Plasticity of the human visual system studied in response to retinal gene therapy

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Project Summary: The impact of changes in visual input on neuronal circuitry is complex and much of our knowledge of plasticity in the visual system comes from animal studies. While these studies have started to highlight the specific neural underpinnings responsible for visual cortex plasticity in response to visual impairment, restored vision and environment interactions, similar studies have not been possible in humans due to the unethical invasiveness of the procedures involved. Having access to a group of well-characterized subjects with Leber’s Congenital Amaurosis due to RPE65 mutations (LCA2) who will participate in an LCA2 Phase 3 clinical trial provides the unique opportunity to study this process in blind humans who gain vision through gene therapy (GT). We hope to draw parallels between cortical plasticity changes reported in animal studies with reverse eye-lid suture (regaining sight) and human retinal GT in LCA patients (gaining sight). Noninvasive brain imaging before and after intervention in these subjects will provide us the opportunity to not only study the effects of regaining vision on the human brain and the underlying mechanisms of plasticity, but also to bring focus on alternate visual pathways used by the LCA2 patients before GT. One such pathway appears to utilize intrinsically photosensitive Retinal Ganglion Cells (ipRGC) and one question is whether there is a relative change in retinal signaling to the brain after GT. To our knowledge this will be the first longitudinal study to combine structural and functional neuroimaging techniques to examine and gain a deeper understanding of the process of brain plasticity in humans in vivo, focusing on a large group of individuals born with severe visual impairment with measurements before and after an intervention that restores vision. The Phase 3 LCA clinical trial will enroll 24 patients, including 8 randomly assigned to be followed for one year before receiving GT. All subjects will undergo imaging consisting of sub-millimeter 3D structural imaging, and a powerful new method of diffusion MRI (dMRI) that provides microstructural information reflecting degree of dendritic sprouting and myelination. These tests will provide detailed assessment of the changes of the visual cortex in response to GT. Primary and higher visual functions will also be measured in all subjects using a battery of functional MRI (fMRI) paradigms. Visual function will be assessed separately, during the Phase 3 clinical trial and data will be made available to this study. The visual function data will then be correlated with the CNS imaging and visual function data. Completion of this project will provide important temporal-spatial data on the degree of neuroplasticity of the human visual system and the role it plays in enhancement of visual function following GT. These data may have future potential application to studies evaluating gene therapy-mediated reversal of blindness.