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Safety and Efficacy in 15 Children and Adults Followed Up to 3 Years

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

Arch Ophthalmol. Published online September 12, 2011. doi:10.1001/archophthalmol.2011.298

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.

Design  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.

Main Outcome Measures  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.

Application to Clinical Practice  Gene therapy for inherited retinal disease has the potential to become a future part of clinical practice.

Trial Registration  clinicaltrials.gov Identifier: NCT00481546

Author Affiliations: Scheie Eye Institute, Perelman School of Medicine at the University of Pennsylvania (Drs Jacobson, Cideciyan, Aleman, Sumaroka, and Swider, Ms Schwartz, Olivares, and Mullins, and Mr Roman), and Gene Therapy Program, Department of Pathology, Laboratory of Medicine, University of Pennsylvania School of Medicine (Dr Calcedo), Philadelphia; Department of Ophthalmology (Drs Ratnakarama, Peden, Conlon, Pang, Kaushal, and Hauswirth and Mr Boye), Powell Gene Therapy Center (Ms Erger and Drs Byrne and Hauswirth), University of Florida, Gainesville, and Bascom Palmer Eye Institute, Miller School of Medicine, University of Miami (Mr Feuer), Florida; Department of Ophthalmology and Vision Sciences, Hospital for Sick Children, University of Toronto, Ontario, Canada (Dr Heon); Hamilton Eye Institute, Department of Ophthalmology, University of Tennessee Health Science Center, Memphis (Dr Iannaccone); The Pangere Center for Inherited Retinal Diseases, The Chicago Lighthouse, Illinois (Dr Fishman); and Department of Ophthalmology, University of Iowa Carver College of Medicine, Iowa City (Dr Stone).

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