Abstract
Purpose :
Therapies targeting vascular endothelial growth factor A (VEGFA) are first-line treatments for diabetic macular edema (DME). Among them, intravitreal aflibercept (IVT-AFL) also inhibits all ligands involved in VEGF receptor 1 (VEGFR1) signaling, namely VEGFA, placenta growth factor (PlGF) and VEGFB. Pre-clinical, and clinical studies suggest a superior effect of IVT-AFL on DME compared to VEGFA-only inhibitors. An in silico model was created to explore the mechanisms of action of IVT-AFL on the pathophysiology of DME beyond anti-angiogenic effects.
Methods :
Therapeutic Performance Mapping System (Anaxomics Biotech, Spain), which combines systems biology and artificial intelligence techniques, was used to create a protein network-based DME model. We evaluated the signal flow through the model network to study the effects of IVT-AFL treatment via VEGFR1/VEGFR2 signaling pathways. Predicted protein activity and full signal (range -1 to 1) were used to analyze pathophysiological processes and individual proteins and specifically evaluate the role of VEGFR1 pathway inhibition on DME treatment. A Mann–Whitney U test was used for statistical analysis.
Results :
According to our models, co-inhibition of VEGFR1 and VEGFR2 pathways by IVT-AFL treatment augments the impact on pathophysiological processes involved in DME including angiogenesis, blood-retinal barrier (BRB) permeability and remodeling, inflammation and oxidative stress compared to inhibition of the VEGFR2 pathway alone, while maintaining VEGFR1 activation (Figure 1). Inflammation was predicted to be the process that would benefit most from sustained VEGFR1 signaling inhibition, with effects on leukostasis and cytokine-related protein effectors (Figure 2).
Conclusions :
The models obtained simulated the pathophysiology of DME and the mechanisms of action of IVT-AFL treatment via inhibition of VEGFR1 and VEGFR2 signaling. The action of IVT-AFL through both signaling pathways allows for the modulation of several other processes in addition to angiogenesis. Given the role of VEGFR1 signaling on the modulation of pathways related to inflammation, IVT-AFL may offer therapeutic advantages through sustained VEGFR1 pathway inhibition.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.