Gene therapy of the human retina

Retinal gene therapy holds great promise in treating different forms of non-inherited and inherited blindness.

In 2008, three independent research groups reported that patients with the rare genetic retinal disease Leber's Congenital Amaurosis had been successfully treated using gene therapy with adeno-associated virus (AAV). In all three studies, an AAV vector was used to deliver a functional copy of the RPE65 gene, which restored vision in children suffering from LCA. These results were widely seen as a success in the gene therapy field, and have generated excitement and momentum for AAV-mediated applications in retinal disease.

In retinal gene therapy, the most widely used vectors for ocular gene delivery are based on adeno-associated virus. The great advantage in using adeno-associated virus for the gene therapy is that it poses minimal immune responses and mediates long-term transgene expression in a variety of retinal cell types. For example, tight junctions that form the blood-retina barrier, separate subretinal space from the blood supply, providing protection from microbes and decreasing most immune-mediated damages.

In 2008, three groups reported positive results of clinical trials using adeno-associated virus for Leber's Congenital Amaurosis. In these studies, an AAV vector encoding the RPE65 gene was delivered via a "subretinal injection," where a small amount of fluid is injected underneath the retina in a short surgical procedure.

Initial results from all three studies indicate that AAV is safe in the retina, with no dose-limiting toxicities observed. Across the three trials, no serious adverse events were observed. Furthermore, patients in all three studies showed improvement in their visual function as measured by a number of methods. The methods used varied among the three trials, but included both functional methods such as visual acuity and functional mobility as well as objective measures that are less susceptible to bias, such as the pupil's ability to respond to light and improvements on functional MRI. Improvements were sustained over the long-term, with patients continuing to do well after more than 1.5 years.

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