Gene therapy for retinal disease

Abstract

Gene therapy strategies for the treatment of inherited retinal diseases have made major advances in recent years. This review focuses on adeno-associated viral (AAV) vector approaches to treat retinal degeneration and, thus, prevent or delay the onset of blindness. Data from human clinical trials of gene therapy for retinal disease show encouraging signs of safety and efficacy from AAV vectors. Recent progress in enhancing cell-specific targeting and transduction efficiency of the various retinal layers plus the use of AAV-delivered growth factors to augment the therapeutic effect and limit cell death suggest even greater success in future human trials is possible.

Figure 1. Basic vertebrate retinal structure.

Light must pass through the ganglion cell layer (GCL, consisting of ganglion cells and displaced amacrine cells) through the inner nuclear layer (INL) of bipolar, Müller and horizontal cells and then beyond the outer nuclear layer (ONL) to the photoreceptor outer segments that lie at the back of the retina prior to the supporting retinal pigment epithelium (RPE).

Figure 2. C57BL/6 retina following subretinal injection of rAAV2/5 hGRK1 promoter-GFP vector

a) nuclei staining and GFP expression; b) GFP only revealing photoreceptor-specific expression. Human retinal explants transduced ex-vivo with rAAV2/5 CAG promoter-GFP: c) nuclei staining and GFP expression; d) GFP only revealing mostly photoreceptor expression with some INL expression. INL = inner nuclear layer, ONL = outer nuclear layer.