Hereditary retinal degeneration, in which mutations in photoreceptors and other delicate cells of the eye's outermost retinal layer lead to deterioration and visual impairment, affects roughly 1 in 3,000 people worldwide. Gene therapy can successfully deliver normal copies of the mutated genes to the affected cells using adeno-associated virus (AAV) but requires that the virus be injected through the retina. These injections reach only a fraction of the affected cells and, moreover, can damage the fragile retina, making them unsuitable for treating the many forms of retinal degeneration in which the retinal tissue is structurally compromised.

A technique recently published in Science Translational Medicine (5, 189ra76; 2013) addresses the resultant need for a less invasive method of delivering gene therapy across the retina. John Flannery and David Schaffer (University of California Berkeley) led the project, engineering a variant of AAV to pass through the retina with its genetic cargo. This variant, 7m8, can be injected into the vitreous, the more accessible gel-like fluid that fills the center of the eye, sparing the retina. The genes it carries are expressed throughout the retina and the optic nerve but not outside the eye. Expression of the cargo genes can be further restricted to cells of interest (e.g., photoreceptors) by using a specific promoter to control the activation of 7m8.

Flannery and Schaffer's group tested 7m8-based gene therapy in mouse models of two forms of inherited retinal degeneration: X-linked retinoschisis and Leber congenital amaurosis type 2. In both cases, delivery of wild-type copies of the affected genes using 7m8 rescued the disease phenotype and improved the mice's vision on a long-term basis.

The team also evaluated 7m8-based gene delivery across the retina in cynomolgus macaques and confirmed its success. The inner layers of the retina are thicker in nonhuman primates than in rodents, presenting a more difficult barrier to trans-retinal gene therapy.

“Building upon 14 years of research, we have now created a virus that you can inject into the liquid vitreous humor inside the eye and it delivers genes to a very difficult-to-reach population of delicate cells in a way that is surgically much less invasive and safer,” Schaffer told NIH Research Matters. The technique's success suggests that this approach may also be applicable to developing gene therapy vectors that can cross other barriers: endothelial (such as the blood–brain barrier), intra-organ or tumoral.