Language

English

Publication Date

8-12-2026

Journal

Science Translational Medicine

DOI

10.1126/scitranslmed.adv1289

PMID

42585291

PMCID

PMC7619540

PubMedCentral® Posted Date

10-11-2026

PubMedCentral® Full Text Version

Author MSS

Abstract

Mutations in the transcription factor gene Wilms Tumor 1 (WT1) 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 Wt1 (Wt1+/R394W) 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 Wt1+/R394W mice, delivering angiopoietin-1 (Angpt1) mRNA, a vascular growth factor critical for glomerular health that is reduced in Wt1+/R394W podocytes. Angpt1 nanocomplex therapy reduced albuminuria, preserved glomerular endothelial integrity, prevented podocyte loss, and alleviated glomerulosclerosis in Wt1+/R394W 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.

Keywords

Animals, Angiopoietin-1, WT1 Proteins, Podocytes, Humans, Disease Progression, Kidney Glomerulus, RNA, Messenger, Mice, Ultrasonography, Disease Models, Animal, Integrin alphaVbeta3, Kidney Diseases

Published Open-Access

yes

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