allele-selective antisense oligonucleotide targeting umod

This drug is an allele-selective antisense oligonucleotide (ASO) designed to treat Autosomal dominant tubulointerstitial kidney disease caused by UMOD mutations (ADTKD-UMOD). It functions by selectively targeting and silencing the mutant uromodulin (UMOD) transcript, specifically the p.Arg185Ser variant, while sparing the wild-type allele. This selective knockdown of mutant uromodulin mRNA and protein aims to reduce the formation of toxic intracellular aggregates in thick ascending limb (TAL) cells, thereby mitigating tubulointerstitial damage and progressive kidney disease. Preclinical studies in humanized knock-in Umod R186S/+ mice demonstrated potent, dose-dependent, and allele-selective knockdown of mutant uromodulin, leading to reduced endoplasmic reticulum stress, lower inflammatory infiltrate, improved urate handling, decreased polyuria, and restored uromodulin secretion.