Gene therapy for bestrophinopathies

Abstract

AbstractHuman bestrophinopathies, a group of inherited retinal disorders caused by mutations in BEST1, are one of the most common early‐onset macular dystrophies still considered incurable. The disease is usually diagnosed in early childhood or adolescence, and primarily affects macular region leading to major declines in central vision later in life. Canine multifocal retinopathy, a spontaneous animal model of BEST1‐associated retinopathies in man, captures the full spectrum of clinical and molecular features observed in human disease, including the salient predilection of lesions to the canine fovea‐like region, and constitutes an important translational model for development and testing of therapeutic strategies. We have previously shown that rAAV2‐mediated BEST1 gene delivery controlled by human VMD2 promoter specifically targets RPE cells, and is well tolerated in the wt canine retina. Here, we demonstrate that rAAV2‐mediated BEST1 gene augmentation reverses the characteristic BEST1 lesions and pathology in cmr models up to 23 months post‐injection. The talk will highlight the natural history of the disease and elaborate on the potential of rAAV2‐mediated BEST1 gene replacement therapy for prevention as well as reversal of disease.