Gene therapy appears safe in LCA patients

Two-year data from a phase I clinical trial shows that adeno-associated virus-mediated RPE65 gene replacement therapy is generally safe in adults and children with retinal degeneration, with young patients showing the greatest visual benefit.

Mutations of RPE65 result in a profound deficiency of the active chromophore, accounting for approximately 6% to 16% of Leber congenital amaurosis (LCA) cases and 2% of cases of severe early childhood onset retinal dystrophy (SECORD). Sponsored by Applied Genetic Technologies Corporation (AGTC), this study adds to previously published proof of concept data supporting gene therapy applications for inherited retinal diseases.

Scientists from Oregon Health & Science University’s Casey Eye Institute and Baylor College of Medicine’s Cullen Eye Institute used a viral vector to insert a normal copy of the RPE65 gene into retinal cells. Subjects included 8 adults and 4 children ages 6 to 39 with LCA or SECORD, who received 2 subretinal injections of the recombinant AAV vector into the poorer-seeing eye.

All patients tolerated subretinal injections, with no systemic toxicity or serious treatment-related adverse events. Common adverse events were those associated with the surgical procedure and included subconjunctival hemorrhage in 8 patients and ocular hyperemia in 5 patients.

Nine out of 12 patients (75%) experienced an improvement in at least 1 measure of visual function. Two years after treatment, the 4 pediatric patients showed a 6- to 14-letter increase in BCVA in the treated eye. Improvement was evident as early as 2 weeks after treatment, with patients showing progressive improvement up to 3 months before stabilizing. Clinical examination also revealed reduced nystagmus.

However, visual improvement was more varied among adult patients. Of concern, 2 patients showed a decrease in BCVA or visual field area, which was worse in their treated eye compared with the untreated eye. Among the 5 adults with baseline visual acuity of counting fingers or hand movements, none showed a change in BCVA.

The authors write that this trend in favor of visual improvement in the younger patients suggests that early treatment may prevent progression of photoreceptor degeneration. Longer follow up is required to document the stability of visual function and to assess for long term toxicity.