Gene Augmentation Therapy Restores Retinal Function and Visual Behavior in a Sheep Model of CNGA3 Achromatopsia – Long Term Follow-up

Abstract

Purpose : Recently we reported that unilateral subretinal delivery of an adeno-associated virus serotype 5 (AAV5) vector carrying either mouse (mCNGA3) or human (hCNGA3) cDNA results in recovery of photopic vision in CNGA3-mutant dayblind sheep. Following recent reports that the efficacy of gene therapy in LCA patients starts declining after 6-12 months, our aim was to evaluate long-term treatment efficacy in our treated sheep cohort.

Methods : Animals that underwent mCNGA3 (n=4) or hCNGA3 (n=5) gene augmentation therapy 3.8±0.5 and 3.0±0.2 years ago, respectively, were studied. Photopic vision was evaluated by maze navigation. Cone function was evaluated by light adapted, full-field flash electroretinography. Flicker responses to eight increasing frequencies were recorded and the critical flicker fusion frequency (CFFF) determined.

Results : Mean±SD passage time of mCNGA3- and hCNGA3-treated animals was 4.7±0.6 and 4.0±0.5 seconds, respectively, without any collisions with obstacles. However, when the treated eye was covered, average passage time increased significantly (P<0.0005) to 24.2±9.4 and 23.3±7.3 seconds, respectively, and the number of collisions increased to 1.6±1.3 and 5.8±2.2 in mCNGA3- and hCNGA3-treated animals, respectively. The CFFF of mCNGA3 and hCNGA3-treated eyes was 70±8.2 and 65±5.8 Hz, respectively, compared to 25±5.8 and 32.5±25 Hz in the untreated control eyes (p<0.0005).

Conclusions : A single, subretinal injection of a AAV5 carrying the CNGA3 cDNA resulted in significant improvement in photopic vision and cone function, lasting over 3 years. Our results confirm long-term efficacy and safety of CNGA3 gene therapy in our dayblind sheep model, paving the way for clinical trials in achromatopsia patients.

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