Perivascular Astrocytic Gliosis Induced by Retinal Gene Therapy

This retrospective follow-on study reviewed 25 consecutive patients with genetically confirmed choroideremia who were treated with subretinal AAV2-CAG-REP1 in dose-escalation gene therapy clinical trials conducted at Oxford University Hospitals NHS Foundation Trust and the University Eye Hospital Tübingen. Six patients in Oxford received 10¹⁰ vector genomes in 100 µL, while a further 19 patients across both centers received 10¹¹ vector genomes in 100 µL. Although the primary safety outcomes of both investigator-led academic studies have previously been reported, retinal imaging changes were observed during follow-up, prompting a more detailed characterization of these findings. Twelve of 25 treated eyes developed imaging features consistent with perivascular astrocytic gliosis during follow-up, representing 48% of the cohort. All affected eyes had received the higher dose, accounting for 12 of 19 eyes treated with 10¹¹ vector genomes. No patients receiving the lower dose (1.0 × 10¹⁰ vector genomes) developed this phenotype. The lesions followed the major vascular arcades toward the optic disc, and optical coherence tomography demonstrated inner retinal thickening with a fine, granular hyperreflective texture, without intraretinal cysts. Longitudinal imaging showed no progressive expansion of the involved regions. Clinically, the findings were silent: no patient reported uveitic symptoms, ocular examinations were largely quiet, and no peripheral cellular immune responses were detected in patients with available assays. Perivascular astrocytic gliosis therefore appears to be a common, clinically silent, nonprogressive, and noninflammatory retinal response after subretinal AAV2-CAG-REP1 gene therapy for choroideremia at a dose of 10¹¹ vector genomes, which is generally accepted as the therapeutic human dose for targeting photoreceptors. We hypothesize that local REP1 overexpression in perivascular astrocytes suppresses FOXO3-mediated apoptosis and engages EGFR/STAT3 signaling, driving benign perivascular astrocytic accumulation analogous to retinal astrocytic hamartomas seen in phacomatoses. Gene therapy involving ubiquitous promoters may have unexpected effects, and while benign, may not be predicted.