First Gene Supplementation Therapy for CNGA3-linked Achromatopsia

Abstract

Purpose : To proof the safety and efficacy of the first gene therapy targeting cone photoreceptors in man.

Methods : Nine patients with CNGA3-linked achromatopsia received a single subfoveal injection of rAAV.hCNGA3 in an open label, monocentric, exploratory, dose-escalation trial (NCT02610582). Three patients were treated per dose group (1x10¹⁰, 5x10¹⁰, and 1x10¹¹ vector genomes). Safety of application as primary endpoint was assessed by clinical examination and best corrected visual acuity (BCVA), vital signs, blood chemistry (CRP, ESR, blood counts), and immunopathology assays over a period of 12 months. Biodistribution/shedding was monitored in blood, urine, saliva and lacrimal fluid.

Results : The primary endpoint was met with an excellent safety profile of AAV8.hCNGA3 delivered in the subretinal space. Surprisingly, BCVA increased slightly despite foveal detachment (-0.05±0.02 logMAR [mean±se; p = 0.038]). No serious adverse event occurred. Ocular adverse events (AEs) were either unrelated or associated with the surgical procedure, but not the study drug. There were no unexpected AEs outside side effect profile of the study procedure and study drug. Analysis of vital signs, blood chemistry, immunopathology and shedding corroborate the excellent safety profile.

Conclusions : The first clinical gene therapy for achromatopsia in man was well tolerated and did not lead to unexpected (serious) adverse events. Even though the study was not designed and powered to demonstrate efficacy, exploration of endpoints support the notion that CNGA3 linked achromatopsia can be treated by gene supplementation therapy.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.

 

Intraoperative OCT was used to guide and confirm injection in the subretinal space. Here, the initial phase just prior to the foveal detachment is shown.