Gene Augmentation Therapy for Bestrophinopathies: Targeting BEST1 in the Clinic

The bestrophin-1 (BEST1) gene encodes a calcium-dependent chloride channel, a transmembrane protein critical for the function of the retinal pigment epithelium (RPE) in the eye. Pathogenic variants in BEST1 are the underlying cause for bestrophinopathies, a group of inherited retinal diseases (IRDs) that vary in their pattern of inheritance, clinical appearance, and underlying molecular disease mechanisms. This article focuses on gene therapy strategies to treat Best vitelliform macular dystrophy (BVMD) and autosomal recessive bestrophinopathy (ARB), two conditions for which there are currently no available treatments. Gene therapy represents an attractive strategy to treat BVMD and ARB, in particular gene augmentation, which has a successful track record for treating IRDs. This review examines the clinical diversity of bestrophinopathies and identifies the specific molecular disease mechanism of the pathogenic BEST1 genetic variants as an important parameter for designing future gene therapy strategies. Finally, we highlight the ongoing BIRD-1 (BEST1 Inherited Retinal Diseases) clinical trial as a significant step in translating the gene augmentation strategy into a clinical reality for treating BVMD and ARB.