Short-term assessment of subfoveal injection of AAV2-hCHM gene augmentation in Choroideremia using adaptive optics ophthalmoscopy

Abstract

Purpose : Subretinal injection for gene augmentation in inherited retinal degenerations forcefully detaches the neural retina from the retinal pigment epithelium (RPE), potentially damaging photoreceptors and/or RPE cells. Here, we use adaptive optics scanning light ophthalmoscopy (AOSLO) to assess the short-term integrity of the cone mosaic following subretinal injections of AAV2-hCHM gene augmentation in subjects with choroideremia (CHM).

Methods : Nine CHM patients, ages 26-57, received uniocular subfoveal injections of low dose (up to 5x10¹⁰ vector genome (vg) per eye, n=5) or high dose (up to 1x10¹¹ vg per eye, n=4) AAV2-hCHM. The macular regions of both eyes were imaged pre- and one-month post-injection using a custom-built, multimodal AOSLO. Images were montaged at each timepoint individually, then manually aligned with cellular accuracy longitudinally. Post-injection cone inner segment mosaics were compared to pre-injection mosaics at multiple regions of interest (ROIs). Co-localized spectral-domain optical coherence tomography (OCT) and dark-adapted cone sensitivity was also acquired at each time point.

Results : Post-injection AOSLO images showed preservation of the cone mosaic in all 9 AAV2-hCHM injected eyes. Mosaics appeared intact and contiguous one-month post-injection, with the exception of foveal disruption in one patient. Cone-by-cone longitudinal alignment was accurate at multiple ROIs in every case. OCT images post-injection showed foveal cone outer segment (COS) shortening (significant, n=4; non-significant, n=4; unchanged, n=1). Cone-mediated sensitivities were unchanged in 8/9 injected and 9/9 uninjected eyes. One patient showed acute loss of foveal OCT COS-related signals along with cone sensitivity loss that co-localized with disruption of the mosaic on AOSLO.

Conclusions : Integrity of the cone mosaic is maintained following subretinal delivery of AAV2-hCHM, providing strong evidence in support of the safety of the injections. Minor foveal thinning observed following surgery corresponds with short-term COS shortening rather than cone cell loss. Foveal cone loss in one patient raises the possibility of individual vulnerability to the subfoveal injection. Further observation is needed to evaluate long-term safety and efficacy.

This is a 2020 ARVO Annual Meeting abstract.