title: 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.
abstract: Gene 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.
  
  
  
  Individuals 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.
  
  
  
  Seven participants with RPE65 mutations who were part of the follow-on clinical trial gave informed consent to participate in a longitudinal neuroimaging fMRI study.
  
  
  
  All 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.
  
  
  
  The 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.
  
  
  
  Functional 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.
  
  
  
  Participants 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.
authors.affiliation: 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.
authors.forename: Manzar
authors.initials: M
authors.lastname: Ashtari
authors.affiliation: University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Elena S
authors.initials: ES
authors.lastname: Nikonova
authors.affiliation: Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Marshall
authors.affiliation: Center for Advanced Retinal and Ocular Therapeutics, Department of Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Gloria J
authors.initials: GJ
authors.lastname: Young
authors.affiliation: Center for Advanced Retinal and Ocular Therapeutics, Department of Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Puya
authors.initials: P
authors.lastname: Aravand
authors.affiliation: Westat Biostatistics and Data Management Core, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
authors.forename: Wei
authors.initials: W
authors.lastname: Pan
authors.affiliation: Westat Biostatistics and Data Management Core, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
authors.forename: Gui-Shuang
authors.initials: GS
authors.lastname: Ying
authors.affiliation: Center for Advanced Retinal and Ocular Therapeutics, Department of Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Aimee E
authors.initials: AE
authors.lastname: Willett
authors.affiliation: Center for Advanced Retinal and Ocular Therapeutics, Department of Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Mani
authors.initials: M
authors.lastname: Mahmoudian
authors.affiliation: 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; Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
authors.forename: Albert M
authors.initials: AM
authors.lastname: Maguire
authors.affiliation: 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; Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
authors.forename: Jean
authors.initials: J
authors.lastname: Bennett
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D003118:Color Perception / Q000502:physiology; D000229:Dependovirus / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D056965:Injections, Intraocular; D057130:Leber Congenital Amaurosis / Q000235:genetics / Q000503:physiopathology / Q000628:therapy*; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009154:Mutation; D012025:Reflex, Pupillary / Q000502:physiology; D012160:Retina / Q000503:physiopathology*; D014793:Visual Cortex / Q000502:physiology*; D014795:Visual Pathways / Q000502:physiology; D019745:cis-trans-Isomerases / Q000235:genetics*; D000099178:Retinoid Isomerohydrolase
chemical_list: D019745:cis-trans-Isomerases; D000099178:Retinoid Isomerohydrolase