Clinical Trial of Gene Therapy for Early Onset Severe Retinal Dystrophy Caused by Defects in RPE65

Abstract

Purpose: : A number of previous studies have demonstrated that recombinant adeno-associated virus (rAAV) vector-mediated gene replacement therapy improves retinal function and visual behaviour in animal models of retinal degeneration caused by defects in the gene encoding RPE65. The purpose of this study is to determine whether gene therapy for retinal dystrophy caused by RPE65 mutations is safe and effective in humans.

Methods: : In a phase I/II dose-escalation trial, we have administered by subretinal injection a rAAV-2/2 vector expressing human RPE65 cDNA under the control of a human RPE65 promoter in 4 human subjects with early onset severe retinal dystrophy caused by mutations in RPE65. We have examined systemic vector dissemination and immune responses, assessed the effect of vector administration on visual function using a range of psychophysical techniques, and performed detailed electrophysiology and retinal imaging studies.

Results: : There have been no complications associated with the surgical delivery of vector in the subjects enrolled to date. We have detected no systemic dissemination of vector genome and no evidence of immune responses to rAAV vector capsid or RPE65 proteins. We have found no evidence of any significant adverse effect on retinal function.

Conclusions: : The outcomes in the first subjects to date suggest that subretinal administration of rAAV vector is safe in humans. We will report on further results of this ongoing trial as these become available.

Clinical Trial: : EudraCT 2006-001571-37

Keywords: retinal degenerations: hereditary • gene transfer/gene therapy • clinical (human) or epidemiologic studies: outcomes/complications