Gene therapy for leber congenital amaurosis caused by RPE65 mutations: safety and efficacy in 15 children and adults followed up to 3 years

Samuel G Jacobson; Artur V Cideciyan; Ramakrishna Ratnakaram; Elise Heon; Sharon B Schwartz; Alejandro J Roman; Marc C Peden; Tomas S Aleman; Sanford L Boye; Alexander Sumaroka; Thomas J Conlon; Roberto Calcedo; Ji-Jing Pang; Kirsten E Erger; Melani B Olivares; Cristina L Mullins; Malgorzata Swider; Shalesh Kaushal; William J Feuer; Alessandro Iannaccone; Gerald A Fishman; Edwin M Stone; Barry J Byrne; William W Hauswirth

doi:10.1001/archophthalmol.2011.298

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Gene therapy for leber congenital amaurosis caused by RPE65 mutations: safety and efficacy in 15 children and adults followed up to 3 years

Journal article

Open access

Peer reviewed

Gene therapy for leber congenital amaurosis caused by RPE65 mutations: safety and efficacy in 15 children and adults followed up to 3 years

Samuel G Jacobson, Artur V Cideciyan, Ramakrishna Ratnakaram, Elise Heon, Sharon B Schwartz, Alejandro J Roman, Marc C Peden, Tomas S Aleman, Sanford L Boye, Alexander Sumaroka, …

Archives of ophthalmology (1960), Vol.130(1), pp.9-24

01/2012

DOI: 10.1001/archophthalmol.2011.298

PMCID: PMC3600816

PMID: 21911650

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Abstract

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. 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. 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. 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. 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. Gene therapy for inherited retinal disease has the potential to become a future part of clinical practice. clinicaltrials.gov Identifier: NCT00481546.

Dependovirus - genetics

Visual Fields - physiology

Pupil - physiology

Follow-Up Studies

Humans

Male

Photoreceptor Cells, Vertebrate - physiology

Psychomotor Performance - physiology

Young Adult

Adult

Female

Eye Proteins - genetics

Child

Leber Congenital Amaurosis - therapy

Visual Acuity - physiology

cis-trans-Isomerases

Leber Congenital Amaurosis - physiopathology

Tomography, Optical Coherence

Treatment Outcome

Leber Congenital Amaurosis - genetics

Carrier Proteins - genetics

Adolescent

Mutation

Genetic Vectors

Photic Stimulation

Injections, Intraocular

Genetic Therapy - adverse effects

Genetic Therapy - methods

Details

Title: Subtitle: Gene therapy for leber congenital amaurosis caused by RPE65 mutations: safety and efficacy in 15 children and adults followed up to 3 years
Creators: Samuel G Jacobson - Scheie Eye Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, USA. jacobsos@mail.med.upenn.edu
Artur V Cideciyan
Ramakrishna Ratnakaram
Elise Heon
Sharon B Schwartz
Alejandro J Roman
Marc C Peden
Tomas S Aleman
Sanford L Boye
Alexander Sumaroka
Thomas J Conlon
Roberto Calcedo
Ji-Jing Pang
Kirsten E Erger
Melani B Olivares
Cristina L Mullins
Malgorzata Swider
Shalesh Kaushal
William J Feuer
Alessandro Iannaccone
Gerald A Fishman
Edwin M Stone
Barry J Byrne
William W Hauswirth
Resource Type: Journal article
Publication Details: Archives of ophthalmology (1960), Vol.130(1), pp.9-24
DOI: 10.1001/archophthalmol.2011.298
PMID: 21911650
PMCID: PMC3600816
NLM abbreviation: Arch Ophthalmol
ISSN: 0003-9950
eISSN: 1538-3601
Publisher: American Medical Association; United States
Grant note: U10 EY017280 / NEI NIH HHS P30 EY021721 / NEI NIH HHS U10EY017280 / NEI NIH HHS
Language: English
Date published: 01/2012
Academic Unit: Iowa Neuroscience Institute; Ophthalmology and Visual Sciences
Record Identifier: 9983980032902771

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