Phenotype-Driven therapeutic discovery for kidney proteinopathy

Autosomal dominant tubulointerstitial kidney disease caused by UMOD mutations (ADTKD-UMOD) is one of the most common monogenic causes of chronic kidney disease and represents a unique, kidney-restricted proteinopathy. UMOD encodes uromodulin, a protein exclusively produced by cells of the thick ascending limb (TAL) of the loop of Henle. Disease-causing missense mutations disrupt uromodulin folding, leading to its intracellular retention and aggregation within the endoplasmic reticulum (ER). The resulting ER stress and toxic signaling cascade drive tubular injury, inflammation, interstitial fibrosis, and progressive kidney failure. Despite its well-defined genetic cause and predictable clinical course, no disease-modifying therapy currently exists. The tissue-specific expression of uromodulin and the gain-of-toxic-function pathogenic mechanism provide a powerful and tractable system to test whether enhancing intracellular quality-control pathways can reverse disease progression. Our previous work identified autophagy and ER-phagy as critical mechanisms for mutant uromodulin clearance and demonstrated that both nutritional and pharmacologic interventions can reduce aggregate burden and improve kidney phenotype in cellular systems and Umod knock-in (KI) mouse models. Together, these findings establish intracellular aggregate clearance as a therapeutically actionable target in ADTKD-UMOD and provide a strong rationale for a phenotype-driven therapeutic discovery strategy.

In this project, we will use our disease-relevant kidney cell systems to identify repurposed compounds that enhance mutant uromodulin clearance or correct mutant protein trafficking and ultimately restore tubular homeostasis. Promising candidates will undergo mechanistic prioritization and in vivo evaluation in Umod KI mice, supported by pharmacodynamic biomarkers of treatment response. By directly targeting the toxic effects of mutant uromodulin, this work seeks to establish a rational therapeutic framework for ADTKD-UMOD and generate broader insights applicable to other dominant storage disorders.