Effects of Subretinal AAV8 Gene Therapy on Microperimetry in CNGA3 Achromatopsia Patients

Abstract

Purpose : Mutations in the gene encoding the cyclic nucleotide-gated channel subunit alpha 3 (CNGA3) are a major cause for achromatopsia (ACHM), a genetic disease characterized by photophobia, reduced visual acuity and nystagmus due to an impairment of cone photoreceptor function. We measured the effects of recombinant adeno-associated virus serotype 8 (AAV8) encoding human CNGA3 (rAAV8.hCNGA3) on microperimetry in patients with ACHM.

Methods : In a dose escalation Phase I/II clinical trial, 9 patients with CNGA3-linked ACHM were administered AAV8.CNGA3 (0.1-1.0x10¹¹ vector genomes, vg) via subretinal injection. Changes in visual function from baseline in terms of micro-perimetry were assessed over a period of 12 months post treatment and analyzed using the Visual Field Modeling and Analysis (VFMA) hill of vision approach of the central 10° macular area.

Results : All patients had an excellent safety profile for rAAV8.hCNGA3 after surgery. Although ACHM patients experience no cone-mediated visual cortex stimulation during childhood in ACHM, 5 out of 9 treated patients’ eyes demonstrated some degree of improvement in microperimetry at 12 months post-treatment. The hill of vision volume of the full 10° macular area improved on average by 0.0613 dB-sr (s.d. = 0.098; p = 0.12). The highest improvement of 0.153 dB-sr (s.d. = 0.106) was shown in the intermediate dose (0.5x10¹¹ vg) cohort (n = 3) at month 12.

Conclusions : Subretinal delivery of rAAV8.hCNGA3 has demonstrated an excellent safety profile and some degree of improvement of sensitivity in microperimetry. Best results were obtained in the intermediate dose cohort. However, as the trial was not designed to formally assess efficacy in a dose dependent manner, its limitations include a small sample size. As technical reasons precluded analysis of the treated area specifically, current analysis combines results from treated and untreated macular regions. Trial registration: NCT02610582.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.