Efficacy of anti-VEGF single-chain variable fragment AAV-based gene therapy in a laser-induced choroidal neovascularisation mouse model

Summary

This study, published in the Molecular Therapy Advances, looks at a gene therapy for wet age-related macular degeneration in mice. The team used a virus to deliver a small protein that blocks VEGF, which helps cause new blood vessels to grow in the eye. In the mice, the treatment reduced leaking from these vessels and did not seem to harm eye function.

The paper suggests that this kind of treatment might one day help people by giving a longer-lasting way to stop harmful vessel growth in the retina. It is still early-stage work, so more testing would be needed before it could be used in patients.

Keywords: age-related macular degeneration, anti-VEGF, gene therapy, mouse model, choroidal neovascularisation, retina, leakage.

Abstract

Age-related macular degeneration (AMD) is a leading cause of vision loss in the elderly. Neovascular AMD (nAMD) is characterized by abnormal growth of new blood vessels from the choroid (choroidal neovascularization, CNV), with retinal pigment epithelium dysfunction leading to fluid leakage, bleeding, and central vision loss. nAMD is primarily driven by vascular endothelial growth factor (VEGF). Anti-VEGF therapies are widely used, with brolucizumab, a humanized monoclonal single-chain variable fragment (scFv) that inhibits VEGF, showing promise due to its high molar concentration and superior ability to dry the retina. However, concerns over retinal vasculitis have limited its clinical use. In this proof-of-principle study, we evaluated an AAV-delivered anti-VEGF scFv transgene derived from the brolucizumab sequence, packaged into two recombinant adeno-associated virus serotypes (rAAV6 and rAAV8), and delivered via subretinal injections in a laser-induced CNV mouse model. Leakage in 79 mice across seven groups was assessed by fundus fluorescein angiography. Compared with controls, AAV-treatment showed reduced leakage, particularly at week 9 (3.1% for rAAV6 and ∼10% for rAAV8 high doses), compared with controls (71.9%). Vector genomes were detectable by qPCR at 12 weeks, and electroretinography showed no obvious functional deficit. These findings support further evaluation of sustained AAV-mediated anti-VEGF delivery for nAMD.