Treatment of Patients with Leber Congenital Amaurosis Type 2 with an AAV Vector Expressing RPE65

Abstract

Purpose: To evaluate the safety and efficacy of rAAV2-CB-hRPE65 in patients with Leber congenital amaurosis (LCA) caused by mutations in the RPE65 gene.

Methods: Twelve patients (aged 6-39y) with RPE65 mutations were treated with a single, unilateral subretinal dose of 1.8 x 1011 or 5.4 x 1011 viral genomes in 450 μL. Serial postoperative examinations included measurements of acuity, static and kinetic perimetry, optical coherence tomography, fundus photography, luminance sensitivity and visual quality-of-life function.

Results: All subjects tolerated the surgery and study agent administration well without significant or unexpected complications. No instances of persistent subretinal fluid or ocular inflammatory disease were observed. Visual acuities were transiently depressed in the treated eye of all patients during the first 1 to 2 weeks after surgery, but returned to baseline or better in all of but two patients to date. Improvements in visual acuity after treatment were seen in the four youngest patients (age 6 to 11 years - with better baseline visual acuities of 40 to 62 ETDRS letters) with increases ranging from 6 to 12.5 ETDRS letters in the treated eye. For the three subjects with visual acuity of 20 to 31 ETDRS letters, one had a 2.5 letter increase and two had a 6.5 or 12 letter decrease in the treated eye. GATE total and central 30O hill of vision analysis trended towards improvement in treated eyes when compared to baseline values. The five subjects with the poorest baseline visual acuity (0 or 1 ETDRS letters) had little or no change in their visual acuity over time, but for the four subjects followed for at least 6 months three had a small but statistically significant increase in kinetic perimetry visual field area with the V4e target in the treated eye compared to baseline. An improvement in visual functioning and quality of life was noted by most patients.

Conclusions: Treatment of LCA2 patients with rAAV2-CB-hRPE65 is safe and appears effective. The greatest improvements in visual acuity were observed in younger patients who presented with better baseline visual acuity.

Keywords: 538 gene transfer/gene therapy • 696 retinal degenerations: hereditary