PRMT5 is a therapeutic target in choroidal neovascularization

Area of Science:

• Ophthalmology
• Molecular Biology
• Epigenetics

Background:

• Neovascular age-related macular degeneration (nvAMD) is a leading cause of blindness with unmet therapeutic needs.
• Current anti-vascular endothelial growth factor (VEGF) therapies are not effective for all patients.
• Protein arginine methyltransferase 5 (PRMT5) is an epigenetic enzyme previously linked to cancer progression.

Purpose of the Study:

• To investigate PRMT5 as a novel therapeutic target for nvAMD.
• To assess the antiangiogenic activity of the PRMT5 inhibitor, PR5-LL-CM01, in ocular cells.

Main Methods:

• Immunostaining of human nvAMD and laser-induced choroidal neovascularization (L-CNV) mouse models to assess PRMT5 expression.
• Inhibition of PRMT5 using PR5-LL-CM01 or shRNA in human retinal endothelial cells (HRECs) and iPSC-derived choroidal endothelial cells (iCECs).
• Assessed effects on nuclear factor kappa B (NF-κB) activity, gene expression (TNF-α, VEGF-A), cell proliferation, tube formation, and cell cycle progression.

Main Results:

• PRMT5 is highly expressed in ocular tissues affected by neovascularization in human nvAMD and mouse L-CNV models.
• PRMT5 inhibition by PR5-LL-CM01 or shRNA reduced NF-κB activity and expression of its target genes in ocular endothelial cells.
• PR5-LL-CM01 demonstrated antiangiogenic effects, inhibiting proliferation and tube formation, and induced G1/S-phase cell cycle arrest.

Conclusions:

• PRMT5 plays a significant role in ocular neovascularization.
• Inhibition of PRMT5 effectively impedes angiogenesis in ocular endothelial cells.
• PRMT5 inhibition represents a promising therapeutic strategy for treating nvAMD and other ocular neovascular diseases.