Genome editing for treatment of Autosomal Dominant Tubulointerstitial Kidney Disease

• Applicants: Dr. Michael Kaminski; Dr. Verena Klämbt
• Subject Area: Nephrology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 547398809

Mendelian mutations cause 10-34% of adult chronic kidney disease (CKD) of unknown etiology, and are even more frequent in pediatric CKD patients. Dialysis and transplantation are the sole treatment options; yet, dialysis increases mortality, while organ shortage and life-long immunosuppression limit transplantation. Thus, the need for treatment alternatives is urgent. Correcting causative variants is appealing; however, until now technological constraints have been prohibitive. Nevertheless, recent CRISPR-Cas methodologies promise to make genome editing a realistic option. CRISPR base editing combines high efficacy and easy programmability without requiring double-strand breaks (DSB) or donor templates. Recent in-vivo applications underscore its potential. Current base editors provide programmed C-to-T, A-to-G, A-to-Y and C-to-G edits. Here, we will extend CRISPR base editing for treatment of a monogenic kidney disease. First, we target UMOD variants (1), causing autosomal dominant tubulointerstitial kidney disease (ADTKD) by in-vitro base editing and validate results in primary cells from mouse models and human tubuloids. Second, we optimize adeno-associated virus (AAV) based kidney delivery (2) through various access routes and AAV serotypes. Split-inteins will enable base editors’ packaging and dual-AAV delivery, to establish renal base editing in-vivo (3) in reporter mouse models. Finally, we explore if pathogenic variant correction can prevent, halt or reverse ADTKD progression.

• DFG Programme: Research Grants