Institute of Molecular Toxicology and Pharmacology, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany.
Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.
Gastroenterology. 2023 Jul;165(1):187-200.e7. doi: 10.1053/j.gastro.2023.03.216. Epub 2023 Mar 24.
BACKGROUND & AIMS: Excess copper causes hepatocyte death in hereditary Wilson's disease (WD). Current WD treatments by copper-binding chelators may gradually reduce copper overload; they fail, however, to bring hepatic copper close to normal physiological levels. Consequently, lifelong daily dose regimens are required to hinder disease progression. This may result in severe issues due to nonadherence or unwanted adverse drug reactions and also due to drug switching and ultimate treatment failures. This study comparatively tested bacteria-derived copper binding agents-methanobactins (MBs)-for efficient liver copper depletion in WD rats as well as their safety and effect duration.
Copper chelators were tested in vitro and in vivo in WD rats. Metabolic cage housing allowed the accurate assessment of animal copper balances and long-term experiments related to the determination of minimal treatment phases.
We found that copper-binding ARBM101 (previously known as MB-SB2) depletes WD rat liver copper dose dependently via fecal excretion down to normal physiological levels within 8 days, superseding the need for continuous treatment. Consequently, we developed a new treatment consisting of repetitive cycles, each of ∼1 week of ARBM101 applications, followed by months of in-between treatment pauses to ensure a healthy long-term survival in WD rats.
ARBM101 safely and efficiently depletes excess liver copper from WD rats, thus allowing for short treatment periods as well as prolonged in-between rest periods.
过量的铜会导致遗传性威尔逊病（WD）中的肝细胞死亡。目前，通过铜结合螯合剂进行 WD 治疗可以逐渐减少铜过载；然而，它们未能使肝脏内的铜接近正常生理水平。因此，需要终身每日剂量方案来阻止疾病进展。由于不遵守规定、不希望的药物不良反应、药物更换以及最终的治疗失败，这可能会导致严重的问题。本研究比较了细菌来源的铜结合剂——甲烷菌素（MBs），以评估其在 WD 大鼠中有效耗竭肝脏铜的能力以及它们的安全性和作用持续时间。
在 WD 大鼠中进行了体外和体内铜螯合剂测试。代谢笼饲养允许准确评估动物的铜平衡，并进行与确定最小治疗阶段相关的长期实验。
我们发现，铜结合剂 ARBM101（以前称为 MB-SB2）通过粪便排泄依赖性地耗竭 WD 大鼠肝脏内的铜，使其降至正常生理水平，这取代了连续治疗的需要。因此，我们开发了一种新的治疗方案，包括重复的周期，每个周期约为 1 周的 ARBM101 应用，然后是数月的治疗暂停期，以确保 WD 大鼠的健康长期生存。
ARBM101 安全有效地从 WD 大鼠中耗竭多余的肝脏铜，从而允许进行短期治疗和延长治疗暂停期。
