Leber's Congenital Amaurosis (LCA) is a rare retinal disease with fourteen different known gene mutations. LCA2 is the form of LCA caused by RPE65 mutations, a form which has been amenable to gene augmentation therapy in both animals and humans. At the Children's Hospital of Philadelphia (CHOP), LCA2 patients are currently being offered with the new hope of gene therapy to restore their vision. Successful results from this clinical trial have been recently reported. It is evident that of all human sensory systems, vision provides the most information to the brain and there is supporting evidence that confirms gray and white matter brain tissue are affected in individuals with prolonged sensory deprivation. An exciting question is whether such brain abnormalities could be normalized after vision is restored. With a unique opportunity at CHOP, this project proposes a longitudinal comprehensive functional and structural neuroimaging study in three groups of subjects: Group 1 is fifteen LCA2 type patients who are candidates for gene transfer therapy. Group 2 is 10 LCA patients with other gene mutations who are not candidates for surgery. Group 3 is ten normally sighted individuals. For the LCA2 group, non-invasive functional and structural brain imaging will be obtained at baseline, three months after gene transfer (acute effect), and one year following gene transfer (long-term effect). For comparison groups, baseline and follow up scans will be obtained one year apart. Brain changes will be assessed using state-of-the-art image acquisition and processing techniques exclusively available at CHOP/University of Pennsylvania. Imaging will be performed on a newly installed research dedicated 3T Siemens Verio system using a 32- channel head coil. In addition to the volume of gray and white matter, cortical thickness and cortical folding of the brain and in particular the visual cortex will be assessed. DTI analyses and tractography will be employed to evaluate the changes in optic pathways within and between subjects at baseline and follow up. Acute and long-term functional changes due to sub-retinal gene transfer surgery will be studied using fMRI. Specific fMRI paradigms are proposed to evaluate the brain's primary and second order visual functions separately. An additional task is also planned to assess the cross modal plasticity of the occipital cortex that may occur in individuals with longstanding visual deprivation. By the end of the project we hope to identify structural/functional brain biomarkers to predict the success of gene transfer treatment for the LCA2 patients. For example, baseline measures of white or gray matter volumes of the occipital cortex and/or diffusion indices of optic pathways may be a predictor of patients'response to gene therapy. Such structural/functional correlations may also be useful in the future for predicting success of gene based therapies aiming to restore vision in other forms of blindness. With the unique imaging resources and neuroimaging expertise available at CHOP and University of Pennsylvania along with the cutting-edge clinical trials conducted on this unique patient population, CHOP is an ideal place to perform this study.

Public Health Relevance

A rare type of pediatric congenital blindness (Leber's Congenital Amaurosis type 2 (LCA2)) is being treated at CHOP using an exciting and advanced method of gene therapy. This proposal will attempt to evaluate functional and structural brain changes before and after gene therapy in a group of previously blind LCA2 patients who have had their vision restored. This would be the first time scientists have evaluated brain changes in humans after vision restoration.

National Institute of Health (NIH)
National Eye Institute (NEI)
Exploratory/Developmental Grants (R21)
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Central Visual Processing Study Section (CVP)
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Wiggs, Cheri
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Children's Hospital of Philadelphia
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Bennett, Jean (2017) Taking Stock of Retinal Gene Therapy: Looking Back and Moving Forward. Mol Ther 25:1076-1094
Ashtari, Manzar; Nikonova, Elena S; Marshall, Kathleen A et al. (2017) The Role of the Human Visual Cortex in Assessment of the Long-Term Durability of Retinal Gene Therapy in Follow-on RPE65 Clinical Trial Patients. Ophthalmology 124:873-883
Bennett, Jean; Wellman, Jennifer; Marshall, Kathleen A et al. (2016) Safety and durability of effect of contralateral-eye administration of AAV2 gene therapy in patients with childhood-onset blindness caused by RPE65 mutations: a follow-on phase 1 trial. Lancet 388:661-72
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