Safety and Efficacy of Gene Transfer for Leber's Congenital Amaurosis

TLDR

Leber's congenital amaurosis is an inherited childhood blinding disease, with LCA2 caused by mutations in the RPE65 gene. The study aimed to assess the safety of subretinal delivery of an AAV vector carrying RPE65 cDNA. The authors delivered a recombinant AAV2 vector expressing hRPE65v2 subretinally to patients. Three patients tolerated the therapy with acceptable adverse events and modest visual acuity gains, though one developed an asymptomatic macular hole; despite limited follow‑up and no restoration of normal vision, the results support further gene‑therapy trials.

Abstract

Leber's congenital amaurosis (LCA) is a group of inherited blinding diseases with onset during childhood. One form of the disease, LCA2, is caused by mutations in the retinal pigment epithelium-specific 65-kDa protein gene (RPE65). We investigated the safety of subretinal delivery of a recombinant adeno-associated virus (AAV) carrying RPE65 complementary DNA (cDNA) (ClinicalTrials.gov number, NCT00516477 [ClinicalTrials.gov]). Three patients with LCA2 had an acceptable local and systemic adverse-event profile after delivery of AAV2.hRPE65v2. Each patient had a modest improvement in measures of retinal function on subjective tests of visual acuity. In one patient, an asymptomatic macular hole developed, and although the occurrence was considered to be an adverse event, the patient had some return of retinal function. Although the follow-up was very short and normal vision was not achieved, this study provides the basis for further gene therapy studies in patients with LCA.