Research ArticleBLINDNESS

In Vivo–Directed Evolution of a New Adeno-Associated Virus for Therapeutic Outer Retinal Gene Delivery from the Vitreous

Science Translational Medicine  12 Jun 2013:
Vol. 5, Issue 189, pp. 189ra76
DOI: 10.1126/scitranslmed.3005708

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New Eye Pod

Gene therapy mediated by adeno-associated virus (AAV) vectors has been clinically successful for the treatment of certain inherited diseases of the retina—the light-sensitive structure at the back of the eye that houses the photoreceptor cells (rods and cones). These degenerative disorders arise from mutated genes that either fail to express an essential protein or express harmful proteins that drive structural breakdown, cell death, and, ultimately, blindness. Current gene therapy regimens require damaging injections of gene-carrying vectors into the space between the rod and cone photoreceptors and the retinal pigment epithelium. By this route, the genetic material is delivered to only part of the retina. Now, Dalkara et al. show that delivery of a new vector into the eye’s easily accessible vitreous humour transduces the entire retina and rescues degenerative eye disease phenotypes.

The authors used in vivo–directed evolution to fashion an AAV vector that delivers wild-type versions of defective genes throughout the retina after noninjurious injection into the eye’s easily accessible vitreous humour—the gel-like liquid between the lens and the retina. The newly engineered gene therapy systems rescued disease phenotypes in two mouse models of inherited eye diseases (X-linked retinoschisis and Leber’s congenital amaurosis) and transduced photoreceptor cells in nonhuman primates when delivered via the vitreous. Development of these next-generation therapeutic “eye pods” suggests that gene therapy vectors can be designed to penetrate dense tissues, which currently constitute barriers to gene delivery.