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

了解 1 型原发性高草酸尿症以制定创新治疗策略

• 批准号: 314138814
• 负责人: Privatdozent Dr. Bodo Beck
• 金额: --
• 依托单位: Institut für Humangenetik
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/314138814?language=en
• 关键词: Understanding; primary; hyperoxaluria; type; towards

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.

原发性高草酸尿症 1 型 (PH1) 是一种罕见的常染色体隐性遗传代谢性疾病，由肝丙氨酸乙醛酸转氨酶 (AGT) 突变引起。 AGT 缺陷导致草酸盐合成过多，从而诱发尿石症、肾钙质沉着症、慢性肾功能衰竭，并最终导致终末期肾病和草酸盐的多系统沉积。肝肾联合移植是唯一的治疗方法，但其发病率、死亡率和费用较高。移植需要医疗基础设施，而全世界大多数 PH1 患者都无法获得这种基础设施。因此，迫切需要除移植之外的新疗法。我们的目标是将大量的分子知识转化为 PH1 疾病模型的生成，从而开发（协同）新颖的治疗方法。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) 使用肝脏特异性 AAV 载体开发 AAV 介导的基因疗法，用于体内基因组编辑，以及 iii) 鉴定 PH1 中的疾病修饰剂，从而实现更好的预后评估甚至进一步的治疗开发。 ERAdicatPH 的优势在于建立了一个跨国多学科网络，该网络将研究小组广泛的基因组和分子生物学专业知识与致力于 PH1 患者护理的大学中心的出色临床经验相结合。 ERAdicatPH 将与 OXALEurope 注册中心合作，将这些雄心勃勃的目标付诸实践。

项目成果

Genetische Nierensteinerkrankungen

遗传性肾结石疾病

• DOI: 10.1007/s11825-018-0227-x
• 发表时间: 2018
• 期刊: medizinische genetik
• 影响因子: 1.1
• 作者: Weigert A;Beck BB;Hoppe B
• 通讯作者: Hoppe B

Generation of an induced pluripotent stem cell line (CIMAi001-A) from a compound heterozygous Primary Hyperoxaluria Type I (PH1) patient carrying p.G170R and p.R122* mutations in the AGXT gene.

从携带 AGXT 基因 p G170R 和 p R122* 突变的复合杂合原发性高草酸尿症 I 型 (PH1) 患者中产生诱导多能干细胞系 (CIMAi001-A)

• DOI: 10.1016/j.scr.2019.101626
• 发表时间: 2019
• 期刊: Stem cell research
• 影响因子: 1.2
• 作者: Martinez-Turrillas R;Rodriguez-Diaz S;Rodriguez-Marquez P;Martin-Mallo A;Salido E;Beck BB;Prosper F;Rodriguez-Madoz JR
• 通讯作者: Rodriguez-Madoz JR