Successful delivery of rAAV8.CNGA3 in a patient with CNGA3 achromatopsia

Abstract

Purpose : The aim of this clinical interventional study (NCT02610582) was to test safety aspects of AAV8 based supplementation gene therapy in patients with CNGA3 achromatopsia.

Methods : After extensive safety testing in a dose escalation study in 34 non-human primates (NHP), we selected a dosing range of 1x10¹⁰, 5x10¹⁰, and 1x10¹¹ vector genomes (vg) for an exploratory, dose-escalation clinical phase I/II trial. A first patient with homozygous mutations in CNGA3 received a single subretinal injection of 1x10¹⁰ vg in 0.2ml balanced salt solution. Concomitant steroid treatment (Prednisolone 1mg/kg/d) was initiated 1 day prior surgery. The primary endpoint - safety of application - was assessed by clinical examination and best corrected visual acuity (BCVA).

Results : NHP safety data showed no persisting test item-related changes after application of ≤ 1x10¹² vg 90 days after dosing. In the clinical trial, the first patient received the low dose (1x10¹⁰ vg) safely and without surgical or post-surgical complications such as retinal detachment, haemorrhage or inflammation unresponsive to treatment. BCVA reached baseline levels as soon as 14 days post treatment. Structural changes at the level of the retinal pigment epithelium and inner/outer photoreceptor segments as tested by optical coherence tomography were attributed to the surgical procedure.

Conclusions : The NHP safety study showed that ≤ 1x10¹² vg could be applied without relevant sequelae. The first clinical gene therapy for achromatopsia in man was well tolerated and did not lead to clinically apparent inflammation under concomitant Prednisolone treatment. Even though the application involved macular detachment, visual acuity reached baseline levels within 14 days.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.