• Manzar Ashtari, Elena S Nikonova, Kathleen A Marshall, Gloria J Young, Puya Aravand, Wei Pan, Gui-Shuang Ying, Aimee E Willett, Mani Mahmoudian, Albert M Maguire, and Jean Bennett.
• Center for Advanced Retinal and Ocular Therapeutics, Department of Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania; F. M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, Department of Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address: ashtari@mail.med.upenn.edu.
• Ophthalmology. 2017 Jun 1; 124 (6): 873-883.

PurposeGene therapy (GT) has offered immense hope to individuals who are visually impaired because of RPE65 mutations. Although GT has shown great success in clinical trials enrolling these individuals, evidence for stability and durability of this treatment over time is still unknown. Herein we explored the value of functional magnetic resonance imaging (fMRI) as an objective measure to assess independently the longevity of retinal GT.DesignIndividuals with RPE65 mutations who underwent GT in their worse-seeing eye in a phase 1 clinical trial received a second subretinal injection in their contralateral eye in a follow-on clinical trial. Functional magnetic resonance imaging (MRI) was performed longitudinally to assess brain responses of patients with RPE65 mutations after stimulation of their most recently treated eye before and 1 to 3 years after GT.ParticipantsSeven participants with RPE65 mutations who were part of the follow-on clinical trial gave informed consent to participate in a longitudinal neuroimaging fMRI study.MethodsAll participants underwent fMRI using a 3-Tesla MRI system and a 32-channel head coil. Participants' cortical activations were assessed using a block design paradigm of contrast reversing checkerboard stimuli delivered using an MRI-compatible video system.Main Outcome MeasuresThe primary parameters being measured in this study were the qualitative and quantitative fMRI cortical activations produced by our population in response to the visual task.ResultsFunctional MRI results showed minimal or no cortical responses before GT. Significant increase in cortical activation lasting at least 3 years after GT was observed for all participants. Repeated measures analysis showed significant associations between cortical activations and clinical measures such as full-field light sensitivity threshold for white, red, and blue colors; visual field; and pupillary light reflex.ConclusionsParticipants with RPE65 mutations showed intact visual pathways, which became responsive and strengthened after treatment. Functional MRI results independently revealed the efficacy and durability of a 1-time subretinal injection. The fMRI results paralleled those recently reported during the long-term clinical evaluations of the same patients. Results from this study demonstrated that fMRI may play an important role in providing complementary information to patients' ophthalmic clinical evaluation and has usefulness as an outcome measure for future retinal intervention studies.Copyright © 2017 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.

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