Safety and Long-Term Efficacy of AAV4 Gene Therapy in Patients with RPE65 Leber Congenital Amaurosis

Abstract

The aim of this study was the evaluation of the safety and efficacy of unilateral subretinal injection of the adeno-associated vector (AAV) serotypes 2 and 4 (AAV2/4) RPE65-RPE65 vector in patients with Leber congenital amaurosis (LCA) associated with RPE65 gene deficiency. We evaluated ocular and general tolerance and visual function up to 1 year after vector administration in the most severely affected eye in nine patients with retinal degeneration associated with mutations in the RPE65 gene. Patients received either low (1.22 × 10 to 2 × 10 vector genomes [vg]) or high (between 3.27 × 10 and 4.8 × 10 vg) vector doses. An ancillary study, in which six of the original nine patients participated, extended the follow-up period to 2-3.5 years. All patients showed good ophthalmological and general tolerance to the rAAV2/4-RPE65-RPE65 vector. We observed a trend toward improved visual acuity in patients with nystagmus, stabilization and improvement of the visual field, and cortical activation along visual pathways during fMRI analysis. OCT analysis after vector administration revealed no retinal thinning, except in cases of macular detachment. Our findings show that the rAAV2/4.RPE65.RPE65 vector was well tolerated in nine patients with RPE65-associated LCA. Efficacy parameters varied between patients during follow-up.

Long-Term Effects of In Vivo Genome Editing in the Mouse Retina Using Campylobacter jejuni Cas9 Expressed via Adeno-Associated Virus

“…In the treatment of retinal diseases such as Leber congenital amaurosis, AAV is a widely utilized platform for therapeutic gene delivery and has demonstrated long-term efficacy and safety. [23][24][25] Intravitreally administered AAVs do not significantly affect the gene expression in other organs. [26][27][28] Similarly, both AAV-CjCas9: Vegfa and Hif1a did not induce any change in body weights of treated mice, regardless of their local effects.…”

Liver Expression of a MiniATP7B Gene Results in Long‐Term Restoration of Copper Homeostasis in a Wilson Disease Model in Mice

“…Gene therapy represents a promising therapeutic option for many inherited diseases, as has been recently demonstrated for genetic immunodeficiencies, hemophilia, inherited blindness, or spinal muscular atrophy . Those studies have demonstrated that selection of the proper vector is key for success of the therapy.…”

Emerging Treatments for Leber's Hereditary Optic Neuropathy and Other Genetic Causes of Visual Loss

“…Until recently, management of most forms of LCA/EOSRD has been symptomatic, but the previous decade has brought major scientific advances leading to a major breakthrough in the treatment of the specific form associated with mutations in the RPE65 gene. A total of five phase 1/2 gene replacement therapy trials [23][24][25][26][27] have shown that subretinal injection of a recombinant AAV2 vector containing the RPE65 cDNA is safe and can substantially improve retinal function based on measurements of visual acuity, dark-adapted perimetry, dark-adapted full-field sensitivity testing, static 30-degree perimetry, kinetic perimetry visual field area, as well as cortical activation along visual pathways measured by fMRI techniques. The phase 3 trial of subretinal administration of an AAV2/2 vector reported clinically meaningful and statistically significant benefit at 1 year, reaching its primary end point for efficacy with improved performance on standardized multiluminance mobility testing (MLMT).…”