ERAdicatPH

Primary hyperoxaluria type 1 (PH1) is a rare, autosomal recessive metabolic disorder caused by mutations in the hepatic alanine-glyoxylate aminotransferase (AGT). Defective AGT results in excessive oxalate synthesis that induces urolithiasis, nephrocalcinosis, chronic renal failure, and ultimately leading to end-stage renal disease from infancy to late adulthood. Combined liver-kidney transplantation is the only curative treatment, but associated with significant morbidity, mortality and high healthcare costs. Thus, there is an urgent need for new and safe therapies besides transplantation. Our previous work in the field make a breach for the development of new therapeutic options. The project aims to expand molecular knowledge into the generation of disease models for PH1 that allow the development of (synergistic) novel therapeutic approaches. We aim i) to identify small molecule compounds able to restore AGT peroxisomal localization by high-throughput screening, ii) develop AAV-mediated gene therapy with liver-specific AAV vectors for in vivo genome editing, and iii) identify disease modifiers and regulatory elements in PH1. The strength of ERAdicatPH is the establishment of a transnational multidisciplinary network that combines the broad genomic and molecular biology expertise of research groups with the excellent clinical experience at the university centers dedicated to the care of PH1 patients. ERAdicatPH will team up with OXALEurope, the largest PH-registry worldwide, to achieve the ambitious goals to develop a therapeutic approach from an idea to the bedside.