Comparative transcriptome analysis of human and murine choroidal neovascularization identifies fibroblast growth factor inducible-14 as phylogenetically conserved mediator of neovascular age-related macular degeneration.

Julian Wolf,Hansjürgen Agostini,Dennis-Dominik Rosmus,Günther Schlunck,Peter Wieghofer,Anja Schlecht,Clemens Lange,Stefaniya Boneva

doi:10.1016/j.bbadis.2022.166340

Abstract

Visual outcome of patients with neovascular age-related macular degeneration has significantly improved during the last years following the introduction of anti-vascular endothelial growth factor (VEGF) therapy. However, about one third of patients show persistent exudation and decreasing visual acuity despite recurrent anti-VEGF treatment, which implies a role of other, still unknown proangiogenic mediators. The present study applied transcriptional profiling of human and mouse (C57BL/6J wildtype) choroidal neovascularization (CNV) membranes each with reference to healthy control tissue to identify yet unrecognized mediators of CNV formation. Key factors were further investigated by immunohistochemistry as well as by intravitreal inhibition experiments and multiplex protein assays in the laser-induced CNV mouse model. Transcriptional profiles of CNV membranes were characterized by enhanced activation of blood vessel development, cytoskeletal organization, and cytokine production, with angiogenesis and wound healing processes predominating in humans and activation of immune processes in mice. Besides several species-specific factors, 95 phylogenetically conserved CNV-associated genes were detected, among which fibroblast growth factor inducible-14 (FN14), a member of the tumor necrosis factor (TNF) receptor family, was identified as a key player of CNV formation. Blocking the pathway by intravitreal injection of a FN14 decoy receptor modulated the cytokine profile - most notably IL-6 - and led to a significant reduction of CNV size in vivo. This study characterizes the transcriptome of human and mouse CNV membranes in an unprejudiced manner and identifies FN14 as a phylogenetically conserved mediator of CNV formation and a promising new therapeutic target for neovascular AMD. This study was funded by the Helmut Ecker Foundation and the Volker Homann Foundation.

Highlights

Age-related macular degeneration (AMD) is the most common cause of permanent blindness in elderly people in developed countries
About 40 million people suffer from the neovascular form of AMD (Wong et al, 2014), which is characterized by the formation of pathological choroidal neovascularisation (CNV) leading to edema, hemorrhage, scarring and irreversible impairment of central vision (Mitchell et al, 2018)
Patients with treatment-naive classical CNV associated with typical AMD changes such as drusen and RPE alterations were included in the study

Summary

Introduction

Age-related macular degeneration (AMD) is the most common cause of permanent blindness in elderly people in developed countries. An important proangiogenic mediator in this process is the vascular endothelial growth factor (VEGF), which increases vascular permeability and promotes the development of CNV. Anti-VEGF therapy has significantly improved visual outcomes in nAMD (Bressler et al, 2011; Mitchell et al, 2018). About one third of patients with nAMD show persistent exudation and a slow decrease in visual acuity despite intensive anti-VEGF therapy Visual outcome of patients with neovascular age-related macular degeneration has significantly improved during the last years following the introduction of anti-vascular endothelial growth factor (VEGF) therapy. About one third of patients show persistent exudation and decreasing visual acuity despite recurrent anti-VEGF treatment, which implies a role of other, still unknown proangiogenic mediators

Methods

Results

Conclusion