Analyzing the therapeutic efficacy of bis-choline-tetrathiomolybdate in the Atp7b−/− copper overload mouse model
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 al...
Gespeichert in:
| Hauptverfasser: | , , , , , , , |
|---|---|
| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
8 December 2021
|
| In: |
Biomedicines
Year: 2021, Jahrgang: 9, Heft: 12, Pages: 1-18 |
| ISSN: | 2227-9059 |
| DOI: | 10.3390/biomedicines9121861 |
| Online-Zugang: | Verlag, kostenfrei, Volltext: https://doi.org/10.3390/biomedicines9121861 Verlag, kostenfrei, Volltext: https://www.mdpi.com/2227-9059/9/12/1861 
|
| Verfasserangaben: | Philipp Kim, Chengcheng Christine Zhang, Sven Thoröe-Boveleth, Eva Miriam Buhl, Sabine Weiskirchen, Wolfgang Stremmel, Uta Merle, Ralf Weiskirchen |
MARC
| LEADER | 00000caa a2200000 c 4500 | ||
|---|---|---|---|
| 001 | 1799939359 | ||
| 003 | DE-627 | ||
| 005 | 20230427150851.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 220421s2021 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.3390/biomedicines9121861 |2 doi | |
| 035 | |a (DE-627)1799939359 | ||
| 035 | |a (DE-599)KXP1799939359 | ||
| 035 | |a (OCoLC)1341459091 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rda | ||
| 041 | |a eng | ||
| 084 | |a 33 |2 sdnb | ||
| 100 | 1 | |a Kim, Philipp |e VerfasserIn |0 (DE-588)1222063751 |0 (DE-627)1740914805 |4 aut | |
| 245 | 1 | 0 | |a Analyzing the therapeutic efficacy of bis-choline-tetrathiomolybdate in the Atp7b−/− copper overload mouse model |c Philipp Kim, Chengcheng Christine Zhang, Sven Thoröe-Boveleth, Eva Miriam Buhl, Sabine Weiskirchen, Wolfgang Stremmel, Uta Merle, Ralf Weiskirchen |
| 264 | 1 | |c 8 December 2021 | |
| 300 | |a 18 | ||
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a Computermedien |b c |2 rdamedia | ||
| 338 | |a Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Gesehen am 21.04.2022 | ||
| 500 | |a "−/−" bei Atp7b-/- ist hochgestellt | ||
| 520 | |a 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. | ||
| 650 | 4 | |a Atp7b | |
| 650 | 4 | |a ALXN-1840 | |
| 650 | 4 | |a bis-choline-tetrathiomolybdate | |
| 650 | 4 | |a copper | |
| 650 | 4 | |a D-penicillamine | |
| 650 | 4 | |a laser ablation inductively coupled plasma mass spectrometry | |
| 650 | 4 | |a therapy | |
| 650 | 4 | |a trientine | |
| 650 | 4 | |a Wilson’s disease | |
| 650 | 4 | |a WTX101 | |
| 700 | 1 | |a Zhang-Hagenlocher, Christine |d 1990- |e VerfasserIn |0 (DE-588)1072012200 |0 (DE-627)826776248 |0 (DE-576)433478691 |4 aut | |
| 700 | 1 | |a Thoröe-Boveleth, Sven |e VerfasserIn |4 aut | |
| 700 | 1 | |a Buhl, Eva Miriam |d 1987- |e VerfasserIn |0 (DE-588)1127785109 |0 (DE-627)882230263 |0 (DE-576)485390485 |4 aut | |
| 700 | 1 | |a Weiskirchen, Sabine |e VerfasserIn |4 aut | |
| 700 | 1 | |a Stremmel, Wolfgang |d 1952- |e VerfasserIn |0 (DE-588)142773638 |0 (DE-627)640118747 |0 (DE-576)33331560X |4 aut | |
| 700 | 1 | |a Merle, Uta |d 1974- |e VerfasserIn |0 (DE-588)123211069 |0 (DE-627)706210174 |0 (DE-576)293606854 |4 aut | |
| 700 | 1 | |a Weiskirchen, Ralf |d 1964- |e VerfasserIn |0 (DE-588)123920167 |0 (DE-627)085524700 |0 (DE-576)293943044 |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Biomedicines |d Basel : MDPI, 2013 |g 9(2021), 12, Artikel-ID 1861, Seite 1-18 |h Online-Ressource |w (DE-627)750370483 |w (DE-600)2720867-9 |w (DE-576)384589596 |x 2227-9059 |7 nnas |a Analyzing the therapeutic efficacy of bis-choline-tetrathiomolybdate in the Atp7b−/− copper overload mouse model |
