BEST1 gene therapy corrects a diffuse retina-wide microdetachment modulated by light exposure

Abstract

SignificanceOne of the most common forms of monogenic macular degeneration worldwide is caused by dominant or recessive bestrophinopathies associated with mutations in the BEST1 gene. Disease expression is known to start with a retina-wide electrophysiological defect leading to localized vitelliform and atrophic lesions and vision loss. To develop lasting therapies for this incurable disease, there is a need for greater understanding of the early pathophysiology before lesion formation. Here we find that the loss of retinal pigment epithelium apical microvilli and resulting microdetachment of the retina represent the earliest features of canine bestrophinopathies. We show that retinal light exposure expands, and dark adaptation contracts, the microdetachments. Subretinal adeno-associated virus-based gene therapy corrects both the vitelliform lesions and the light-modulated microdetachments.

Novel BEST1 mutations and special clinical characteristics of autosomal recessive bestrophinopathy in Chinese patients

“…A definitive diagnosis of ARB should be based on molecular genetics; thus, ARB patients can be expected to be cured by BEST1 gene therapy (Guziewicz et al. ).…”

Inhibition of Ca 2+ channel surface expression by mutant bestrophin‐1 in RPE cells

“…However, recent data from a gene therapy study detected a new aspect of Best vitelliform macular dystrophy, such a microdetachments, that occur apart of the reduction of the light peak in the EOG. 18 Thus, mutant-dependent changes in the Ca 2+ signalling might be one aspect of the pathology in this disease. A connection between Ca 2+ signalling and microdetachment might be, however, possible but has not been explored so far.…”

“…Enhancement of L‐type channel activity might be an important therapeutic target for these patients. However, recent data from a gene therapy study detected a new aspect of Best vitelliform macular dystrophy, such a microdetachments, that occur apart of the reduction of the light peak in the EOG . Thus, mutant‐dependent changes in the Ca 2+ signalling might be one aspect of the pathology in this disease.…”

“…The mutation‐dependent loss of basolateral Cl − conductance might explain the reduced light‐peak in the patients' EOG because this signal results from light‐dependent activation of basolateral Cl − channels in the RPE and subsequent depolarization of the basolateral membrane . Furthermore, a direct loss of Cl − and water transport or its disturbed regulation might explain the recently detected microdetachments in the retina of a dog bestrophinopathy model that could be cured by gene therapy . As mutant bestrophin‐1 in the dog model and human mutant bestrophin‐1 have the trafficking defect in common, it is likely that patients with BEST1 mutations display a reduced Cl − and water transport like in dog models.…”

“…4,5,9 Furthermore, a direct loss of Cl − and water transport or its disturbed regulation might explain the recently detected microdetachments in the retina of a dog bestrophinopathy model that could be cured by gene therapy. 18 As mutant bestrophin-1 in the dog model and human mutant bestrophin-1 have the trafficking defect in common, it is likely that patients with BEST1 mutations display a reduced Cl − and water transport like in dog models. Using iPSC-generated RPE from patients with BEST1 mutations showed a reduction in the phagocytosis of photoreceptor outer segment membranes, [19][20][21] a process that is essential for the renewal process of the photoreceptors and might explain the accumulation of lipofuscin.…”