AAV2 Gene Therapy Readministration in Three Adults with Congenital Blindness

Repeat administration of gene therapy to the contralateral retina of three congenitally blind patients was safe and resulted in improved vision. Shining a Light with Gene Therapy Gene therapy has great potential for treating certain diseases by providing therapeutic genes to target cells. Administration of a gene therapy vector carrying the RPE65 gene in 12 patients with congenital blindness due to RPE65 mutations led to improvements in retinal and visual function and proved to be a safe and stable procedure. In a follow-up study, the same group of researchers led by Jean Bennett set out to discover whether it would be possible to safely administer the vector and the therapeutic transgene to the contralateral eye of the patients. A big concern was whether the first gene therapy injection might have primed the patients’ immune system to respond to the adeno-associated virus (AAV) vector or the product of the therapeutic transgene that it had delivered. To test the safety and efficacy of a second administration of gene therapy to the second eye, the authors demonstrated that readministration was both safe and effective in animal models. Then, they selected 3 of the original 12 patients and readministered the AAV vector and its RPE65 transgene to the contralateral eye. They assessed safety by evaluating inflammatory responses, immune reactions, and extraocular exposure to the AAV vector. Efficacy was assessed through qualitative and quantitative measures of retinal and visual function including the ability to read letters, the extent of side vision, light sensitivity, the pupillary light reflex, the ability to navigate in dim light, and evidence from neuroimaging studies of cortical activation (which demonstrated that signals from the retina were recognized by the brain). The researchers did not discover any safety concerns and did not identify harmful immune responses to the vector or the transgene product. Before and after comparisons of psychophysical data and cortical responses provided the authors with evidence that gene therapy readministration was effective and mediated improvements in retinal and visual function in the three patients. The researchers report that the lack of immune response and the robust safety profile in this readministration gene therapy study may be due in part to the immune-privileged nature of the eye, and the low dose and very pure preparation of the AAV vector. Demonstration of safe and stable reversal of blindness after a single unilateral subretinal injection of a recombinant adeno-associated virus (AAV) carrying the RPE65 gene (AAV2-hRPE65v2) prompted us to determine whether it was possible to obtain additional benefit through a second administration of the AAV vector to the contralateral eye. Readministration of vector to the second eye was carried out in three adults with Leber congenital amaurosis due to mutations in the RPE65 gene 1.7 to 3.3 years after they had received their initial subretinal injection of AAV2-hRPE65v2. Results (through 6 months) including evaluations of immune response, retinal and visual function testing, and functional magnetic resonance imaging indicate that readministration is both safe and efficacious after previous exposure to AAV2-hRPE65v2.