Elesclomol alleviates Menkes pathology and mortality by escorting Cu to cuproenzymes in mice

Loss-of-function mutations in the copper (Cu) transporter ATP7A cause Menkes disease. Menkes is an infantile, fatal, hereditary copper-deficiency disorder that is characterized by progressive neurological injury culminating in death, typically by 3 years of age. Severe copper deficiency leads to mul...

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Published inScience (American Association for the Advancement of Science) Vol. 368; no. 6491; pp. 620 - 625
Main Authors Guthrie, Liam M, Soma, Shivatheja, Yuan, Sai, Silva, Andres, Zulkifli, Mohammad, Snavely, Thomas C, Greene, Hannah Faith, Nunez, Elyssa, Lynch, Brogan, De Ville, Courtney, Shanbhag, Vinit, Lopez, Franklin R, Acharya, Arjun, Petris, Michael J, Kim, Byung-Eun, Gohil, Vishal M, Sacchettini, James C
Format Journal Article
LanguageEnglish
Published United States The American Association for the Advancement of Science 08.05.2020
Subjects
Abnormalities
Adenosine
Adenosine triphosphatase
Animal models
Brain
Connective tissues
Coordination compounds
Copper
Copper compounds
Cytochrome
Cytochrome-c oxidase
Cytochromes
Electron transport
Electron transport chain
Histidine
Medical treatment
Menkes syndrome
Mitochondria
Mutation
Oxidase
Signs and symptoms
Triphosphatase
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Summary:Loss-of-function mutations in the copper (Cu) transporter ATP7A cause Menkes disease. Menkes is an infantile, fatal, hereditary copper-deficiency disorder that is characterized by progressive neurological injury culminating in death, typically by 3 years of age. Severe copper deficiency leads to multiple pathologies, including impaired energy generation caused by cytochrome c oxidase dysfunction in the mitochondria. Here we report that the small molecule elesclomol escorted copper to the mitochondria and increased cytochrome c oxidase levels in the brain. Through this mechanism, elesclomol prevented detrimental neurodegenerative changes and improved the survival of the mottled-brindled mouse-a murine model of severe Menkes disease. Thus, elesclomol holds promise for the treatment of Menkes and associated disorders of hereditary copper deficiency.
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Present address: Charles River Laboratories, Durham, NC27703, USA.
Author contributions: L.M.G. established mo-br rodent colony, husbandry and breeding, drug formulations, and pharmacokinetics and toxicological (PK/Tox) experiments; developed interventional protocols, efficacy studies, and behavioral studies; and wrote the manuscript. A.S., T.C.S., S.S., M.Z., H.F.G., B.L., C.D.V., and E.N. assisted in husbandry and biological sample processing for PK/Tox, histology, and biochemical experiments. S.S. and M.Z. performed tissue, Cu, and biochemical studies. A.A. synthesized ES-Cu2+ complex. V.S. and M.J.P. developed the ATP7A−/− B16 melanoma cell line and provided technical expertise. F.R.L. performed histopathology sectioning, generation of digital slide sets, and analysis. S.Y. and B.-E.K. established cardiac Ctr1 KO rodent colony, husbandry and breeding, efficacy studies, histology, and biochemical studies. V.M.G. and J.C.S. developed the concept of ES drug therapy for hereditary Cu disorders, provided administrative and technical expertise, undertook data analysis, and helped write the manuscript.
ISSN:0036-8075
1095-9203
DOI:10.1126/science.aaz8899