The human visual cortex responds to gene therapy–mediated recovery of retinal function
Manzar Ashtari, … , Kenneth S. Shindler, Jean Bennett
Manzar Ashtari, … , Kenneth S. Shindler, Jean Bennett
Published May 23, 2011
Citation Information: J Clin Invest. 2011;121(6):2160-2168. https://doi.org/10.1172/JCI57377.
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The human visual cortex responds to gene therapy–mediated recovery of retinal function

Abstract

Leber congenital amaurosis (LCA) is a rare degenerative eye disease, linked to mutations in at least 14 genes. A recent gene therapy trial in patients with LCA2, who have mutations in RPE65, demonstrated that subretinal injection of an adeno-associated virus (AAV) carrying the normal cDNA of that gene (AAV2-hRPE65v2) could markedly improve vision. However, it remains unclear how the visual cortex responds to recovery of retinal function after prolonged sensory deprivation. Here, 3 of the gene therapy trial subjects, treated at ages 8, 9, and 35 years, underwent functional MRI within 2 years of unilateral injection of AAV2-hRPE65v2. All subjects showed increased cortical activation in response to high- and medium-contrast stimuli after exposure to the treated compared with the untreated eye. Furthermore, we observed a correlation between the visual field maps and the distribution of cortical activations for the treated eyes. These data suggest that despite severe and long-term visual impairment, treated LCA2 patients have intact and responsive visual pathways. In addition, these data suggest that gene therapy resulted in not only sustained and improved visual ability, but also enhanced contrast sensitivity.

Authors

Manzar Ashtari, Laura L. Cyckowski, Justin F. Monroe, Kathleen A. Marshall, Daniel C. Chung, Alberto Auricchio, Francesca Simonelli, Bart P. Leroy, Albert M. Maguire, Kenneth S. Shindler, Jean Bennett

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Figure 3

Results for subject CH13.

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Results for subject CH13. (B) fMRI results 1 year after gene transfer fo...
(B) fMRI results 1 year after gene transfer for the treated right eye presented with the high-contrast stimuli showed significant (fdr < 5%, corrected P < 0.003, cca ≥ 100 mm2) unilateral cortical activation, primarily confined to the left lateral occipital lobe. (A) No activation was observed after exposure of the untreated left eye to the high-contrast stimuli. No activation was observed after medium-contrast stimulus was presented to the treated (D) or untreated (C) eye. (E and F) Measured and predicted VFs. The predicted VF for the treated eye showed a lateralized predicted VF in the lower right quadrant. This predicted VF was mostly confined to the right of the vertical meridian and located primarily below the horizontal meridian. Such distribution predicts cortical activation in the left upper area of the cortex, with no activation in the contralateral hemisphere. The island of activation for the treated eye occurred in the predicted hemisphere (see B), although it was located far lateral to primary visual cortex. (G) These results are consistent with the location of CH13’s subretinal injection. Composite of retinal fundus images demonstrating pigmentary deposits, vascular attenuation, and “window defects” caused by degeneration particularly in the central macula. As a result, CH13 had a subretinal injection located more peripheral (predominantly superotemporal to the macula).