Fighting blindness with adeno-associated virus serotype 8.

Abstract

The paper by Mihelec and colleagues in the current issue of Human Gene Therapy highlights the potential of adenoassociated virus serotype 8 (AAV8) as a gene therapy vector for transduction of retinal photoreceptors. Photoreceptors are key neurons in the retina. For vision to occur, light is focused on the retina, where cone and rod photoreceptors ‘‘capture’’ and convert photons into electrical signals that are then conveyed to the brain. The photoreceptors are overlaid by the retinal pigment epithelium (RPE), which takes part in the visual cycle and provides them with nutrients and removes their waste products. Several blinding conditions are associated with loss of photoreceptors. Among them, the group of inherited retinal degenerations (IRDs), including retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA), are a common cause of blindness worldwide and are currently lacking effective treatment. The eye is small, enclosed, and immune-privileged and therefore an attractive target for gene therapy. These favorable characteristics were instrumental in obtaining the first clinical success in the field of ocular gene therapy: the results from three independent clinical trials showed that subretinal administrations of adeno-associated viral (AAV) vector type 2 are safe and efficacious in patients with a form of LCA due to mutations in RPE65, a gene expressed specifically in the RPE. Despite early-onset severe vision impairment, patients with LCA2 have improved visual function and reactivation of the visual cortex after AAV2-RPE65 administration. LCA2 is quite favorable as a target for gene therapy: (1) it is an enzymatic defect inherited in an autosomal recessive pattern, and thus low transduction levels are expected to be therapeutically relevant; (2) despite profound, early-onset vision impairment, in some patients with LCA2 the retinal architecture is partially preserved until their 20s or 30s; and (3) LCA2 requires gene transfer to the RPE, and AAV2 transduces the RPE very well. Prompted by the favorable results of these initial trials, scientists are planning to target other IRDs with gene therapy. However, the majority of mutations that cause IRDs occur in genes expressed in photoreceptors, and these cells are more challenging targets than the RPE for AAVmediated gene transfer. Virtually every AAV serotype tested thus far transduces the RPE efficiently, whereas only a few, such as AAV2 and AAV5, transduce photoreceptors efficiently. The reasons for this have not been elucidated yet. A plethora of novel AAV serotypes have been identified. One in particular, AAV8, has emerged as one of the most interesting, with impressive transduction abilities in various tissues. AAV8 transduces the liver of several species, including humans, at levels that are therapeutically relevant. In testing the retinal transduction characteristics of several novel AAV serotypes, we observed that AAV8 outperforms AAV5, at the time the ‘‘gold standard’’ for photoreceptor targeting, in terms of ability to transduce both murine (Allocca et al., 2007) and pig (Mussolino et al., 2011) photoreceptors. In addition, Vandenberghe and colleagues have compared the transduction ability of AAV2 and AAV8 in the nonhuman primate (NHP) retina (Vandenberghe et al., 2011). Only the primate retina contains the cone-enriched macula, the area responsible for visual acuity and color vision. Vandenberghe and colleagues observed that AAV8 transduces photoreceptors at doses that are 10-fold lower than for AAV2. Most of the transduced photoreceptors were rods. The authors also observed that AAV8-mediated cone transduction was more robust inside the fovea. Using these titers, the levels of photoreceptor transduction mediated by AAV8 appear potentially therapeutic for conditions like RP, or some forms of LCA, where the primary targets are rods. The ultimate preclinical proof of the potential of AAV8 for retinal gene therapy is the correction of photoreceptor-specific diseases in animal models. The group of Robin Ali at University College London has tested, side by side, the ability of AAV2 and AAV8 to prevent photoreceptor degeneration in a severe model of LCA. The subretinal administrations of AAV8, but not of AAV2, resulted in long-term improvement of the disease phenotype in the Aipl1 mouse model of LCA4 (Tan et al., 2009). In the current issue of Human Gene Therapy, the same group (Mihelec et al., 2011) builds on their previous observations and provides sound and convincing proof of the ability of AAV8 to preserve photoreceptor

DOI: 10.1089/hum.2011.2521

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@article{Auricchio2011FightingBW, title={Fighting blindness with adeno-associated virus serotype 8.}, author={Alberto Auricchio}, journal={Human gene therapy}, year={2011}, volume={22 10}, pages={1169-70} }