Evaluation of electroretinography in cynomolgus monkeys after subretinal injection of rAAV.hPDE6A

Abstract

Purpose : A GLP conform toxicological study was performed in non-human primates (NHP) after subretinal injection of rAAV.hPDE6A in order to explore safety issues for implementation of a phase I/II clinical gene therapy trial.

Methods : 22 purpose-bread NHPs (macaca fascicularis) were allocated to either control (n=3 per sex) receiving vehicle only, low dose (1x10¹¹ total vector genomes (vg)) or high dose (1x10¹² vg) groups (n=4 per sex). Each test item cohort (subretinal dosing on day 1 only) consisted of 4 animals per sex. GLP-compliant, scotopic and photopic fullfield electroretinographic recordings (ERGs) were obtained during the pre-dose phase, and at 4 and 12 weeks after dosing. Rod function were recorded in response to increasing light intensities in dark adapted state as well as cone responses after light adaptation, according to the recommendations of the ERG- Standard of the International Society for Clinical Electrophysiology of Vision (ISCEV).

Results : In one animal of the control group retinal atrophy in the treated eye resulted in about 60% reduced ERG amplitudes. ERG results of all treated animals showed no signs of severe deterioration. No significant changes could be seen in implicit times in any response, indicating a well-preserved function of the responding cell population in each animal.

Conclusions : Fullfield ERG as a summed potential is able to detect relevant and irreversible deterioration of retinal function. No signs of irreversible damage could be seen up to 12 weeks after subretinal injection of rAAV.hPDE6A. This supports the notion that PDE6A gene therapy with the vector used is safe in non-human primates.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.