Allele-selective targeting of uromodulin by antisense oligonucleotides reduces aggregates and kidney damage in a mouse model of autosomal dominant tubulointerstitial kidney disease.

An antisense gapmer targeting the UMOD c.553C > A (p.R185S) allele selectively silences mutant uromodulin in Umod R186S/+ mice, reducing aggregates and kidney damage.

• Why it matters: Gain-of-toxic-function UMOD mutations cause mutant uromodulin accumulation in TAL cells, driving stress, inflammation, and tubulointerstitial injury; allele-selective suppression is needed.
• What they did: In established Umod R186S/+ mice, a murine UMOD ASO reduced mutant mRNA and protein, with kidney ASO uptake reaching ~320,000 copies per TAL cell after 4 weeks.
• The result: The ASO suppressed premature mutant uromodulin and toxic aggregates, improved tubular function, and decreased tubulointerstitial inflammation in Umod R186S/+ kidneys, while leaving wild-type Umod +/+ uromodulin unaffected.

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