AAV-Mediated Gene Therapy in Mouse Models of Recessive Retinal Degeneration

J.-J.      Pang; L.      Lei; X.      Dai; W.      Shi; X.      Liu; A.      Dinculescu; J.      H. McDowell

Abstract

In recent years, more and more mutant genes that cause retinal diseases have been detected. At the same time, many naturally occurring mouse models of retinal degeneration have also been found, which show similar changes to human retinal diseases. These, together with improved viral vector quality allow more and more traditionally incurable inherited retinal disorders to become potential candidates for gene therapy. Currently, the most common vehicle to deliver the therapeutic gene into target retinal cells is the adenoassociated viral vector (AAV). Following delivery to the immuno-privileged subretinal space, AAV-vectors can efficiently target both retinal pigment epithelium and photoreceptor cells, the origin of most retinal degenerations. This review focuses on the AAV-based gene therapy in mouse models of recessive retinal degenerations, especially those in which delivery of the correct copy of the wild-type gene has led to significant beneficial effects on visual function, as determined by morphological, biochemical, electroretinographic and behavioral analysis. The past studies in animal models and ongoing successful LCA2 clinical trials, predict a bright future for AAV gene replacement treatment for inherited recessive retinal diseases.

Keywords: Adeno-associated viral vector, gene therapy, inherited retinal disease, monogenic recessive mutation, mouse model, photoreceptors, autosomal dominant, autosomal recessive, X-linked recessive, stem cell therapy, neuroprotective factors, gene replacement therapy, wild-type protein, RPE65 gene delivery, mutant allele