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Titel:

ARBM101 (Methanobactin SB2) Drains Excess Liver Copper via Biliary Excretion in Wilson's Disease Rats.

Dokumenttyp:
Journal Article
Autor(en):
Einer, Claudia; Munk, Ditte Emilie; Park, Eok; Akdogan, Banu; Nagel, Judith; Lichtmannegger, Josef; Eberhagen, Carola; Rieder, Tamara; Vendelbo, Mikkel H; Michalke, Bernhard; Wimmer, Ralf; Blutke, Andreas; Feuchtinger, Annette; Dershwitz, Philip; DiSpirito, Ana A; Islam, Tawhidul; Castro, Rui E; Min, Byong-Keol; Kim, Taewon; Choi, Seoyoung; Kim, Dasol; Jung, Chunwon; Lee, Hongjae; Park, Dongsik; Im, Weonbin; Eun, So-Young; Cho, You-Hee; Semrau, Jeremy D; Rodrigues, Cecília M P; Hohenester, Simon...     »
Abstract:
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. 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 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. CONCLUSIONS: 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.
Zeitschriftentitel:
Gastroenterology
Jahr:
2023
Band / Volume:
165
Heft / Issue:
1
Seitenangaben Beitrag:
187-200.e7
Volltext / DOI:
doi:10.1053/j.gastro.2023.03.216
PubMed:
http://view.ncbi.nlm.nih.gov/pubmed/36966941
Print-ISSN:
0016-5085
TUM Einrichtung:
Institut für Toxikologie und Umwelthygiene
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