# Paradoxical role of anti-VEGF therapy in subretinal fibrosis of wet AMD

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2024 · $670,496

## Abstract

Project Summary
Neovascular age-related macular degeneration (nAMD) with choroidal neovascularization (CNV) is a leading
cause of vision loss in elderly Americans and is currently treated by anti-angiogenic drugs against vascular
endothelial growth factor (VEGF) with limited efficacy. While anti-VEGF drugs are widely used as the first-line
therapy for nAMD, more than half of treated patients develop subretinal fibrosis (SRF) or scar that disrupts retinal
function and hinders visual acuity improvement with unknown causes. Anti-VEGF therapy has a paradoxical role
in fibrosis of other diseases with poorly defined mechanisms. Likewise, the causal link between anti-VEGF
therapy and SRF remains elusive but is of profound importance to mitigate the new epidemic and save the vision
for nAMD patients. The objective of this project is to investigate mechanisms of Janus-faced anti-VEGF therapy
in SRF of CNV and develop novel dual anti-angiogenesis and anti-fibrosis therapy. The central hypothesis is
that inhibition of angiogenesis by anti-VEGF drugs during early stages of CNV alleviates SRF, whereas anti-
VEGF therapy at late stages of the disease exacerbates SRF. In Aim 1, we will investigate anti-VEGF therapy
at early and late stages of CNV in different animal models to test the central hypothesis. In Aim 2, we will
investigate whether two novel VEGF-independent anti-angiogenic therapies possess dual anti-CNV and anti-
fibrosis activity at any stage of the disease. In Aim 3, we will characterize combination therapy of anti-VEGF drug
with novel VEGF-independent anti-angiogenic inhibitors to synergistically alleviate CNV and SRF via different
receptor signaling pathways. The successful implementation of this project will confirm the causal link between
anti-VEGF therapy and SRF and provide a clinical strategy to mitigate the emerging epidemic by limiting anti-
VEGF therapy to early stages of the disease. This may help reduce SRF in nAMD patients and improve visual
acuity. Furthermore, this study will also develop first-in-class dual anti-angiogenesis and anti-fibrosis therapies
to circumvent the emerging epidemic of anti-VEGF-induced SRF.

## Key facts

- **NIH application ID:** 10939269
- **Project number:** 1R01EY036417-01
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Wei Li
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $670,496
- **Award type:** 1
- **Project period:** 2024-09-01 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10939269

## Citation

> US National Institutes of Health, RePORTER application 10939269, Paradoxical role of anti-VEGF therapy in subretinal fibrosis of wet AMD (1R01EY036417-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10939269. Licensed CC0.

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