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.     «

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 t...     »