Ocular Safety and Efficacy of AAV-mediated Tyrosinase Gene Augmentation in a Nonhuman Primate Model.

PURPOSE: Oculocutaneous albinism type 1 (OCA1) is an inherited disorder caused by tyrosinase ( TYR ) gene mutations. Affected individuals experience visual impairment and severe photosensitivity from ocular hypomelanosis, with no current treatments. We evaluated the safety and efficacy of a TYR -encoding adeno-associated virus (AAV) vector in healthy rhesus macaques as a potential OCA1 treatment.

METHODS

A novel AAV2-based capsid (ATX002) was packaged with the human VMD2 promoter and TYR (h TYR ) fused with mGreenLantern (mGL). Two adult rhesus macaques were injected with ATX002-hVMD2-h TYR - mGL subretinally (OD) and intravitreally (OS). Safety and efficacy were assessed via comprehensive ophthalmic examination, fundus photography, spectral-domain optical coherence tomography (SD-OCT), and full-field electroretinography at baseline and defined timepoints up to 12 weeks post-injection, followed by post-mortem immunohistochemistry (IHC).

RESULTS

Both subretinal doses induced localized hypermelanosis by 3 weeks post-injection, which persisted through the study endpoint and was accompanied by measurable thickening of the retinal pigment epithelium (RPE) on SD-OCT. Histological IHC confirmed successful RPE transduction via robust mGL fluorescence, corroborating in vivo findings by revealing localized RPE hyperplasia and transgene-expressing cells adjacent to regions of de novo hypermelanosis. Intravitreal delivery did not induce any changes to the RPE. Transient uveitis was observed but successfully managed with anti-inflammatory treatment.

CONCLUSIONS

Subretinal AAV- TYR delivery is a safe and effective approach with the potential to induce RPE pigmentation. These findings support the use of AAV- TYR gene therapy for OCA1, demonstrating efficacy and a manageable safety profile in a large-animal model, and provide a critical bridge toward human clinical translation.