VEGF 수용체 변형형을 발현하는 아데노부속바이러스의 노화 관련 황반 변성 치료제 가능성 (규명)

Abstract

Purposes: With anti-VEGF-based treatments for wet age-related macular degeneration (AMD) requiring frequent injections, it is often burdensome to both patients and healthcare providers. To explore its possibility as a desirable alternative, I investigated the therapeutic potential of a recombinant adeno-associated virus 2 expressing a soluble variant of VEGF receptor-1 (rAAV2-sVEGFRv-1) in a laser-induced choroidal neovascularization (CNV) model, as CNV is a defining feature of AMD progression. Methods: C57/B6 mice were intravitreally administered with rAAV2-sVEGFRv-1, rAAV2-GFP, or clinically-used bevacizumab after CNV lesions were induced via laser photocoagulation. Immunostaining was performed with phalloidin and CD31 to measure CNV extensiveness, F4/80 and CD11b for inflammatory cell infiltration, and pan-cytokeratin to visualize fibrotic progression. Results: rAAV2-sVEGFRv-1 (5.0x107 v.g.) possesses anti-angiogenic, anti-inflammatory, and anti-fibrotic properties. rAAV2-sVEGFRv-1 was demonstrated to significantly decrease retinal CNV lesion size (1336±186) when compared to rAAV2-GFP-treated (2949±437, p=0.0043), mock-treated (3075±265, p=0.0013), and bevacizumab-treated models (995±234). Infiltration by inflammatory cells significantly decreased with rAAV2-sVEGFRv-1 administration, while groups treated with rAAV2-GFP did not. Additionally, anti-apoptotic activity was observed via TUNEL assay in rAAV2-sVEGFRv-1 (16.0±3.6) and rAAV2-GFP (46.0±7.5, p=0.003). Overall, the rAAV2-sVEGFRv-1 viral vector was positively comparable to bevacizumab, indicating it as effective as approved therapeutics. Conclusions: The ability of a low dose of rAAV2-sVEGFRv-1 to exert a therapeutically relevant anti-VEGF effect in a CNV model is demonstrated, and strongly suggests gene therapy as an effective and convenient treatment for sustained VEGF suppression.