作者
Claudia Einer,Ditte Emilie Munk,Eok Park,Banu Akdogan,Judith Nagel,Josef Lichtmannegger,Carola Eberhagen,Tamara Rieder,Mikkel Holm Vendelbo,Bernhard Michalke,Ralf Wimmer,Andreas Blutke,Annette Feuchtinger,Philip Dershwitz,Ana A. DiSpirito,Tawhidul Islam,Rui E. Castro,Byong-Keol Min,TaeWon Kim,Seo-Young Choi,Dasol Kim,Chunwon Jung,Hong-Jae Lee,Dongsik Park,Weonbin Im,So Young Eun,You‐Hee Cho,Jeremy D. Semrau,C.M.P. Rodrigues,Simon Hohenester,Thomas Damgaard Sandahl,Alan A. DiSpirito,Hans Zischka
摘要
Background Excess copper causes hepatocyte death in hereditary Wilson 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 non-adherence or unwanted drug reactions, but also in drug switching and ultimate treatment failures. Study aims To comparatively test bacteria-derived copper binding agents – methanobactins (MBs) – for efficient liver copper depletion in WD rats, as well as their safety and effect duration. Methods 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. Results 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 eight days, superseding the need for continuous treatment. Consequently, we developed a new treatment consisting of repetitive cycles, each of approximately one week of ARBM101 applications, followed by months of in-between treatment pauses to ensure a healthy long-term survival in WD rats. Conclusions ARBM101 safely and efficiently depletes excess liver copper from Wilson disease rats, thus allowing for short treatment periods as well as prolonged in-between rest periods.