Safety of AdGVPEDF.11D Administered by Subtenon Injection Following Laser Disruption of the Bruch's Membrane in Cynomolgus Monkey Eyes

Abstract

Abstract: : Purpose: Antiangiogenic gene therapy has the potential to significantly advance therapy for age-related macular degeneration (AMD). PEDF (pigment epithelium-derived factor) is a potent endogenous inhibitor of ocular angiogenesis. In vivo studies have shown that adenoviral vectored PEDF (Ad_GVPEDF.11D) administered by subtenon injection, inhibits murine choroidal neovascularization. The safety of Ad_GVPEDF.11D given by subtenon injection was assessed in cynomolgus monkeys with laser-induced disruption of the Bruch's membrane in both eyes, a model that mimics the ocular condition of AMD. Methods: After laser treatment, the right eye was given a subtenon injection (150 µL) of vehicle and the left eye was given a single subtenon injection (150 µL) of vehicle or single doses of 1 x10⁸ pu, 1 x10⁹ pu, and 1 x10¹⁰ pu of Ad_GVPEDF.11D. An additional group of animals were given a single subtenon dose of 1 x10⁹ pu once every three weeks for a total of three doses in their left eye. Clinical evaluations, body weight, food consumption, clinical pathology, biomicroscopic and indirect ophthalmoscopic examinations, electroretinography (ERG), and presence of gross and microscopic pathologies were evaluated. Results: There were no drug-related systemic or ocular toxicities associated with a single subtenon injection of Ad_GVPEDF.11D at doses of up to 1 x 10¹⁰ pu. There were no drug-related ophthalmologic or ERG changes observed in eyes treated with Ad_GVPEDF.11D. Repeat dosing (x3) of 1 x 10⁹ pu did not result in any evidence of toxicity. Conclusions: Single doses of up to 1 x 10¹⁰ pu or multiple doses of 1 x 10⁹ pu of Ad_GVPEDF.11D given by subtenon injection were considered safe in a cynomolgus monkey eye with laser disruption of the Bruch's membrane.

Keywords: age-related macular degeneration • adenovirus • Bruch's membrane