| 773 | 1 | 8 | |g volume:9 |g year:2021 |g number:12 |g elocationid:1861 |g pages:1-18 |g extent:18 |a Analyzing the therapeutic efficacy of bis-choline-tetrathiomolybdate in the Atp7b−/− copper overload mouse model |
| 856 | 4 | 0 | |u https://doi.org/10.3390/biomedicines9121861 |x Verlag |x Resolving-System |z kostenfrei |3 Volltext |
| 856 | 4 | 0 | |u https://www.mdpi.com/2227-9059/9/12/1861 |x Verlag |z kostenfrei |3 Volltext |
| 951 | |a AR | ||
| 992 | |a 20220421 | ||
| 993 | |a Article | ||
| 994 | |a 2021 | ||
| 998 | |g 123211069 |a Merle, Uta |m 123211069:Merle, Uta |d 910000 |d 910100 |e 910000PM123211069 |e 910100PM123211069 |k 0/910000/ |k 1/910000/910100/ |p 7 | ||
| 998 | |g 1072012200 |a Zhang-Hagenlocher, Christine |m 1072012200:Zhang-Hagenlocher, Christine |d 910000 |d 910100 |e 910000PZ1072012200 |e 910100PZ1072012200 |k 0/910000/ |k 1/910000/910100/ |p 2 | ||
| 999 | |a KXP-PPN1799939359 |e 4119710327 | ||
| BIB | |a Y | ||
| SER | |a journal | ||
| JSO | |a {"relHost":[{"physDesc":[{"extent":"Online-Ressource"}],"title":[{"subtitle":"open access journal","title":"Biomedicines","title_sort":"Biomedicines"}],"part":{"pages":"1-18","text":"9(2021), 12, Artikel-ID 1861, Seite 1-18","volume":"9","issue":"12","year":"2021","extent":"18"},"id":{"eki":["750370483"],"issn":["2227-9059"],"zdb":["2720867-9"]},"language":["eng"],"type":{"media":"Online-Ressource","bibl":"periodical"},"origin":[{"publisher":"MDPI","dateIssuedKey":"2013","dateIssuedDisp":"2013-","publisherPlace":"Basel"}],"recId":"750370483","pubHistory":["1.2013 -"],"note":["Gesehen am 12.08.20"],"disp":"Analyzing the therapeutic efficacy of bis-choline-tetrathiomolybdate in the Atp7b−/− copper overload mouse modelBiomedicines"}],"title":[{"title_sort":"Analyzing the therapeutic efficacy of bis-choline-tetrathiomolybdate in the Atp7b−/− copper overload mouse model","title":"Analyzing the therapeutic efficacy of bis-choline-tetrathiomolybdate in the Atp7b−/− copper overload mouse model"}],"person":[{"display":"Kim, Philipp","family":"Kim","given":"Philipp","role":"aut"},{"role":"aut","given":"Christine","family":"Zhang-Hagenlocher","display":"Zhang-Hagenlocher, Christine"},{"role":"aut","display":"Thoröe-Boveleth, Sven","family":"Thoröe-Boveleth","given":"Sven"},{"role":"aut","given":"Eva Miriam","display":"Buhl, Eva Miriam","family":"Buhl"},{"role":"aut","given":"Sabine","display":"Weiskirchen, Sabine","family":"Weiskirchen"},{"role":"aut","given":"Wolfgang","display":"Stremmel, Wolfgang","family":"Stremmel"},{"given":"Uta","display":"Merle, Uta","family":"Merle","role":"aut"},{"display":"Weiskirchen, Ralf","family":"Weiskirchen","given":"Ralf","role":"aut"}],"physDesc":[{"extent":"18 S."}],"id":{"doi":["10.3390/biomedicines9121861"],"eki":["1799939359"]},"language":["eng"],"type":{"media":"Online-Ressource","bibl":"article-journal"},"origin":[{"dateIssuedKey":"2021","dateIssuedDisp":"8 December 2021"}],"recId":"1799939359","note":["Gesehen am 21.04.2022","\"−/−\" bei Atp7b-/- ist hochgestellt"],"name":{"displayForm":["Philipp Kim, Chengcheng Christine Zhang, Sven Thoröe-Boveleth, Eva Miriam Buhl, Sabine Weiskirchen, Wolfgang Stremmel, Uta Merle, Ralf Weiskirchen"]}} | ||
| SRT | |a KIMPHILIPPANALYZINGT8202 | ||