Ophthalmology science · 2026
Serial Aqueous Humor Proteomics in Diabetic Macular Edema: Correlation of Novel Targets with Retinal Fluid Volume.
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Cehofski Lasse Jørgensen, Klaassen Ingeborg, Cao Jessica, Zhou Avery, Ørskov Marie, Bøgsted Martin, Vorum Henrik, Wykoff Charles C, Honoré Bent
Аннотация
OBJECTIVE: Diabetic macular edema (DME) with incomplete response to anti-VEGF therapy is a significant challenge. Here, we integrated advanced proteomics and an artificial intelligence (AI)-driven platform to elucidate molecular mechanisms associated with resistance to anti-VEGF treatment.
DESIGN: Translational longitudinal study.
SUBJECTS: Patients with DME (n = 30) under treatment with anti-VEGF therapy who had reached their plateau phase.
METHODS: Aqueous humor samples were obtained at the time of 6 consecutive anti-VEGF injections. OCT scan fluid volumes were assessed by an AI-based platform (Discovery OCT Fluid and Biomarker Detector, RetinAI). Proteomics analysis of the samples collected during the first 3 time points was performed by label-free liquid chromatography-tandem mass spectrometry. Confirmatory enzyme-linked immunosorbent assay (ELISA) was performed for afamin and VEGF for time points 4 to 6.
MAIN OUTCOME MEASURES: Differentially expressed aqueous humor proteins and their correlation with AI-quantified OCT fluid volumes.
RESULTS: Proteomics identified 202 proteins in ≥70% of the samples. Ten proteins were consistently differentially regulated in patients with substantial edema versus no edema. Upregulated proteins included afamin (highest fold change 1.8 ± 0.4), alpha-1B-glycoprotein, and angiotensinogen, whereas cystatin-C, clusterin, apolipoprotein E, epidermal growth factor-containing fibulin-like extracellular matrix protein, Ig lambda chain V-I, latent transforming growth factor beta-binding protein 2, and reelin were downregulated. Afamin levels correlated with fluid volumes (total, inner retinal, inner macular ring). The upregulation of afamin was confirmed by ELISA.
CONCLUSIONS: In this hypothesis-generating study using serial aqueous humor proteomics, multiple novel targets were identified that correlated with retinal fluid volumes. Specifically, afamin, a wingless/integrated (Wnt)-signaling carrier protein and established biomarker of type 2 diabetes, was consistently upregulated in eyes with anti-VEGF-refractory DME. Whether this reflects active Wnt pathway involvement in eyes demonstrating anti-VEGF treatment resistance or vascular dysfunction warrants additional study. Concurrent downregulation of cystatin-C and clusterin suggests impaired endogenous anti-inflammatory pathways in eyes with refractory DME.
FINANCIAL DISCLOSURES: The authors have no proprietary or commercial interest in any materials discussed in this article.
DESIGN: Translational longitudinal study.
SUBJECTS: Patients with DME (n = 30) under treatment with anti-VEGF therapy who had reached their plateau phase.
METHODS: Aqueous humor samples were obtained at the time of 6 consecutive anti-VEGF injections. OCT scan fluid volumes were assessed by an AI-based platform (Discovery OCT Fluid and Biomarker Detector, RetinAI). Proteomics analysis of the samples collected during the first 3 time points was performed by label-free liquid chromatography-tandem mass spectrometry. Confirmatory enzyme-linked immunosorbent assay (ELISA) was performed for afamin and VEGF for time points 4 to 6.
MAIN OUTCOME MEASURES: Differentially expressed aqueous humor proteins and their correlation with AI-quantified OCT fluid volumes.
RESULTS: Proteomics identified 202 proteins in ≥70% of the samples. Ten proteins were consistently differentially regulated in patients with substantial edema versus no edema. Upregulated proteins included afamin (highest fold change 1.8 ± 0.4), alpha-1B-glycoprotein, and angiotensinogen, whereas cystatin-C, clusterin, apolipoprotein E, epidermal growth factor-containing fibulin-like extracellular matrix protein, Ig lambda chain V-I, latent transforming growth factor beta-binding protein 2, and reelin were downregulated. Afamin levels correlated with fluid volumes (total, inner retinal, inner macular ring). The upregulation of afamin was confirmed by ELISA.
CONCLUSIONS: In this hypothesis-generating study using serial aqueous humor proteomics, multiple novel targets were identified that correlated with retinal fluid volumes. Specifically, afamin, a wingless/integrated (Wnt)-signaling carrier protein and established biomarker of type 2 diabetes, was consistently upregulated in eyes with anti-VEGF-refractory DME. Whether this reflects active Wnt pathway involvement in eyes demonstrating anti-VEGF treatment resistance or vascular dysfunction warrants additional study. Concurrent downregulation of cystatin-C and clusterin suggests impaired endogenous anti-inflammatory pathways in eyes with refractory DME.
FINANCIAL DISCLOSURES: The authors have no proprietary or commercial interest in any materials discussed in this article.