BEST1: the Best Target for Gene and Cell Therapies

Abstract

A retinal pigmented epithelial (RPE) disorder, bestrophinopathy has recently been proven to be amenable to gene and cell-based therapies in preclinical models. RPE disorders and allied retinal degenerations exhibit significant genetic heterogeneity, and diverse mutations can result in similar disease phenotypes. Several RPE disorders have recently become targets for gene therapies in humans. The year 2011 brought a new advance in cell-based therapies, with the Food and Drug Administration approving clinical trials using embryonic stem cells for an RPE disorder known as age-related macular degeneration. Recent studies on induced pluripotent stem (iPS)-RPE generation indicate strong potential for developing patient-specific disease models in vitro, which could eventually enable personalized treatment. This mini-review will briefly highlight the suitability of the retina for gene and cell therapies, the pathophysiology of bestrophinopathy, and the research and treatment opportunities afforded by stem cell and genetic therapies.

Figure 1

Healthy eyes. The fundus autofluoresence (FA) (a) and spectral-domain optical coherence tomography (b) of a healthy individual are provided for comparison with disease states. The white line in (a) corresponds to the location of the retinal cross section shown in (b), and the arrows indicate the photoreceptor mitochondrial band.

Figure 2

Early bestrophinopathy vitelliform macular degeneration (VMD (MIM#153700)). Mild phenotypic manifestation in a 5-year-old VMD patient with a BEST1, p. Ala10Thr mutation. Color fundus photograph of the left eye shows the vitelliform lesion in the central macula (a). Subretinal fluid* and outer segment debris are visible in the spectral-domain optical coherence tomography images (b). The central opaque region* corresponds to an area of serous detachment. Photoreceptor outer segments are hyper-autofluorescent in FA imaging. *= subretinal fluid; black arrows = photoreceptor mitochondrial band.

Figure 3

Moderate vitelliform macular degeneration (VMD). Moderate phenotypic manifestation in a 58-year-old VMD patient with a novel p. Asp302Ala mutation. The vitelliform is pronounced in the color fundus imaging (a), the photoreceptor layer is thin compared to that of a healthy individual, and extensive fluid has developed subretinally in optical coherence tomography imaging (b). *= subretinal fluid; black arrows = photoreceptor mitochondrial band.

Figure 4

Severe vitelliform macular degeneration (VMD). Severe phenotypic manifestation in a 42-year-old VMD patient with p. Asp302Ala (novel) and p. Arg218His mutations. Photoreceptor mitochondrial band has disintegrated at various points, indicated by black arrows. FA is absent in the central area, which exhibits dystrophic RPE and loss of photoreceptors.

Figure 5

Autosomal recessive bestrophinopathy (ARB (MIM#611809)). (a): Right eye; (b): Left eye. Color montage fundus photographs are from a 6-year-old ARB patient with the homozygous mutation p. Phe283del. In the right eye, there is vitelliform material nasal to the optic disc, while the left eye exhibits multifocal, curvilinear, yellowish subretinal deposits along the superotemporal arcade.