An Anti-VEGF Gene Therapy for Neovascular Age-related Macular Degeneration - Efficacy and Safety Studies in Murine and Primate Models

Abstract

Purpose: : To demonstrate safety and efficacy of a soluble anti-VEGF molecule (sFLT01) delivered by intravitreal injection of an adeno associated viral (AAV2) vector in both murine and primate models of ocular neovascularization.

Methods: : Efficacy of AAV2-sFLT01 was investigated in the murine OIR and murine laser induced-CNV models as well as the primate model of laser induced-CNV. A 12 month safety study of AAV2-sFLT01 administered intravitreally in cynomolgus monkeys was performed. Animals were dosed with vehicle, 2E9 or 2E10 vector particles/eye. Assessments included ocular examinations, ERGs, FAs and IOP measurements.

Results: : In the OIR model experiments performed in newborn C57B/6 mice, intravitreal injection of AAV2-sFLT01 significantly reduced the occurrence of neovascularization (p < 0.001) as compared to the untreated or AAV-null treated contralateral eye. Inhibition of neovascularization was also demonstrated in the murine laser induced-CNV model. Efficacy was demonstrated at 5 months post vector injection in the primate model of laser induced-CNV. In the eyes of primates, AAV2-sFLT01 gives persistent expression levels for at least one year. Self-limiting mild to moderate vitreal haze and cells were observed only in the high dose (2E10 vector particles) group and AAV2 capsid protein has been identified as the source of inflammation. ERG, FA and IOP measurements revealed no test article-related adverse events. Histological evaluation of the eyes in this study found no structural changes in any part of the eye including the retina.

Conclusions: : We have demonstrated long term efficacy with minimal side effects following intravitreal delivery of AAV2-sFLT01 in rodent and primate models. Current treatments of neovascular AMD with VEGF antagonists require monthly injections. Our results suggest an alternate method of long-term treatment for diseases involving ocular neovascularization without the need for repeated injections.

Keywords: age-related macular degeneration • gene transfer/gene therapy • choroid: neovascularization