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Einer, C. ; Munk, D.E.* ; Park, E.* ; Akdogan, B. ; Nagel, J.* ; Lichtmannegger, J. ; Eberhagen, C. ; Rieder, T.* ; Vendelbo, M.H.* ; Michalke, B. ; Wimmer, R.* ; Blutke, A. ; Feuchtinger, A. ; Dershwitz, P.* ; DiSpirito, A.M.* ; Islam, T.* ; Castro, R.E.* ; Min, B.K.* ; Kim, T.W.* ; Choi, S.* ; Kim, D.* ; Jung, C.* ; Lee, H.* ; Park, D.* ; Im, W.* ; Eun, S.Y.* ; Cho, Y.H.* ; Semrau, J.D.* ; Rodrigues, C.M.P.* ; Hohenester, S.* ; Damgaard Sandahl, T.* ; DiSpirito, A.A.* ; Zischka, H.

ARBM101 (Methanobactin SB2) drains excess liver copper via biliary excretion in Wilson's disease rats.

Gastroenterology 165, 187-200.e7 (2023)
Verlagsversion DOI PMC
Open Access Hybrid
Creative Commons Lizenzvertrag
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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Copper Depletion ; Liver ; Methanobactin ; Mitochondria ; Wilson's Disease; Cell-penetrating Peptides; Strain; Mechanisms; Binding; Penicillamine; Atpase; Atp7b
Sprache englisch
Veröffentlichungsjahr 2023
HGF-Berichtsjahr 2023
ISSN (print) / ISBN 0016-5085
e-ISSN 1528-0012
Zeitschrift Gastroenterology
Quellenangaben Band: 165, Heft: 1, Seiten: 187-200.e7 Artikelnummer: , Supplement: ,
Verlag Elsevier
Verlagsort 1600 John F Kennedy Boulevard, Ste 1800, Philadelphia, Pa 19103-2899 Usa
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Molecular Toxicology and Pharmacology (TOX)
Research Unit BioGeoChemistry and Analytics (BGC)
Research Unit Analytical Pathology (AAP)
POF Topic(s) 30203 - Molecular Targets and Therapies
30202 - Environmental Health
30205 - Bioengineering and Digital Health
Forschungsfeld(er) Enabling and Novel Technologies
Environmental Sciences
PSP-Element(e) G-505200-003
G-504800-002
G-500390-001
Förderungen ArborMed Co. Ltd.
European Union
r Bildung und Forschung (BMBF)
Bundesministerium fuuml
Deutsche Forschungsgemeinschaft (DFG)
DOI 10.1053/j.gastro.2023.03.216
WOS ID 001037237600001
Scopus ID 85161498142
PubMed ID 36966941
Erfassungsdatum 2023-12-08
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