265. Brain Pathways Enabling Vision in LCA Patients Before and After Gene Therapy
Authors: Manzar Ashtari, Philip Cook, Hui Zhang, Laura Cyckowski, Elena Nikonova, Gloria Young, Kathleen Marshall, James Gee, David Leopold, Chris Baker, Albert Maguire, Jean Bennett
Journal: Molecular Therapy (2016)

Leber's Congenital Amaurosis (LCA) is an incurable eye disease. Due to slow retinal degeneration, LCA patients with RPE65 gene mutations (LCA2) are good candidates for gene therapy (GT). LCA2 patients in a Phase 1 clinical trial showed improvement in multiple measures of retinal and visual function of their treated eye after delivery of a normal copy of RPE65 to viable retinal cells with AAV2. We used functional (fMRI) and diffusion (dMRI) MR imaging to study specific brain pathways mediating vision in LCA2 patients before and after GT and assessed processes of brain plasticity that enable vision before and after GT. 10 LCA2 patients and 11 matched controls enrolled in the neuroimaging study. Based on clinical evaluation 9/10 patients received GT to the right eye and one to the left eye. On average, two years after receiving GT only in one eye, patients underwent MR imaging. MRI scans were performed on a research 3T system using a 32-channel head coil. fMRI data was acquired using the checkerboard stimuli. The dMRI sequence was used with a total of 30 non-parallel diffusion gradient directions. In response to a contrast reversing checkerboard paradigm, control subjects showed to be using the expected geniculostriate (GS) pathway by activating the bilateral lateral geniculate nucleus (LGN) and the primary visual cortices (V1). Using the same stimuli for the untreated eye in LCA2 patients, they failed to activate the GS pathway. Instead, fMRI results from the untreated eye (before GT) showed that the majority of LCA2 subjects used an alternate pathway known as retinotectal (RT) activating superior colliculus (SC), pulvinar and extrastriatal cortices. Stimulation of the treated eye (after GT) in LCA2 patients showed a similar result as the one observed for control subjects (GS pathway). To verify the fMRI results we performed tractography for both GS and RT visual fibers to examine if retinal GT affects brain structures. Tractography results showed higher RT tract density for LCA2 patients in the hemisphere ipsilateral to their untreated eye and a higher GS tract density ipsilateral to their treated eyes. Control subjects showed symmetrical tracts for both RT and GS pathways. fMRI and dMRI results for the one subject treated in the left eye was the reverse of those treated in the right eye. Conclusion: Preliminary neuroimaging results offer compelling evidence that before GT LCA2 patients do not use the same visual pathway as sighted controls. Instead, our results suggest the use of RT pathway through which newly discovered melanopsin based intrinsically photosensitive ganglion cells are thought to send information to the brain. After GT the mechanism by which visual signals are transmitted to the brain change to the traditional GS pathway used by sighted controls. Our preliminary neuroimaging results also confirm that the long term stimulation of visual pathways prompted by gene therapy are necessary to shape brain structure and how these activities are critical for the proper wiring of the visual pathways.