Modulation of clinical neovascular AMD activity by systemic proteome – an analysis from the BIOMAC study

Abstract

Purpose : To identify candidate systemic proteomic factors which may modulate the choroidal neovascularization (CNV) activity and subsequently determine the need for intravitreal anti-VEGF injections (IAI) in patients with neovascular AMD.

Methods : Cohort study on 46 patients with neovascular AMD, treated with anti-VEGF injections. The cohort was stratified by treatment need. One group (N=25) received regular IAI at intervals of 6 weeks or less, while still having signs of CNV activity (high frequency group – HF). The second stratum (N=21) included subjects with a treatment interval of 10 weeks or longer and having no signs of CNV activity (low frequency group – LF). Full ophthalmological profiling has been done and EDTA blood samples were collected. Proteomic factors were analyzed using Hyper Reaction Monitoring (HRM) mass spectrometry. Welch’s two sample t-test was performed on log2-transformed data for statistical analysis. Proteins which were differentially expressed between HF and LF at a ratio of >1.5 and p<0.05 were considered as candidate proteins for further analysis.

Results : Both strata were well balanced with regards to age (HF 78.4±8.14; LF 79.7±7.00 years), gender (HF: 40% LF: 61.9% female) and BCVA (HF 61.4±15.7; LF 65.0±12.4). Central retinal thickness differed HF 352.2±98.0 vs. LF 274.8±45.7μm. 1’182 proteins represented by 20’826 peptide ion variants were quantified across all samples. Nine of these met the criteria. Six were up- and three downregulated in HF vs. LF. Up-regulated proteins: complement c1q subcomponent subunit b (C1QB) (95% CI HF 18.69-19.52; LF 18.09-18.66; ratio HF/LF=1,84; p=0.0068), cytosol aminopeptidase (LAP3) (95% CI HF 14.41-15.21; LF 14.16-14.66; ratio HF/LF=1.54; p=0.0318), and insulin-like growth factor-binding protein 3 (IGFBP3) (95% CI HF 13.44-14.90; LF 12.64-13.39; ratio HF/LF=4.1496; p=0.0106). Down-regulated proteins: Acidic leucine-rich nuclear phosphoprotein 32 family member A (ANP32A) (95% CI HF 8.19-12.63; LF 11.33-14.09; ratio HF/LF=0.67; p=0.0482).

Conclusions : Nine protein candidates were identified, which were differentially expressed between HF and LF. Factors with angiogenic potential such as C1QB, LAP3 and IGFBP3 were elevated in the high frequency treatment group, while factors with anti-angiogenic potential were increased in the low-frequency group. The data suggest a potential for systemic modulation of CNV activity.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.