Abstract 1102 Repurposing elesclomol for genetic disorders of copper deficiency

Copper is an essential micronutrient that acts as a catalytic cofactor for enzymes involved in vital cellular functions, including mitochondrial energy generation.Copper deficiency due to genetic defects in copper transporters results in fatal pediatric disorders such as Menkes disease, for which no approved treatment is available.To discover an effective therapeutic agent for these lethal diseases, we designed a targeted yeast-based screen for discovering copper-transporting drugs.Through this screen, we identified elesclomol, an investigational chemotherapy drug, as a potent copper ionophore that transports copper to mitochondria and restores cytochrome c oxidase, an essential cuproenzyme, in yeast, zebrafish, and mice with genetic defects in copper acquisition.Elesclomol improved survival and prevented detrimental neurodegenerative changes in a murine model of severe Menkes disease.Inspired by our studies, the Spanish Agency of Medicines and Health Products recently approved the use of elesclomol-copper in infants with Menkes disease, where the initial results are promising.Our work illustrates how simple model organisms such as yeast can be used to discover human therapeutics for rare genetic disorders.