Photoreceptor structure following gene therapy in CNGA3-mediated Achromatopsia: adaptive optics imaging results from a Phase 1/2 dose escalation clinical trial for AGTC-402 (rAAV2tYF-PR1.7-hCNGA3)

Abstract

Purpose : To assess photoreceptor mosaic integrity using adaptive optics scanning light ophthalmoscopy (AOSLO) following subretinal delivery of AGTC-402 (rAAV2tYF-PR1.7-hCNGA3) gene therapy in CNGA3-mediated achromatopsia.

Methods : A custom-built AOSLO equipped with nonconfocal split detection and confocal imaging modalities was used to image the inner segment and waveguiding photoreceptor mosaics in both treated and control eyes before and 3-months, 1-year, and 2-years post uniocular subretinal injection of AGTC-402 gene therapy. Images were registered and montaged within and across time points and foveal cone density was quantified.

Results : AOSLO montages were successfully obtained in 13 of 18 study participants aged 7-69 years, foveal cone densities could be quantified in 10 of the 13. Image acquisition in 5 participants was hindered by nystagmus. Pretreatment inner segment cone densities were not significantly different between treated and control eyes (treated: 25,900 ± 14,400 cones/mm², control: 28,400 ± 18,600 cones/mm², p=0.19). At 3-months post-treatment, qualitative changes in cone arrangement were found in 9 of 13 treated eyes and foveal cone density was decreased (18,600 ± 12,900 cones/mm², p<0.01). Cone density was stable in the control eye at 3 months (27,200 ± 18,200 cones/mm², p=0.088). From 3-months to 2-years, overall cone mosaic arrangement qualitatively appeared stable in treated eyes. Pre-treatment confocal images revealed dark ‘holes’ void of outer segment waveguiding co-located with cone inner segments observed on split detection. Post-treatment however, the treated eye of 2 of 18 participants (aged 8 and 9 years) exhibited waveguided reflectance in ~25% of foveal cones on confocal. Waveguiding cones were not observed at any time point in control eyes. These pediatric participants also had the two highest cone densities in the treated eyes at screening.

Conclusions : The foveal cone loss observed following subretinal injection of AGTC-402 may be a consequence of the surgical procedure and/or a short-term response to the study agent. The emergence of waveguiding cones in a subset of pediatric participants suggests younger individuals may be more amenable to treatment. Further investigation is needed to evaluate whether the appearance of waveguiding cones alters visual function.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.