Human retinal gene therapy for Leber congenital amaurosis shows advancing retinal degeneration despite enduring visual improvement

TLDR

The first RPE65 gene therapy for human blindness has focused on safety and vision improvement, but the fate of photoreceptors in progressive retinal degeneration remains understudied. Gene therapy improves vision for at least three years, yet photoreceptor degeneration continues unabated in humans and in canine models, underscoring the need for combinatorial approaches to sustain vision and slow retinal degeneration.

Abstract

Significance The first retinal gene therapy in human blindness from RPE65 mutations has focused on safety and efficacy, as defined by improved vision. The disease component not studied, however, has been the fate of photoreceptors in this progressive retinal degeneration. We show that gene therapy improves vision for at least 3 y, but photoreceptor degeneration progresses unabated in humans. In the canine model, the same result occurs when treatment is at the disease stage equivalent to humans. The study shows the need for combinatorial therapy to improve vision in the short term but also slow retinal degeneration in the long term.