title: 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.
abstract: BACKGROUND
  Safety and efficacy have been shown in a phase 1 dose-escalation study involving a unilateral subretinal injection of a recombinant adeno-associated virus (AAV) vector containing the RPE65 gene (AAV2-hRPE65v2) in individuals with inherited retinal dystrophy caused by RPE65 mutations. This finding, along with the bilateral nature of the disease and intended use in treatment, prompted us to determine the safety of administration of AAV2-hRPE65v2 to the contralateral eye in patients enrolled in the phase 1 study.
  
  
  METHODS
  In this follow-on phase 1 trial, one dose of AAV2-hRPE65v2 (1.5 × 10(11) vector genomes) in a total volume of 300 μL was subretinally injected into the contralateral, previously uninjected, eyes of 11 children and adults (aged 11-46 years at second administration) with inherited retinal dystrophy caused by RPE65 mutations, 1.71-4.58 years after the initial subretinal injection. We assessed safety, immune response, retinal and visual function, functional vision, and activation of the visual cortex from baseline until 3 year follow-up, with observations ongoing. This study is registered with ClinicalTrials.gov, number NCT01208389.
  
  
  RESULTS
  No adverse events related to the AAV were reported, and those related to the procedure were mostly mild (dellen formation in three patients and cataracts in two). One patient developed bacterial endophthalmitis and was excluded from analyses. We noted improvements in efficacy outcomes in most patients without significant immunogenicity. Compared with baseline, pooled analysis of ten participants showed improvements in mean mobility and full-field light sensitivity in the injected eye by day 30 that persisted to year 3 (mobility p=0.0003, white light full-field sensitivity p<0.0001), but no significant change was seen in the previously injected eyes over the same time period (mobility p=0.7398, white light full-field sensitivity p=0.6709). Changes in visual acuity from baseline to year 3 were not significant in pooled analysis in the second eyes or the previously injected eyes (p>0.49 for all time-points compared with baseline).
  
  
  CONCLUSIONS
  To our knowledge, AAV2-hRPE65v2 is the first successful gene therapy administered to the contralateral eye. The results highlight the use of several outcome measures and help to delineate the variables that contribute to maximal benefit from gene augmentation therapy in this disease.
  
  
  BACKGROUND
  Center for Cellular and Molecular Therapeutics at The Children's Hospital of Philadelphia, Spark Therapeutics, US National Institutes of Health, Foundation Fighting Blindness, Institute for Translational Medicine and Therapeutics, Research to Prevent Blindness, Center for Advanced Retinal and Ocular Therapeutics, Mackall Foundation Trust, F M Kirby Foundation, and The Research Foundation-Flanders.
authors.affiliation: Center for Advanced Retinal and Ocular Therapeutics, Scheie Eye Institute, University of Pennsylvania, Philadelphia, PA, USA; F M Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, PA, USA; Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA. Electronic address: jebennet@mail.med.upenn.edu.
authors.forename: Jean
authors.initials: J
authors.lastname: Bennett
authors.affiliation: Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA; Spark Therapeutics, Philadelphia, PA, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Wellman
authors.affiliation: Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Marshall
authors.affiliation: Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: McCague
authors.affiliation: Center for Advanced Retinal and Ocular Therapeutics, Scheie Eye Institute, University of Pennsylvania, Philadelphia, PA, USA; F M Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, PA, USA; Department of Radiology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: Manzar
authors.initials: M
authors.lastname: Ashtari
authors.affiliation: Westat Biostatistics and Data Management Core, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: Julie
authors.initials: J
authors.lastname: DiStefano-Pappas
authors.affiliation: Westat Biostatistics and Data Management Core, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: Okan U
authors.initials: OU
authors.lastname: Elci
authors.affiliation: Center for Advanced Retinal and Ocular Therapeutics, Scheie Eye Institute, University of Pennsylvania, Philadelphia, PA, USA; F M Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, PA, USA; Spark Therapeutics, Philadelphia, PA, USA.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Chung
authors.affiliation: Center for Advanced Retinal and Ocular Therapeutics, Scheie Eye Institute, University of Pennsylvania, Philadelphia, PA, USA; Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: Junwei
authors.initials: J
authors.lastname: Sun
authors.affiliation: Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA; Spark Therapeutics, Philadelphia, PA, USA.
authors.forename: J Fraser
authors.initials: JF
authors.lastname: Wright
authors.affiliation: Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: Dominique R
authors.initials: DR
authors.lastname: Cross
authors.affiliation: Center for Advanced Retinal and Ocular Therapeutics, Scheie Eye Institute, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Puya
authors.initials: P
authors.lastname: Aravand
authors.affiliation: Department of Radiology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: Laura L
authors.initials: LL
authors.lastname: Cyckowski
authors.affiliation: Center for Advanced Retinal and Ocular Therapeutics, Scheie Eye Institute, University of Pennsylvania, Philadelphia, PA, USA; F M Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Jeannette L
authors.initials: JL
authors.lastname: Bennicelli
authors.affiliation: Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA; Immunology and Liver Gene Therapy, Généthon, Èvry, France.
authors.forename: Federico
authors.initials: F
authors.lastname: Mingozzi
authors.affiliation: Telethon Institute of Genetics and Medicine, Naples, Italy; Medical Genetics, Department of Pediatrics, University of Naples Federico II, Naples, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Auricchio
authors.affiliation: F M Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, PA, USA; Department of Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, PA, USA; Department of Ophthalmology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA; Ocular Genomics Institute, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Pierce
authors.affiliation: Department of Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Ruggiero
authors.affiliation: Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA; Department of Ophthalmology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA; Department of Ophthalmology and Center for Medical Genetics, Ghent University Hospital and Ghent University, Ghent, Belgium.
authors.forename: Bart P
authors.initials: BP
authors.lastname: Leroy
authors.affiliation: Eye Clinic, Multidisciplinary Department of Medical, Surgical and Dental Sciences, Second University of Naples, Naples, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Simonelli
authors.affiliation: Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA; Spark Therapeutics, Philadelphia, PA, USA; Howard Hughes Medical Institute, Philadelphia, PA, USA.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: High
authors.affiliation: Center for Advanced Retinal and Ocular Therapeutics, Scheie Eye Institute, University of Pennsylvania, Philadelphia, PA, USA; F M Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, PA, USA; Department of Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, PA, USA; Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA; Department of Ophthalmology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: Albert M
authors.initials: AM
authors.lastname: Maguire
mesh_terms: D060433:Administration, Ophthalmic; D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D001766:Blindness / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D002648:Child; D000229:Dependovirus; D019317:Evidence-Based Medicine; D005260:Female; D005500:Follow-Up Studies; D015316:Genetic Therapy / Q000009:adverse effects / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D056965:Injections, Intraocular; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009778:Occipital Lobe / Q000503:physiopathology*; D061214:Patient Safety; D017949:Retinal Cone Photoreceptor Cells / Q000473:pathology; D017948:Retinal Rod Photoreceptor Cells / Q000473:pathology; D019233:Retreatment; D014785:Vision, Ocular; D019745:cis-trans-Isomerases / Q000235:genetics*; D000099178:Retinoid Isomerohydrolase
chemical_list: D019745:cis-trans-Isomerases; D000099178:Retinoid Isomerohydrolase