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

原发性高草酸尿1型（PH1）是一种罕见的常染色体隐性代谢疾病，由肝丙氨酸-乙醛氨基转移酶（AGT）突变引起。AGT缺陷导致草酸盐合成过量，从而诱发尿石症、肾钙化症、慢性肾功能衰竭，最终导致终末期肾病和草酸盐多系统沉积。肝肾联合移植是唯一的治愈性治疗方法，但与显著的发病率、死亡率和费用相关。移植需要医疗基础设施，这是世界上大多数PH1患者无法获得的。因此，除了移植之外，迫切需要新的治疗方法。我们的目标是将分子知识的临界质量转化为PH1疾病模型的生成，从而开发（协同）新的治疗方法。我们的目标是i)鉴定能够恢复AGT过氧化物酶体定位的小分子化合物，ii)开发AAV介导的基因治疗，使用肝脏特异性AAV载体进行体内基因组编辑，以及iii)鉴定PH1中的疾病修饰因子，从而实现更好的预后评估甚至进一步的治疗开发。radicatph的优势在于建立了一个跨国多学科网络，将研究小组广泛的基因组和分子生物学专业知识与大学中心致力于PH1患者护理的优秀临床经验相结合。根除atph将与OXALEurope注册中心合作，将这些雄心勃勃的目标带到床边。

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.