Gene therapy for neovascular age-related macular degeneration: rationale, clinical trials and future directions

Abstract

Age-related macular degeneration (AMD) is one of the leading causes of irreversible blindness in the developed world. Antivascular endothelial growth factor therapy has transformed the management and outcome of neovascular AMD (nAMD), although the need for repeated intravitreal injections-even lifelong-and the related complications, high drug costs, frequent clinic visits and repeated imaging have resulted in an enormous burden both to healthcare systems and patients. The application of gene therapy approaches for sustained delivery of a range of antiangiogenic proteins has the promise of helping to address these aforementioned challenges. A number of early phase clinical trials of gene therapy in nAMD have provided encouraging results, with many more ongoing or anticipated. There remain significant areas of controversy, including regarding the optimal treatment targets, routes of administration and potential safety concerns. In this review we aim to provide an update of the current status of gene therapy for nAMD and briefly discuss future prospects.

Keywords: angiogenesis; clinical trial; degeneration; genetics; retina.

Figure 1

Promising targets for antiangiogenesis in nAMD. The main goal of gene therapy in this condition is to continuously express antiangiogenic factors and lead to a more sustainable treatment. Some have already been extensively studied in the past for intravitreal treatment of nAMD, like bevacizumab and ranibizumab, while others like Angpt2-binding and Tie2-activating antibodies (ABTAA) are currently being investigated and might be useful for combination therapy. The platelet-derived growth factor (PDGF) pathway also represents another potential target as it mediates the recruitment and survival capabilities of pericytes and might be implicated in the development of subretinal fibrosis. Ang1, angiopoietin-1; Ang2, angiopoietin-2; nAMD, neovascular age-related macular degeneration; PIGF, placental growth factor; VEGF, vascular endothelial growth factor.

Figure 2

Delivery routes for gene therapy. Schematic figure of the eye demonstrating the possible routes of delivery to introduce viral vectors into the eye.