Ultrasound-guided renal artery administration of angiopoietin-1 RNA therapy slows the progression of preclinical WT1 glomerular disease.

Abstract

Mutations in the transcription factor gene <i>Wilms Tumor 1</i> (<i>WT1</i>) are one of the leading causes of congenital glomerular disease, characterized by severe urinary protein loss and glomerular scarring. No disease-modifying therapies exist for WT1 glomerulopathies, and affected children rely on dialysis or kidney transplantation. We evaluated a previously uncharacterized treatment in a mouse model with an orthologous human mutation in <i>Wt1</i> (<i>Wt1</i>^{+<i>/R394W</i>}) that replicates the pathology of WT1 glomerulopathy. Lipid nanocomplexes were engineered to target integrin αvβ3 for efficient delivery of mRNA to primary podocytes and glomerular endothelial cells in vitro. A minimally invasive ultrasound-guided renal artery injection enabled precise and specific kidney localization in vivo, a finding not replicated by systemic administration. Nanocomplex-derived protein localized in glomeruli for up to 7 days in healthy and diseased mice. This platform was then used to perform an interventional preclinical trial in <i>Wt1^+/R394W</i> mice, delivering <i>angiopoietin-1</i> (<i>Angpt1</i>) mRNA, a vascular growth factor critical for glomerular health that is reduced in <i>Wt1^+/R394W</i> podocytes. <i>Angpt1</i> nanocomplex therapy reduced albuminuria, preserved glomerular endothelial integrity, prevented podocyte loss, and alleviated glomerulosclerosis in <i>Wt1^+/R394W</i> mice. These findings demonstrate the therapeutic potential of this targeted approach for WT1 glomerulopathy and provide a foundation for clinical translation to improve outcomes in children with glomerular disease.