Understanding primary hyperoxaluria type 1 towards the development of innovative therapeutic strategies

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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 to end-stage renal disease and multisystemic depositionof oxalate salts. Combined liver-kidney transplantation is the only curative treatment approach, but associated with significant morbidity, mortality, and costs. Transplantation requires a medical infrastructure which is not available to most patients suffering from PH1 worldwide. Thus, there is an urgent need for new therapies besides transplantation. Our aims are to transform the critical mass of molecular knowledge into the generation of disease models for PH1 that allow the development of (synergistic) novel therapeuticapproaches. We aim i) to identify small molecule compounds able to restore AGT peroxisomal localization, ii) develop AAV-mediated gene therapy with liver-specific AAV vectors for in vivo genome editing, and iii) identify disease modifiers in PH1 that would enable better prognostic assessment or even further therapeutic exploitation. The strength of ERAdicatPH is the establishment of a transnational multidisciplinary networkthat 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 the OXALEurope registry to bring those ambitious goals to the bedside.