Targeting COL4A1-Related Small Vessel Disease: Repurposed Pharmacotherapies for Genetic Vasculopathies

Abstract

COL4A1-related disorders cause early-onset stroke, intracerebral haemorrhage, visual impairment and kidney disease, often affecting children and young adults, yet no disease-modifying therapies exist. These disorders arise from pathogenic COL4A1 variants that disrupt type IV collagen and impair small-vessel integrity, leading to cerebral small-vessel disease and endothelial dysfunction. We performed a mechanism-guided screen in human brain endothelial cells using a CRISPR-engineered COL4A1 p.G755R line and patient-specific COL4A1 p.G773R iPSC-derived endothelial cells. Simvastatin, L-carnosine, and XPD-101 restored impaired endothelial proliferation, migration, and other markers of endothelial function, including transendothelial electrical resistance (TEER). In a Col4a1Svc/+ mouse model, simvastatin increased pre-weaning survival, improved functional behaviour and reduced cerebral microhaemorrhage burden. These findings identify mechanism-informed candidates that rescue COL4A1-mutant endothelial dysfunction in vitro, with simvastatin demonstrating in vivo efficacy, supporting prioritisation for further preclinical development.