Gene Therapy for Leber Congenital Amaurosis Caused by RPE65 Mutations Safety and Efficacy in 15 Children and Adults Followed Up to 3 Years

被引：483

作者：

Jacobson, Samuel G. ^{[1
]}

Cideciyan, Artur V. ^{[1
]}

Ratnakaram, Ramakrishna ^{[3
]}

Heon, Elise ^{[6
]}

Schwartz, Sharon B. ^{[1
]}

Roman, Alejandro J. ^{[1
]}

Peden, Marc C. ^{[3
]}

Aleman, Tomas S. ^{[1
]}

Boye, Sanford L. ^{[3
]}

Sumaroka, Alexander ^{[1
]}

Conlon, Thomas J. ^{[3
]}

Calcedo, Roberto ^{[2
]}

Pang, Ji-Jing ^{[3
]}

Erger, Kirsten E. ^{[4
]}

Olivares, Melani B. ^{[1
]}

Mullins, Cristina L. ^{[1
]}

Swider, Malgorzata ^{[1
]}

Kaushal, Shalesh ^{[3
]}

Feuer, William J. ^{[5
]}

Iannaccone, Alessandro ^{[7
]}

Fishman, Gerald A.

Stone, Edwin M. ^{[8
]}

Byrne, Barry J. ^{[4
]}

Hauswirth, William W. ^{[3
,4
]}

机构：

[1] Univ Penn, Scheie Eye Inst, Perelman Sch Med, Philadelphia, PA 19104 USA

[2] Univ Penn, Sch Med, Gene Therapy Program, Dept Pathol,Lab Med, Philadelphia, PA 19104 USA

[3] Univ Florida, Dept Ophthalmol, Gainesville, FL USA

[4] Univ Florida, Powell Gene Therapy Ctr, Gainesville, FL USA

[5] Univ Miami, Miller Sch Med, Bascom Palmer Eye Inst, Coral Gables, FL 33124 USA

[6] Univ Toronto, Dept Ophthalmol & Vis Sci, Hosp Sick Children, Toronto, ON M5S 1A1, Canada

[7] Univ Tennessee, Ctr Hlth Sci, Hamilton Eye Inst, Dept Ophthalmol, Memphis, TN 38163 USA

[8] Univ Iowa, Dept Ophthalmol, Carver Coll Med, Iowa City, IA 52242 USA

来源：

ARCHIVES OF OPHTHALMOLOGY | 2012年 / 130卷 / 01期

基金：

美国国家卫生研究院;

关键词：

OCULAR SUBRETINAL INJECTION; PHASE-I TRIAL; RETINITIS-PIGMENTOSA; MOBILITY PERFORMANCE; RETINAL DEGENERATION; CONE PHOTORECEPTORS; CHILDHOOD BLINDNESS; RESTORES VISION; CANINE MODEL; MOUSE MODEL;

D O I：

10.1001/archophthalmol.2011.298

中图分类号：

R77 [眼科学];

学科分类号：

100212 ;

摘要：

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.

引用

页码：9 / 24

页数：16

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