vectors for RPE65 gene replacement in patients affected by LCA due to RPE65 mutations [21]-[24]. This form of LCA is particularly suitable for gene therapy because RPE65 patients have a relatively preserved retinal morphology, despite severe and early vision impairment [25]. The clinical trial results in 15 children and adults followed up to 3 years are indeed promising and constitute the first successful example of gene therapy for inherited ocular diseases [26].

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Gale Document Number: GALE|A498243670