| dc.description.abstract | Copper is an essential micronutrient required for the proper biological function of numerous enzymes. Absorption, transportation, and elimination of copper is highly regulated due to potential pathological effects of copper overload or deficiency. Menkes Disease is an X-linked inherited defect in active, directional copper transport caused by mutations in the ATP7A gene that results in profound copper deficiency and subsequent neurodegeneration in hemizygous male infants. The prognosis for those diagnosed with Menkes Disease is poor with death resulting before three years of age.
Current therapeutic strategies involve parental replacement of systemic copper using histidine as the ionophoric carrier, but clinical trials have failed to significantly alter disease progression in most patients. Poor tissue penetrance and low restoration of cuproenzyme function explain the failure of histidine-based therapy in Menkes patients.
Elesclomol is a chemotherapeutic agent with highly specific copper coordinating properties. The copper (II)-elesclomol complex is highly lipophilic, penetrates the blood-brain barrier, and has demonstrated the ability to restore cuproenzyme function in copper-deficient yeast strains at very low exposure levels.
To assess the efficacy of an elesclomol-based copper replacement therapy, an intervention protocol in mottled-brindled mice was developed resulting in greater than 80% survival of affected male mice. Of these mice, average lifespan within the treatment group approximated wildtype length with multiple individuals surviving greater than 250 days.
Phenotypic characterization of rescued Menkes-affected males reveals subtle deficiencies in neurologic and motor performance. Quantification of tissue copper levels and cuproenzyme function demonstrate partial restoration of copper levels and function of the key cuproenzyme cytochrome c oxidase.
Pharmacokinetics and acute toxicity of the intervention regime were assessed. The complex exhibits biphasic distribution with slow elimination from peripheral tissues, moderate systemic exposure, and is well tolerated at low exposure levels.
Based on these results, the copper (II)-elesclomol complex shows promise as a potential therapeutic agent for the treatment of Menkes Disease. | |
