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Leber congenital amaurosis (LCA) is a rare hereditary retinal degeneration caused
by mutations in more than a dozen genes. RPE65, one of these mutated genes, is highly
expressed in the retinal pigment epithelium where it encodes the retinoid isomerase
enzyme essential for the production of chromophore which forms the visual pigment
in rod and cone photoreceptors of the retina. Congenital loss of chromophore production
due to RPE65-deficiency together with progressive photoreceptor degeneration cause
severe and progressive loss of vision. RPE65-associated LCA recently gained recognition
outside of specialty ophthalmic circles due to early success achieved by three clinical
trials of gene therapy using recombinant adeno-associated virus (AAV) vectors. The
trials were built on multitude of basic, pre-clinical and clinical research defining
the pathophysiology of the disease in human subjects and animal models, and demonstrating
the proof-of-concept of gene (augmentation) therapy. Substantial gains in visual function
of clinical trial participants provided evidence for physiologically relevant biological
activity resulting from a newly introduced gene. This article reviews the current
knowledge on retinal degeneration and visual dysfunction in animal models and human
patients with RPE65 disease, and examines the consequences of gene therapy in terms
of improvement of vision reported.
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