Pharmacological blocking of microfibrillar-associated protein 4 reduces retinal neoangiogenesis and vascular leakage

Area of Science:

• Ophthalmology
• Molecular Biology
• Biochemistry

Background:

• Neovascular age-related macular degeneration and diabetic macular edema cause significant vision loss.
• Retinal neovascularization and vascular leakage are key pathological processes in these diseases.
• Microfibrillar-associated protein 4 (MFAP4) is an extracellular matrix glycoprotein and an integrin αVβ3/5/6 ligand.

Purpose of the Study:

• To investigate the role of MFAP4 in retinal neovascularization and vascular leakage.
• To evaluate the therapeutic potential of the anti-MFAP4 antibody, hAS0326, for treating retinal vascular diseases.

Main Methods:

• Single-cell transcriptomics identified MFAP4 expression in cells near vascular endothelial cells.
• In vitro studies assessed the effect of hAS0326 on endothelial cell motility.
• In vivo studies utilized laser-induced choroidal neovascularization mouse models, streptozotocin-induced retinopathy, and a non-human primate retinopathy model to evaluate hAS0326 efficacy.

Main Results:

• hAS0326 blocked endothelial cell motility in vitro by preventing MFAP4-integrin interaction.
• Intravitreal hAS0326 significantly inhibited retinal vascular lesion area, neovessel volume, and vascular leakage in preclinical models.
• A single dose of hAS0326 demonstrated sustained efficacy for at least 12 weeks in a non-human primate model.
• hAS0326 treatment enriched Gene Ontology terms related to reduced integrin binding.

Conclusions:

• MFAP4 is implicated in retinal neovascularization and vascular leakage.
• The anti-MFAP4 antibody hAS0326 is a potential therapeutic agent for neovascular retinal diseases.
• hAS0326's mechanism involves blocking integrin binding, reducing endothelial cell activity and vascular leakage.