Sphingosine-1-phosphate receptor 1/5 selective agonist alleviates ocular vascular pathologies

Area of Science:

• Ophthalmology
• Vascular Biology
• Pharmacology

Background:

• Abnormal ocular angiogenesis and edema are hallmarks of various eye diseases.
• Sphingosine-1-phosphate (S1P) signaling through S1P1 is crucial for maintaining vascular health.
• Dysregulation of S1P signaling contributes to pathological ocular vascular conditions.

Purpose of the Study:

• To investigate the therapeutic potential of ASP4058, an S1P1/5 agonist, in treating ocular vascular pathologies.
• To evaluate ASP4058's effects on human retinal microvascular endothelial cells (HRMECs) and in animal models of eye disease.

Main Methods:

• Pharmacological assessment of ASP4058 on VEGF-induced proliferation and hyperpermeability in HRMECs.
• Analysis of S1P1 expression in a murine laser-induced choroidal neovascularization (CNV) model.
• Evaluation of ASP4058's efficacy in CNV and retinal vein occlusion (RVO) models following oral administration.

Main Results:

• ASP4058 demonstrated high affinity, inhibiting VEGF-induced proliferation and hyperpermeability in HRMECs.
• In the CNV model, ASP4058 suppressed vascular hyperpermeability and lesion formation, comparable to aflibercept.
• ASP4058 dose-dependently reduced intraretinal edema and perfusion area expansion in the RVO model, also suppressing VEGF production.

Conclusions:

• ASP4058 effectively normalizes abnormal ocular vascular pathology by acting directly on endothelial cells.
• ASP4058 presents a potential therapeutic strategy for exudative age-related macular degeneration and retinal vein occlusion.
• The findings support ASP4058's utility in managing diseases characterized by aberrant ocular angiogenesis and edema.