title: Pseudo-fovea formation after gene therapy for RPE65-LCA.
abstract: OBJECTIVE
  The purpose of this study was to evaluate fixation location and oculomotor characteristics of 15 patients with Leber congenital amaurosis (LCA) caused by RPE65 mutations (RPE65-LCA) who underwent retinal gene therapy.
  
  
  METHODS
  Eye movements were quantified under infrared imaging of the retina while the subject fixated on a stationary target. In a subset of patients, letter recognition under retinal imaging was performed. Cortical responses to visual stimulation were measured using functional magnetic resonance imaging (fMRI) in two patients before and after therapy.
  
  
  RESULTS
  All patients were able to fixate on a 1° diameter visible target in the dark. The preferred retinal locus of fixation was either at the anatomical fovea or at an extrafoveal locus. There were a wide range of oculomotor abnormalities. Natural history showed little change in oculomotor abnormalities if target illuminance was increased to maintain target visibility as the disease progressed. Eleven of 15 study eyes treated with gene therapy showed no differences from baseline fixation locations or instability over an average of follow-up of 3.5 years. Four of 15 eyes developed new pseudo-foveas in the treated retinal regions 9 to 12 months after therapy that persisted for up to 6 years; patients used their pseudo-foveas for letter identification. fMRI studies demonstrated that preservation of light sensitivity was restricted to the cortical projection zone of the pseudo-foveas.
  
  
  CONCLUSIONS
  The slow emergence of pseudo-foveas many months after the initial increases in light sensitivity points to a substantial plasticity of the adult visual system and a complex interaction between it and the progression of underlying retinal disease. The visual significance of pseudo-foveas suggests careful consideration of treatment zones for future gene therapy trials. (ClinicalTrials.gov number, NCT00481546.).
authors.affiliation: Scheie Eye Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States.
authors.forename: Artur V
authors.initials: AV
authors.lastname: Cideciyan
authors.affiliation: Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States.
authors.forename: Geoffrey K
authors.initials: GK
authors.lastname: Aguirre
authors.affiliation: Scheie Eye Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States.
authors.forename: Samuel G
authors.initials: SG
authors.lastname: Jacobson
authors.affiliation: Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States.
authors.forename: Omar H
authors.initials: OH
authors.lastname: Butt
authors.affiliation: Scheie Eye Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States.
authors.forename: Sharon B
authors.initials: SB
authors.lastname: Schwartz
authors.affiliation: Scheie Eye Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Swider
authors.affiliation: Scheie Eye Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States.
authors.forename: Alejandro J
authors.initials: AJ
authors.lastname: Roman
authors.affiliation: Scheie Eye Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States.
authors.forename: Sam
authors.initials: S
authors.lastname: Sadigh
authors.affiliation: Department of Ophthalmology, University of Florida, Gainesville, Florida, United States.
authors.forename: William W
authors.initials: WW
authors.lastname: Hauswirth
mesh_terms: D000328:Adult; D004247:DNA / Q000235:genetics; D004252:DNA Mutational Analysis; D005133:Eye Movements; D005260:Female; D005500:Follow-Up Studies; D005584:Fovea Centralis / Q000473:pathology*; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D057130:Leber Congenital Amaurosis / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009154:Mutation; D016896:Treatment Outcome; D014792:Visual Acuity; D019745:cis-trans-Isomerases / Q000235:genetics* / Q000378:metabolism; D000099178:Retinoid Isomerohydrolase
chemical_list: D004247:DNA; D019745:cis-trans-Isomerases; D000099178:Retinoid Isomerohydrolase
keywords: gene therapy; nystagmus; retinal degeneration