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 IannacconeGerald A. Fishman, Edwin M. Stone, Barry J. Byrne, William W. Hauswirth

Research output: Contribution to journalArticle

380 Citations (Scopus)

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. 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.

Original languageEnglish (US)
Pages (from-to)9-24
Number of pages16
JournalArchives of Ophthalmology
Volume130
Issue number1
DOIs
StatePublished - Jan 2012

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Leber Congenital Amaurosis
Genetic Therapy
Safety
Mutation
Dependovirus
Injections
Retinal Diseases
Vertebrate Photoreceptor Cells
Optical Coherence Tomography
Diabetic Retinopathy
Visual Fields
Visual Acuity
Retina
Outcome Assessment (Health Care)

ASJC Scopus subject areas

  • Ophthalmology

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

In: Archives of Ophthalmology, Vol. 130, No. 1, 01.2012, p. 9-24.

Research output: Contribution to journalArticle

Jacobson, SG, Cideciyan, AV, Ratnakaram, R, Heon, E, Schwartz, SB, Roman, AJ, Peden, MC, Aleman, TS, Boye, SL, Sumaroka, A, Conlon, TJ, Calcedo, R, Pang, JJ, Erger, KE, Olivares, MB, Mullins, CL, Swider, M, Kaushal, S, Feuer, WJ, Iannaccone, A, Fishman, GA, Stone, EM, Byrne, BJ & Hauswirth, WW 2012, 'Gene therapy for leber congenital amaurosis caused by RPE65 mutations: Safety and efficacy in 15 children and adults followed up to 3 years', Archives of Ophthalmology, vol. 130, no. 1, pp. 9-24. https://doi.org/10.1001/archophthalmol.2011.298
Jacobson, Samuel G. ; Cideciyan, Artur V. ; Ratnakaram, Ramakrishna ; Heon, Elise ; Schwartz, Sharon B. ; Roman, Alejandro J. ; Peden, Marc C. ; Aleman, Tomas S. ; Boye, Sanford L. ; Sumaroka, Alexander ; Conlon, Thomas J. ; Calcedo, Roberto ; Pang, Ji Jing ; Erger, Kirsten E. ; Olivares, Melani B. ; Mullins, Cristina L. ; Swider, Malgorzata ; Kaushal, Shalesh ; Feuer, William J ; Iannaccone, Alessandro ; Fishman, Gerald A. ; Stone, Edwin M. ; Byrne, Barry J. ; Hauswirth, William W. / Gene therapy for leber congenital amaurosis caused by RPE65 mutations : Safety and efficacy in 15 children and adults followed up to 3 years. In: Archives of Ophthalmology. 2012 ; Vol. 130, No. 1. pp. 9-24.
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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. 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.",
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T2 - Safety and efficacy in 15 children and adults followed up to 3 years

AU - Jacobson, Samuel G.

AU - Cideciyan, Artur V.

AU - Ratnakaram, Ramakrishna

AU - Heon, Elise

AU - Schwartz, Sharon B.

AU - Roman, Alejandro J.

AU - Peden, Marc C.

AU - Aleman, Tomas S.

AU - Boye, Sanford L.

AU - Sumaroka, Alexander

AU - Conlon, Thomas J.

AU - Calcedo, Roberto

AU - Pang, Ji Jing

AU - Erger, Kirsten E.

AU - Olivares, Melani B.

AU - Mullins, Cristina L.

AU - Swider, Malgorzata

AU - Kaushal, Shalesh

AU - Feuer, William J

AU - Iannaccone, Alessandro

AU - Fishman, Gerald A.

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N2 - 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.

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