Treatment of Autosomal Dominant Tubulointerstitial Kidney Disease Uromodulin (ADTKD-UMOD) with Antisense Oligonucleotides

Background: Autosomal Dominant Tubulointerstitial Kidney Disease-Uromodulin (ADTKD-UMOD) is a genetic disease caused by destabilizing mutations in uromodulin (UMOD). 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 Umod 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 PPMO resulted in a 70% knockdown of UMOD protein in WT mice. The reduction in UMOD protein was sustained for at least 28 days. Two subsequent weekly doses of PPMO increased the amount of UMOD knockdown further, demonstrating an additive effect of PPMO dosing over a two week period. Furthermore, Umod MOD protein expression was reduced in the UMOD C93F animals after a single dose of PPMO. Conclusion: PPMO technology can be used to reduce UMOD transcript and protein levels in vitro and in vivo. These findings demonstrate that PPMOs have the potential to preserve renal function in patients with ADTKD. Funding: Commercial Support - Sarepta Therapeutics