The human visual cortex responds to gene therapy–mediated recovery of retinal function
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
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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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 1

Results for subject CH09.

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Results for subject CH09. (A) fMRI results for high-contrast stimulus pr...
(A) fMRI results for high-contrast stimulus presented to the treated left eye showed significant (fdr < 5%, corrected P < 0.005, cca ≥ 100 mm2) bilateral activations extending from medial to lateral aspects of the occipital poles. All fMRI results show left and right inflated (medial view) and flatmap cortical representations. (C) Medium-contrast stimulus presented to the left eye also showed significant (fdr < 5%, corrected P < 0.002, cca ≥ 20 mm2) bilateral activations. Activations for high- and medium-contrast stimuli were primarily distributed to the upper bank of the CF. (B) The high-contrast stimulus presented to the untreated right eye showed patches of activation outside the primary visual cortex at a lower (uncorrected) statistical threshold and a smaller extent threshold. (D) No activation, even at an uncorrected relaxed statistical threshold, was detected for the right eye presented with the medium-contrast stimulus. (E and F) Measured VFs at baseline (before surgery) and at follow-up. (G) The predicted VF area in E was based on the observed subretinal injection site at the time of treatment, indicated by white arrowheads within the composite retinal fundus image. CH09’s predicted VF was symmetric to the vertical meridian with a greater area below than above the horizontal meridian. Such VF distribution is predictive of cortical activation that is symmetrically distributed to both hemispheres, with a larger area of activation in the upper bank of the CF. CH09’s fMRI results partially correlated with both predicted and measured VFs.