Results at 2 Years after Gene Therapy for RPE65-Deficient Leber Congenital Amaurosis and Severe Early-Childhood–Onset Retinal Dystrophy

Abstract

Treatment with rAAV2-CB-hRPE65 was not associated with serious adverse events, and improvement in 1 or more measures of visual function was observed in 9 of 12 patients. The greatest improvements in visual acuity were observed in younger patients with better baseline visual acuity. Evaluation of more patients and a longer duration of follow-up will be needed to determine the rate of uncommon or rare side effects or safety concerns.

Leber congenital amaurosis/early-onset severe retinal dystrophy: clinical features, molecular genetics and therapeutic interventions

“…48 Weleber et al noted variable improvement in one or more parameters of visual function in 9 of 12 patients. 46 Jacobson et al described visual function improved in all 15 patients, to different degrees, with improvements being localised to treated areas, but a waning of improvement over time and continued retinal degeneration. 49 It has been proposed that continued retinal degeneration may be due to suboptimal RPE65 expression in the human retina, resulting in subsequent work to optimise the vector, promoter and transgene hoping to result in more durable benefit.…”

“…2-4 46 The 2 to 5-year follow-up data on all four trials has been very encouraging, showing the intervention to be safe with varying levels of efficacy noted; however, most studies at later intervals have shown a lack of durability of the improvements, with continuing retinal degeneration even in patients with improved retinal function. [46][47][48][49] Of the 12 patients enrolled in the UK trial, an initial improvement in retinal sensitivity, darkadapted perimetry and vision-guided mobility was noted in six, five and three patients, respectively. This improvement was not sustained, with only two patients having residual improvement greater than preinterventional levels, 3 years following subretinal injection.…”

Genetische Risiken und Therapieentwicklung bei Netzhautdegenerationen

“…In den letzten Jahren haben mehrere Studien gezeigt, dass die Genersatztherapie ein sehr vielversprechender Ansatz für autosomalrezessive Netzhautdystrophien ist [30]. So konnte beispielsweise bei Patienten mit der Leber'schen kongenitalen Amaurose (LCA), einer juvenilen und in der Regel ungünstig verlaufenden Netzhautdystrophie, die gentherapeutisch behandelt wurden, eine deutliche Verbesserung des Sehvermögens beobachtet werden [31]. [32].…”

Should the next step in glaucoma treatment be alternative drug therapies rather than gene therapy?

“…Which necessary genes are absent, non-functioning, or malfunctioning and thus lead to a disease phenotype? Some gene therapy approaches parlay this knowledge into a useful treatment by introducing a copy of the normal, functioning gene; witness the spectacular success of the RP65 treatment for Leber's congenital amaurosis [11,12,13]. However, successful gene therapy does not require knowledge of the genetic basis of the disease.…”