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 4

Results for control subject NC01.

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Results for control subject NC01. Because vision tests showed normal vis...
Because vision tests showed normal vision for both left and right eyes, results from the right eye only are shown. fMRI results showed significant (fdr < 5%, corrected P < 0.003, cca ≥ 100 mm2) bilateral activations in the primary visual cortex extending from posterior to anterior and medial to some lateral aspects of the occipital cortex after presentation of high-contrast (A) and medium-contrast (B) stimuli to his right eye. Medial cortex activation was distributed symmetrically to the upper and lower banks of the CF in both the right and left hemispheres. Similar to the LCA2 participants, and as predicted based on the scotopic light stimulus and/or the size of squares used in the checkerboard stimuli, NC01 did not show any activation in the occipital pole, where foveal activation would otherwise be represented. (C) VF map, which shows symmetrical distribution with respect to the horizontal meridian but covers a greater area to the right of the vertical meridian. Such VF is predictive of bilateral fMRI activations that are equally spread to the superior and inferior aspects of CF. In agreement with his VF, activation was distributed equally to superior and inferior aspects of CF for both hemispheres. Also, as predicted by his VF, activations were bilateral with slightly more activation in the left lateral visual cortex.