Gene Therapy for Inherited Retinal Disease: Long-Term Durability of Effect

Abstract

The recent approval of voretigene neparvovec (Luxturna®) for patients with biallelic RPE65 mutation-associated inherited retinal dystrophy with viable retinal cells represents an important step in the development of ocular gene therapies. Herein, we review studies investigating the episomal persistence of different recombinant adeno-associated virus (rAAV) vector genomes and the pre-clinical and clinical evidence of long-term effects of different RPE65 gene replacement therapies. A targeted review of articles published between 1974 and January 2021 in Medline®, Embase®, and other databases, was conducted, followed by a descriptive longitudinal analysis of the clinical trial outcomes of voretigene neparvovec. Following an initial screening, 14 publications examining the episomal persistence of different rAAV genomes and 71 publications evaluating gene therapies in animal models were included. Viral genomes were found to persist for at least 22 months (longest study follow-up) as transcriptionally active episomes. Treatment effects lasting almost a decade were reported in canine disease models, with more pronounced effects the earlier the intervention. The clinical trial outcomes of voretigene neparvovec are consistent with pre-clinical findings and reveal sustained results for up to 7.5 years for the full-field light sensitivity threshold test and 5 years for the multi-luminance mobility test in the Phase I and Phase III trials, respectively. In conclusion, the therapeutic effect of voretigene neparvovec lasts for at least a decade in animal models and 7.5 years in human subjects. Since retinal cells can retain functionality over their lifetime after transduction, these effects may be expected to last even longer in patients with a sufficient number of outer retinal cells at the time of intervention.

Retinitis Pigmentosa: Current Clinical Management and Emerging Therapies

“…It is possible that photoreceptors continue to degenerate due to insufficient delivery of functional genes, or that photoreceptors had already reached a pre-apoptotic state at the moment of therapeutic intervention [ 294 ]. A recent review demonstrated that the treatment effects of RPE65 gene therapy lasts up to 7.5 years after administration, which suggests that multiple gene-therapy doses are needed to provide clinical stability during a patient’s lifetime [ 295 ]. A single dose of FDA-approved Luxturna costs approximately USD 425,000 per eye per treatment.…”

Delivery Systems in Ocular Retinopathies: The Promising Future of Intravitreal Hydrogels as Sustained-Release Scaffolds

“…One major advantage of subretinal gene therapy is that it is generally considered a “one-and-done” approach, which is to say that one application is expected to be sufficient to have continued efficacy over very long periods of time. However, it is probably pertinent to note here that with gene therapies being so early in their development, it is not entirely clear how long efficacy will last, but as of 2022 we have seen 10 years of continued Luxturna expression in animal models and 7.5 years in humans [ 51 ]. Remarkably, the long-term episomal (not integrated into the host cell genome) persistence of transcriptionally active recombinant AAV genomes has been reported, as recently reviewed by Leroy BP et al [ 51 ].…”

Potential therapeutic strategies for photoreceptor degeneration: the path to restore vision

“…Defects in the RPE65 gene lead to canine and mouse models of LCA which have recently been considered as models for gene therapy [394][395][396]. As to date, Voretigene neparvovec-rzyl (Luxturna, Spark Therapeutics, Philadelphia) was approved by U.S FDA for ocular gene therapy of RPE65 in 2017, which transduces some RPE cells with a cDNA encoding normal human RPE65 protein, making it possible to repair the visual cycle [397,398]. Currently, human clinical trials using a similar vector are continuing.…”