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Updated: May 5, 2026
Author Spotlight: Overcoming Anti-VEGF Resistance Through Advanced Vascular Morphology Assessment in Choroidal Neovascularization
Published on: August 11, 2023
Suboptimal Responses to Anti-VEGF in Retinal Neurovascular Diseases: Linking Aging and Alternative Angioinflammatory
Somayeh Piroozmand1, Hamid Latifi-Navid1,2,3, Zahra-Soheila Soheili1
1Department of Molecular Medicine, National Institute of Genetic Engineering and Biotechnology (NIGEB), Tehran, Iran.
Purpose:
Vision-threatening ocular diseases are impacted by aging-associated molecular changes, including mitochondrial dysfunction, cellular senescence, and chronic inflammation. Anti-VEGF therapies targeting VEGF-A/VEGFR2 signaling remain the frontline standard of care, but many patients exhibit suboptimal or nondurable responses, often due to compensatory and/or compromised antiangiogenic and anti-inflammatory pathways. We aimed to elucidate shared mechanisms underlying treatment failure and disease progression.
Methods:
We applied an integrative systems biology framework that combined multiomics datasets, network-based machine learning, and disease-specific pathway mapping. A comprehensive literature review of conditions, including diabetic retinopathy, age-related macular degeneration, retinitis pigmentosa, glaucoma, and aging, identified 14 core genes consistently associated with angiogenesis, inflammation, and immune signaling. Multialgorithm centrality and enrichment analyses reconstructed disease-specific interaction networks, revealing consensus mechanistic axes. Integration of cell-type-specific single-cell RNA sequencing data from AMD-RPE clusters identified cluster-specific gene hubs and vertical signaling axes, leading to VEGF blockade failure.
Results:
EGFR, HSP90AA1, SIRT1, and STAT3 emerged as central resistance hubs linking angiogenesis and inflammatory processes. Pathway enrichment analyses revealed 21 conserved core signaling cascades, grouped into six functional categories, with AGE-RAGE, PI3K-Akt, HIF-1, MAPK, and chemokine pathways playing central roles. A MiRGD-based peptide nanocomplex delivering htsFLT01 achieved efficient RPE transfection and controlled gene activation under basal conditions.
Conclusions:
This systems-level framework clarifies mechanisms of VEGF blockade resistance and provides a rational basis for next-generation, combinatorial therapeutic strategies requiring validation in disease-relevant models.
Insights
Aging-related eye diseases resist anti-VEGF therapy due to complex molecular pathways. This study identifies key genes and signaling cascades driving resistance, paving the way for new combination treatments.
Area of Science:
- Ophthalmology
- Systems Biology
- Molecular Biology
Background:
- Aging-associated molecular changes contribute to vision-threatening ocular diseases.
- Current anti-VEGF therapies show limited efficacy in some patients due to resistance.
- Understanding shared mechanisms of treatment failure is crucial for developing advanced therapies.
Purpose of the Study:
- To elucidate shared mechanisms underlying treatment failure and disease progression in age-related ocular diseases.
- To identify key molecular players and signaling pathways involved in resistance to anti-VEGF therapy.
- To provide a basis for developing next-generation therapeutic strategies.
Main Methods:
- An integrative systems biology framework combining multiomics, network-based machine learning, and pathway mapping was employed.
- A literature review identified 14 core genes associated with angiogenesis, inflammation, and immune signaling across various ocular conditions.
- Single-cell RNA sequencing data was integrated to identify cell-type-specific gene hubs and signaling axes.
Main Results:
- EGFR, HSP90AA1, SIRT1, and STAT3 were identified as central resistance hubs linking angiogenesis and inflammation.
- Twenty-one conserved core signaling cascades were revealed, with AGE-RAGE, PI3K-Akt, HIF-1, MAPK, and chemokine pathways playing key roles.
- A novel peptide nanocomplex demonstrated efficient retinal pigment epithelium transfection and gene activation.
Conclusions:
- The systems-level framework clarifies mechanisms of VEGF blockade resistance.
- Identified pathways and resistance hubs offer targets for novel therapeutic strategies.
- Findings support the development of combinatorial therapies for improved treatment of resistant ocular diseases.
