Preclinical evaluation of perinatal therapeutic approaches for autosomal recessive polycystic kidney disease (ARPKD)

• Applicant: Professor Dr. Max Christoph Liebau
• Subject Area: Pediatric and Adolescent Medicine ; Nephrology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 547618261

Autosomal recessive polycystic kidney disease (ARPKD) is a severe genetic disorder of early childhood that is typically characterized by intrauterine enlargement of fibrocystic kidneys resulting in early-onset kidney failure and obligatory hepatic involvement presenting as congenital hepatic fibrosis. Most cases of ARPKD are caused by pathogenic variants in the gene PKHD1 encoding the ciliary transmembrane protein fibrocystin (FC). The molecular pathogenesis of ARPKD and the cellular function of FC remain incompletely understood. It has been suggested that FC may influence the same intracellular signaling cascades as the two proteins mainly affected in the more common autosomal dominant polycystic kidney disease (ADPKD). Overlapping clinical and genetic findings between ARPKD and ADPKD have been described. Cellular metabolic reprogramming has been described for ADPKD by various independent groups and first clinical trial examining the therapeutic potential of metabolic interventions are ongoing. Insights obtained in these studies will give important information for ARPKD. We could previously identify metabolic dysregulation in ARPKD in preclinical models and patient samples as a potential therapeutic target. In the suggested project we aim to validate our finding through pre- and perinatal metabolic interventions in a murine model. In a preclinical in vivo approach we will deeply characterize a Pkhd1-associated model and combine this with therapeutic approaches targeting cellular metabolism. The chosen model for the first time recapitulates the human ARPKD kidney phenotype in a Pkhd1-dependent way. Our interventional studies will be complemented by a genetic rescue approach analyzing the effects of Pkhd1 re-expression on cell metabolic changes in renal tubular eipthelial cells and the renal phenotype in vivo. In summary, the results of this project will give insights into the molecular pathogenesis of ARPKD and may serve as a direct translational starting point for first targeted therapeutic strategies for one of the most devastating pediatric kidney diseases.

• DFG Programme: Research Grants