Antisense Oligonucleotide Knock Down of Uromodulin: A Potential Treatment Autosomal Dominant Tubulointerstitial Kidney Disease (ADTKD)

Background: Autosomal Dominant Tubulointerstitial Kidney Disease-Uromodulin (ADTKD-UMOD) is a genetic disease caused by destabilizing mutations in the uromodulin (UMOD) or Tamm-Horsfall protein. Misfolded UMOD protein aggregates and accumulates inside the loop of Henle and the distal convoluted tubule, leading to progressive and irreversible chronic kidney disease. We hypothesized that peptide-conjugated phosphorodiamidate morpholino oligomers (PPMOs) could knock down UMOD expression and potentially reduce the disease-causing UMOD aggregation inside the cells. Methods: A library of PPMOs was designed to bind to the complementary sequences of the mouse Umod gene and induce nonsense-mediated decay. These PPMOs were screened in mIMCD-3 cells, which express endogenous transcript to identify the most active compounds. The most efficacious PPMO compound was tested in both wildtype and UMOD C93F mice, a well characterized disease model of ATDKD, to determine the ability of the PPMO to reduce UMOD expression at the transcript and protein levels. Results: A single dose of lead PPMO resulted in a 70% knockdown of Umod transcript that led to protein reduction that was sustained for at least 28 days. Furthermore, UMOD protein expression was reduced in the UMOD C93F animals after a single dose of PPMO. Conclusions: This study shows the ability of PPMO technology to reduce UMOD transcript and protein levels in vitro and in vivo. Funding: Commercial Support - Sarepta