Autosomal Dominant Tubulointerstitial Kidney disease (ADTKD) caused by pathogenic variants in Uromodulin (UMOD) is the 3rd most common cause of monogenic kidney disease in adults. Dialysis and kidney transplantation are the only therapeutic options for subsequent end-stage-renal-disease. However, these are associated with adverse health effects, hence there is an urgent need for treatment alternatives. CRISPR/Cas base editors, through high efficacy and easy programmability, represent a promising novel treatment strategy. This project aims to establish renal base editing for the treatment of ADTKD. Systematic screening of suitable gRNAs and base editors for correction of pathogenic human UMOD variant C170Y in engineered HEK293T cells resulted in editing efficiencies of up to ~75%. Subsequent base editing in a mIMCD-3 cell line expressing the human C170Y variant attenuated the disease underlying ER-retention of Uromodulin and restored physiological trafficking to the cellular membrane. Two further approaches, independent of the causative pathogenic variant, are based on the observation that Umod-/- mice lack an obvious renal phenotype.  Here, UMOD expression is inactivated by introduction of STOP codons or disruption of splice sites. In HEK293T cells, we achieved up to ~80% and up to ~50% on-target editing respectively. We will further validate our approach in-vitro in human renal organoids derived from patients affected by ADTKD-UMOD. We anticipate base editing to serve as an effective and innovative therapeutic approach for renal monogenic diseases.