Abstract
Bis-choline-tetrathiomolybdate, introduced as WTX101 (now known as ALXN1840), is a first-in-class copper-protein-binding agent for oral therapy of Wilson’s disease. In contrast to other decoppering agents such as trientine or D-penicillamine it acts by forming a tripartite complex with copper and albumin, thereby detoxifying excess liver and blood copper through biliary excretion. Preclinical animal experimentation with this drug was typically done with the alternative ammonium salt of tetrathiomolybdate, which is expected to have identical properties in terms of copper binding. Here, we comparatively analyzed the therapeutic efficacy of ALXN1840, D-penicillamine and trientine in lowering hepatic copper content in Atp7b−/− mouse. Liver specimens were subjected to laser ablation inductively conductively plasma mass spectrometry and electron microscopic analysis. We found that ALXN1840 caused a massive increase of hepatic copper and molybdenum during early stages of therapy. Prolonged treatment with ALXN1840 reduced hepatic copper to an extent that was similar to that observed after administration of D-penicillamine and trientine. Electron microscopic analysis showed a significant increase of lysosomal electron-dense particles in the liver confirming the proposed excretory pathway of ALXN1840. Ultrastructural analysis of mice treated with dosages comparable to the bis-choline-tetrathiomolybdate dosage used in an ongoing phase III trial in Wilson’s disease patients, as well as D-penicillamine and trientine, did not show relevant mitochondrial damage. In contrast, a high dose of ALXN1840 applied for four weeks triggered dramatic structural changes in mitochondria, which were notably characterized by the formation of holes with variable sizes. Although these experimental results may not be applicable to patients with Wilson’s disease, the data suggests that ALXN1840 should be administered at low concentrations to prevent mitochondrial dysfunction and overload of hepatic excretory pathways.
Highlights
Liver lysosomes from TTM-treated Long-Evans Cinnamon (LEC) rats we found to contain lysosomal Cu-Mo-S clusters in which molybdenum (Mo) was coordinated by four sulfurs with approximately three Cu neighbors, suggesting that the formation of these clusters is one critical therapeutic attribute of TTM which is necessary to decrease the bioavailability or redox properties of free Cu in LEC rats [14]
We introduced novel LA-inductively coupled plasma mass spectroscopy (ICP-MS) imaging protocols to identify and quantify changes in hepatic major, minor and trace metals in thin cryosections of Atp7b−/−
In line with our LA-ICP-MS measurements, in our ICP-MS analysis, we found that hepatic Cu content was significantly elevated in the treatment groups, with the highest concentrations in the 1 mg bc-TTM group (Figure S3)
Summary
Cu-binding proteins with much higher affinities for Cu than other chelators used in therapy. Biomedicines 2021, 9, 1861 of Wilson’s disease such as D-penicillamine (DPA) or trientine (TETA). ALXN1840 reduces plasma nonceruloplasmin-bound Cu by forming tripartite complexes with albumin, targets hepatic intracellular Cu and increases biliary Cu excretion [1,2], while other chelators promote the excretion of Cu via urine. TTM forms a stable, tripartite complex with protein, Cu and itself [3]. The therapeutic efficacy of TTM depends on whether it is given with or without food Given with food, it interferes with intestinal uptake of Cu. When administered between meals, it binds plasma Cu, and can further remove Cu from metallothionein (MT) and form insoluble Cu complexes deposited in the liver [4]. Due to its high affinity for Cu, it is generally assumed that bis-choline-tetrathiomolybdate (bc-TTM)
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
