Translational Research for Retinal Degeneration Therapies

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PROJECT SUMMARY . A multi-investigator, multi-center plan is proposed to develop a gene-based retinal therapy for inherited retinal maculopathies caused by mutations in the ABCA4 gene using a naturally-occurring canine model. A subgroup of these patients with ABCA4 bi-allelic truncation mutations show a loss of central cones during childhood that is followed by an “explosive” centrifugal progression of photoreceptor degeneration leading also to peripheral visual malfunction. The proposal builds on success achieved during the current grant period in moving AAV-based gene therapy for RPGR-XLRP to a human clinical trial, as well as developing and validating in a canine model a novel gene therapy for another severe and early-onset ciliopathy, NPHP5- LCA. Results in the dog have shown that the cone-rich central retina can be targeted and rescued even when intervention occurs at late stages of cone disease, a finding that is highly relevant to this proposal. We have recently identified a loss of function mutation in the canine ABCA4 gene that causes a retinal phenotype with striking similarities with human ABCA4-CRD: early accumulation of lipofuscin in the cone-rich central retina followed by pan-retinal degeneration later in life. We will capitalize on availability of this model to improve our understanding of ABCA4 disease and develop a nanoparticle-mediated gene therapy that can accommodate delivery of the large size of this gene. Our proposal is divided into four aims that will: 1- establish the natural history of disease in the canine model; 2- optimize a lead nanoparticle construct that can efficiently transduce cones, rods and RPE in rodents and dogs; 3- identify the optimal route of delivery, dose, and lead vector to target the cone-rich canine central retina, in preparation for 4- proof of concept studies in ABCA4-mutant dogs treated at early and later stages of cone disease/degeneration. While the test system is the ABCA4-mutant dog model, the therapeutic questions that are addressed apply broadly to other retinopathies caused by mutations in large size genes whose delivery may benefit from the development and validation of this nanoparticle delivery platform. The research studies described in this proposal represent a continuation of a longstanding collaboration between a group of vision scientists at the University of Pennsylvania that already have brought retinal gene therapy to the clinic for RPE65-LCA, CNGB3- achromatopsia , and RPGR-XLRP. This new program will greatly benefit from the joint expertise of a consortium of investigators from three academic institutions (University of Pennsylvania, Johns Hopkins University, and Columbia University) that will provide the necessary knowledge in ABCA4 biology, nanoparticle-mediated DNA transfer, small and large animal models, and human ABCA4 disease, to address the current unmet medical need for a treatment for this most common form of inherited retinal degeneration.