Low-dose rAAV-mediated inhibition of VEGF can treat neovascular pathologies without inducing retinal vasculitis

Abstract

Purpose : The wet form of age-related macular degeneration (AMD) is characterized by neovascular pathologies that can result in edemas, which can lead to rapid vision loss if untreated. Inhibition of vascular endothelial growth factor (VEGF) has been used to successfully treat neovascular pathologies of the eye. Nonetheless, some patients require frequent intraocular anti-VEGF injections, raising the risk of complications from the procedure and the burden to both, doctors and patients. rAAV-mediated expression of anti-VEGF proteins is an attractive alternative to reduce the risk to affected patients. However, controversy remains as to the safety of sustained VEGF inhibition in the eye. Here, we test the safety and efficacy of delivering the anti-VEGF drug Conbercept (KH902) with adeno-associated virus (AAV) vectors in two mouse models of vascular pathology.

Methods : To test the efficacy of rAAV-KH902, we used the oxygen-induced retinopathy of prematurity model, as well as the laser damage-induced choroidal neovascularization model. The same cassette expressing KH902 from a ubiquitous promoter was packaged into four different rAAV serotypes. To assess the efficacy of rAAV-KH902, we quantified the number of aneurysms in the oxygen-induced retinopathy model and the number of edemas, as well as the size of the neovascular lesions in the laser damage model.

Results : We found that intravitreal delivery of rAAVs expressing KH902 can successfully reduce the number of aneurysms, edemas, as well as the growth of the choroidal neovascular lesions. Serotypes with high transduction efficiencies were found to induce, in a dose dependent manner, a vascular sheathing pathology that is characterized by immune cell infiltrates, reminiscent of vasculitis. We found that this pathology is accompanied by increased expression in vascular cells adhesion molecule 1 (VCAM1), which promotes extravasation of immune cells from the vasculature. Importantly, low viral doses were still able to reduce edemas and lesion size without causing any vascular sheathing pathology.

Conclusions : The data suggest that rAAV-mediated expression of anti-VEGF drugs can be employed safely for the treatment of neovascular eye pathologies. However, vector design needs to be taken into consideration when determining the appropriate therapeutic dose.

This is a 2021 ARVO Annual Meeting abstract.