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Human RPE65 gene therapy for Leber congenital amaurosis: persistence of early visual improvements and safety at 1 year.

ABSTRACT: Human gene therapy with rAAV2-vector was performed for the RPE65 form of childhood blindness called Leber congenital amaurosis. In three contemporaneous studies by independent groups, the procedure was deemed safe and there was evidence of visual gain in the short term. At 12 months after treatment, our young adult subjects remained healthy and without vector-related serious adverse events. Results of immunological assays to identify reaction to AAV serotype 2 capsid were unchanged from baseline measurements. Results of clinical eye examinations of study and control eyes, including visual acuities and central retinal structure by in vivo microscopy, were not different from those at the 3-month time point. The remarkable improvements in visual sensitivity we reported by 3 months were unchanged at 12 months. The retinal extent and magnitude of rod and cone components of the visual sensitivity between 3 and 12 months were also the same. The safety and efficacy of human retinal gene transfer with rAAV2-RPE65 vector extends to at least 1 year posttreatment.

SUBMITTER: Cideciyan AV

PROVIDER: S-EPMC2829287 | biostudies-literature | 2009 Sep

REPOSITORIES: biostudies-literature

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Human RPE65 gene therapy for Leber congenital amaurosis: persistence of early visual improvements and safety at 1 year.

Cideciyan Artur V AV Hauswirth William W WW Aleman Tomas S TS Kaushal Shalesh S Schwartz Sharon B SB Boye Sanford L SL Windsor Elizabeth A M EA Conlon Thomas J TJ Sumaroka Alexander A Pang Ji-Jing JJ Roman Alejandro J AJ Byrne Barry J BJ Jacobson Samuel G SG

Human gene therapy 20090901 9

Human gene therapy with rAAV2-vector was performed for the RPE65 form of childhood blindness called Leber congenital amaurosis. In three contemporaneous studies by independent groups, the procedure was deemed safe and there was evidence of visual gain in the short term. At 12 months after treatment, our young adult subjects remained healthy and without vector-related serious adverse events. Results of immunological assays to identify reaction to AAV serotype 2 capsid were unchanged from baseline ...[more]

PMID: 19583479

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Project description:PurposeTo report an anatomic change following subretinal injection of voretigene neparvovec-rzyl (VN) for RPE65-mediated Leber congenital amaurosis.DesignMulticenter, retrospective chart review.ParticipantsPatients who underwent subretinal VN injection at each of 4 participating institutions.MethodsPatients were identified as having perifoveal chorioretinal atrophy if (1) the areas of atrophy were not directly related to the touch-down site of the subretinal cannula; and (2) the area of atrophy progressively enlarged over time. Demographic data, visual acuity, refractive error, fundus photographs, OCT, visual fields, and full-field stimulus threshold (FST) were analyzed.Main outcome measuresOutcome measures included change in visual acuity, FST, visual fields, and location of atrophy relative to subretinal bleb position.ResultsA total of 18 eyes of 10 patients who underwent subretinal injection of VN were identified as having developed perifoveal chorioretinal atrophy. Eight of 10 patients (80%) developed bilateral atrophy. The mean age was 11.6 years (range, 5-20 years), and 6 patients (60%) were male. Baseline mean logarithm of the minimum angle of resolution visual acuity and FST were 0.82 (standard deviation [SD], 0.51) and -1.3 log cd.s/m2 (SD, 0.44), respectively. The mean spherical equivalent was -5.7 diopters (D) (range, -11.50 to +1.75 D). Atrophy was identifiable at an average of 4.7 months (SD, 4.3) after surgery and progressively enlarged in all cases up to a mean follow-up period of 11.3 months (range, 4-18 months). Atrophy developed within and outside the area of the subretinal bleb in 10 eyes (55.5%), exclusively within the area of the bleb in 7 eyes (38.9%), and exclusively outside the bleb in 1 eye (5.5%). There was no significant change in visual acuity (P = 0.45). There was a consistent improvement in FST with a mean improvement of -3.21 log cd.s/m2 (P < 0.0001). Additionally, all 13 eyes with reliable Goldmann visual fields demonstrated improvement, but 3 eyes (23.1%) demonstrated paracentral scotomas related to the atrophy.ConclusionsA subset of patients undergoing subretinal VN injection developed progressive perifoveal chorioretinal atrophy after surgery. Further study is necessary to determine what ocular, surgical delivery, and vector-related factors predispose to this complication.

Dataset Information

Human RPE65 gene therapy for Leber congenital amaurosis: persistence of early visual improvements and safety at 1 year.

Publications

Human RPE65 gene therapy for Leber congenital amaurosis: persistence of early visual improvements and safety at 1 year.

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