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

Abstract

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.

Repurposing elesclomol, an investigational drug for the treatment of copper metabolism disorders

“…Using this principle, Soma et al, performed a targeted screen with a number of copper-binding pharmacological agents for their ability to restore respiratory growth in a yeast mutant defective in copper delivery to cytochrome c oxidase (CcO), a mitochondrial cuproenzyme [8]. This screen identified elesclomol as the most potent copper-transporting molecule, which rescued CcO function in a number of in vitro and in vivo models of copper deficiency [8,9].…”

“…Thus, pharmacological interventions that can restore cellular and tissue metal homeostasis could be of therapeutic benefit [17]. Indeed, such approaches have often been used for metal chelation therapy [18], and more recent efforts have focused on restoring the site-and direction-specific transport of metals, as in the case of hinokitiol for iron and elesclomol for copper homeostasis [7][8][9].…”

“…A recent preclinical study showing the efficacy of the elesclomol-copper complex in alleviating neuropathology and mortality in a mouse model of Menkes disease is an exciting development [9]. This is because: 1) the mottledbrindled (mo-br) mouse used in this study recapitulates severe pathology observed in Menkes-affected children, 2) like Menkes patients, mo-br mice are particularly recalcitrant to treatment with hydrophilic copper complexes such as copper-histidinate, 3) just two injections of elesclomolcopper complex extended the median survival of mo-br mice from 14 to 203 days, and 4) along with extended survival, the treated mice thrived as indicated by the normalization of many aspects of animal physiology, biochemistry, and anatomy, including neuromotor function, CcO levels, and hair texture.…”

“…While this promising preclinical study [9] opens up a new avenue for the treatment of this devastating disorder, it is important to identify the next steps in repurposing elesclomol for the treatment of copper deficiency disorders. First, it is critical to determine the exact dosing regimen such that the toxicity of this anticancer drug is minimized while optimal efficacy is achieved.…”

Features Discriminating COVID-19 From Community-Acquired Pneumonia in Pediatric Patients

“…In late December 2019, the pneumonia caused by a novel coronavirus (SARS-Cov-2) was identified in Wuhan Hubei province, China (1). The world health organization named the disease caused by SARS-Cov-2 coronavirus disease 2019 (COVID-19) (2). By September 1st, 2020, 90,383 confirmed cases of COVID-19 in China, and 25,118,689 cases in 216 countries (3).…”