Oligonucleotide-based therapy for UMOD-associated autosomal dominant tubulointerstitial kidney disease (ADTKD-UMOD) by allele-specific siRNA knockdown

• Applicant: Dr. Korbinian Riedhammer
• Subject Area: Nephrology ; Human Genetics
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 519309154

Autosomal dominant tubulointerstitial kidney disease (ADTKD) is part of the spectrum of monogenic kidney diseases. It is an umbrella term for several disorders featuring a slowly progressive decline in kidney function resulting in end-stage kidney failure in the third to seventh decades of life. One form of ADTKD is ADTKD-UMOD resulting from heterozygous disease-causing variants in the gene UMOD. UMOD encodes uromodulin (or Tamm-Horsfall protein), a glycoprotein and the most abundant protein excreted in the urine. Uromodulin is solely expressed in the kidney in epithelial cells of the thick ascending limb of the loop of Henle. Uromodulin is important for urine concentration, protection from urinary tract infections and uric acid excretion in the urine. Loss of kidney function in ADTKD-UMOD results from dominant toxic and negative effects of misfolded mutant uromodulin. The aim of this project is to establish an oligonucleotide-based therapy for ADTKD-UMOD by allele-specific siRNA knockdown. Intended in vitro experiments of the 2-year project are divided into the following milestones: 1) Establish consistent overexpression of wild-type and mutant UMOD in renal epithelial tubular cells (6 months). 2) Establish specific knockdown of mutated UMOD by allele-specific siRNAs (6 months). 3) Investigating cellular effects of UMOD mutants vs. wild-type and exploring rescue potential of allele-specific knockdown in UMOD mutants (9 months). 4) Conclusive data analysis and publication of results (3 months). The hypothesis of the project is that silencing the mutated UMOD-allele via an siRNA-approach will remedy the disease.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professor Dr. Friedhelm Hildebrandt