title: Gene therapy for leber congenital amaurosis caused by RPE65 mutations: safety and efficacy in 15 children and adults followed up to 3 years.
abstract: OBJECTIVE
  To determine the safety and efficacy of subretinal gene therapy in the RPE65 form of Leber congenital amaurosis using recombinant adeno-associated virus 2 (rAAV2) carrying the RPE65 gene.
  
  
  METHODS
  Open-label, dose-escalation phase I study of 15 patients (range, 11-30 years of age) evaluated after subretinal injection of the rAAV2- RPE65 vector into the worse-functioning eye. Five cohorts represented 4 dose levels and 2 different injection strategies.
  
  
  METHODS
  Primary outcomes were systemic and ocular safety. Secondary outcomes assayed visual function with dark-adapted full-field sensitivity testing and visual acuity with Early Treatment Diabetic Retinopathy Study charts. Further assays included immune responses to the vector, static visual fields, pupillometry, mobility performance, and optical coherence tomography.
  
  
  RESULTS
  No systemic toxicity was detected; ocular adverse events were related to surgery. Visual function improved in all patients to different degrees; improvements were localized to treated areas. Cone and rod sensitivities increased significantly in the study eyes but not in the control eyes. Minor acuity improvements were recorded in many study and control eyes. Major acuity improvements occurred in study eyes with the lowest entry acuities and parafoveal fixation loci treated with subretinal injections. Other patients with better foveal structure lost retinal thickness and acuity after subfoveal injections.
  
  
  CONCLUSIONS
  Gene therapy for Leber congenital amaurosis caused by RPE65 mutations is sufficiently safe and substantially efficacious in the extrafoveal retina. There is no benefit and some risk in treating the fovea. No evidence of age-dependent effects was found. Our results point to specific treatment strategies for subsequent phases.
  
  
  CONCLUSIONS
  Gene therapy for inherited retinal disease has the potential to become a future part of clinical practice.
  
  
  BACKGROUND
  clinicaltrials.gov Identifier: NCT00481546.
authors.affiliation: Scheie Eye Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, USA. jacobsos@mail.med.upenn.edu
authors.forename: Samuel G
authors.initials: SG
authors.lastname: Jacobson
authors.forename: Artur V
authors.initials: AV
authors.lastname: Cideciyan
authors.forename: Ramakrishna
authors.initials: R
authors.lastname: Ratnakaram
authors.forename: Elise
authors.initials: E
authors.lastname: Heon
authors.forename: Sharon B
authors.initials: SB
authors.lastname: Schwartz
authors.forename: Alejandro J
authors.initials: AJ
authors.lastname: Roman
authors.forename: Marc C
authors.initials: MC
authors.lastname: Peden
authors.forename: Tomas S
authors.initials: TS
authors.lastname: Aleman
authors.forename: Sanford L
authors.initials: SL
authors.lastname: Boye
authors.forename: Alexander
authors.initials: A
authors.lastname: Sumaroka
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Conlon
authors.forename: Roberto
authors.initials: R
authors.lastname: Calcedo
authors.forename: Ji-Jing
authors.initials: JJ
authors.lastname: Pang
authors.forename: Kirsten E
authors.initials: KE
authors.lastname: Erger
authors.forename: Melani B
authors.initials: MB
authors.lastname: Olivares
authors.forename: Cristina L
authors.initials: CL
authors.lastname: Mullins
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Swider
authors.forename: Shalesh
authors.initials: S
authors.lastname: Kaushal
authors.forename: William J
authors.initials: WJ
authors.lastname: Feuer
authors.forename: Alessandro
authors.initials: A
authors.lastname: Iannaccone
authors.forename: Gerald A
authors.initials: GA
authors.lastname: Fishman
authors.forename: Edwin M
authors.initials: EM
authors.lastname: Stone
authors.forename: Barry J
authors.initials: BJ
authors.lastname: Byrne
authors.forename: William W
authors.initials: WW
authors.lastname: Hauswirth
mesh_terms: D000293:Adolescent; D000328:Adult; D002352:Carrier Proteins / Q000235:genetics*; D002648:Child; D000229:Dependovirus / Q000235:genetics*; D005136:Eye Proteins / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D015316:Genetic Therapy / Q000009:adverse effects / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D056965:Injections, Intraocular; D057130:Leber Congenital Amaurosis / Q000235:genetics* / Q000503:physiopathology / Q000628:therapy*; D008297:Male; D009154:Mutation; D010775:Photic Stimulation; D020419:Photoreceptor Cells, Vertebrate / Q000502:physiology; D011597:Psychomotor Performance / Q000502:physiology; D011680:Pupil / Q000502:physiology; D041623:Tomography, Optical Coherence; D016896:Treatment Outcome; D014792:Visual Acuity / Q000502:physiology; D014794:Visual Fields / Q000502:physiology; D055815:Young Adult; D019745:cis-trans-Isomerases; D000099178:Retinoid Isomerohydrolase
chemical_list: D002352:Carrier Proteins; D005136:Eye Proteins; D019745:cis-trans-Isomerases; D000099178:Retinoid Isomerohydrolase