The tremendous progress in the past decade in delineating the molecular bases of ocular diseases has been accompanied by the realization that it may be possible to harness this information to generate rational treatment strategies. The concept that treatments might be performed at the genetic level has been a driving force in research involving several blinding ocular diseases. Although there has not, as yet, been a demonstration of cure using gene therapy approaches, proof-of-principle has been established in a number of animal models for a diverse set of ocular diseases. Progress to date has been limited by anatomic and immunologic features of the particular ocular compartment that is targeted, by tropism of the available vectors, and by the extent of disease progression at the time of treatment. Systemic delivery of gene therapy agents does not result in gene delivery to ocular structures. Therefore, with the exception of surface corneal epithelium (to which reagent can be applied topically), surgical delivery is necessary to achieve transfer. Either intravitreal or intracameral injection can target structures in the anterior segment (including the corneal endothelium, trabecular meshwork, and iris). These are standard surgical procedures in humans and can be performed for experimental purposes in eyes of small animals. Because the flow of fluid in the eye is from posterior to anterior, intravitreal injection results in exposure of the reagents not only to cells lining the vitreous cavity [retinal ganglion cells (RGCs), lens epithelium, and ciliary epithelium] but also to cells lining the anterior chamber. Ultimately, since intraocular fluid escapes to venous circulation, there is an opportunity for systemic exposure to vector and/or antigen. In contrast to the situation for the anterior segment, exposure to vector delivered to the posterior segment (the subretinal space) is largely limited to cells lining this space [the photoreceptors and the retinal pigment epithelium (RPE)].

The development of gene therapy in general has been limited by the host immune response to foreign antigens in the transgene and/or vector. However, the immunologic features of the eye are unique and have contributed to the rapid progress in ocular gene therapy experiments. Historically, the “immune-privileged” status of the eye has been demonstrated by clinical success in corneal transplantation and experimental delivery of tissue grafts to the eye. This immune-privileged status may be due, at least in part, to sequestration of antigens from systemic circulation in addition to suppression of delayed-type hypersensitivity (DTH). Suppression of