Rapid transcellular hepatic copper depletion by ARBM-101 rescues severe liver damage in Wilson disease rodents

In Wilson disease (WD), excess copper provokes hepatocyte death due to impaired copper excretion, ultimately causing either acute or chronic liver damage. Current therapeutic compounds fail to reduce hepatic copper near to physiological levels, leaving lifelong, several times daily treatment as the only choice for patients. We have previously shown that a bacteria-derived methanobactin, termed ARBM-101, most efficiently depleted excess liver copper in still healthy WD rats. Here we report, for the first time, that mechanistically this is due to endosomal/lysosomal/exosomal trafficking of ARBM-101 in WD hepatocytes, allowing for copper mass excretion via the biliary/fecal route. We further show that such liver copper excretion occurs within minutes in vivo to detect copper-bound ARBM-101 in feces. This efficacy allows for specialized treatment regimen to rescue acute liver failure in WD rats. Moreover, also shown for the first time, it avoids fibrosis development in WD mice. Thus, judging from the results in two rodent species and human hepatocytes, this study advocates the development of ARBM-101 for WD therapy.

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Publication Details

Journal
Biomedicine & Pharmacotherapy
Published
2025-12-01
DOI
https://doi.org/10.1016/j.biopha.2025.118867
Primary Topic
Trace Elements in Health
Type
article
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article

Rapid transcellular hepatic copper depletion by ARBM-101 rescues severe liver damage in Wilson disease rodents

Thomas Damgaard Sandahl, Alan A. DiSpirito, Tamara Rieder, Jonas Engler et al.
Biomedicine & Pharmacotherapy
Trace Elements in Health
article

Rapid transcellular hepatic copper depletion by ARBM-101 rescues severe liver damage in Wilson disease rodents

Thomas Damgaard Sandahl, Alan A. DiSpirito, Tamara Rieder, Jonas Engler, Valentina Medici, Ditte Emilie Munk, Carola Eberhagen, Hans Zischka, Chunwon Jung, Mikkel Holm Vendelbo, Noreene M. Shibata, Banu Akdogan, So-Young Eun, Dongsik Park, Karin Kleigrewe, Quirin Reinold, Eun‐Jung Kim, Dasol Kim, Hong‐Jae Lee, Adriana Fontes, Stefan Engelhardt, Weonbin Im, Judith Sailer, Susanne I. Wudy
article en

Abstract

In Wilson disease (WD), excess copper provokes hepatocyte death due to impaired copper excretion, ultimately causing either acute or chronic liver damage. Current therapeutic compounds fail to reduce hepatic copper near to physiological levels, leaving lifelong, several times daily treatment as the only choice for patients. We have previously shown that a bacteria-derived methanobactin, termed ARBM-101, most efficiently depleted excess liver copper in still healthy WD rats. Here we report, for the first time, that mechanistically this is due to endosomal/lysosomal/exosomal trafficking of ARBM-101 in WD hepatocytes, allowing for copper mass excretion via the biliary/fecal route. We further show that such liver copper excretion occurs within minutes in vivo to detect copper-bound ARBM-101 in feces. This efficacy allows for specialized treatment regimen to rescue acute liver failure in WD rats. Moreover, also shown for the first time, it avoids fibrosis development in WD mice. Thus, judging from the results in two rodent species and human hepatocytes, this study advocates the development of ARBM-101 for WD therapy.

Biomedicine & PharmacotherapyVol. 193
Iowa State University (US), Aarhus University Hospital (DK), Center for Environmental Health (US), Helmholtz Zentrum München (DE), Technical University of Munich (DE), University of California, Davis (US)
Openalex Percentile: Top 54%
Trace Elements in Health
DOIOpen Access PDFOpenAlex
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