A novel copper-transporting small molecule in development for Menkes disease
Menkes disease is the result of a copper transport defect due to mutation of the ATP7A gene.1 Impaired copper transport leads to abnormal distribution of copper throughout the body, including a severe copper deficiency in the brain and an excess of copper in other organs, such as the intestines and kidneys.2 Clinical features include severe neurodegeneration, hypotonia, connective tissue defects, hypopigmentation, and steely hair, and result from deficiencies of various copper-dependent enzymes, such as cytochrome c oxidase, a key enzyme that is crucial for cellular respiration.1,3
There are currently no approved treatments for Menkes disease, and management typically involves daily injections of copper replacement therapy.2,4 Although this approach may increase systemic levels of copper, it does not ensure the copper is transported into mitochondria, where this micronutrient is needed to support cellular respiration.3 Resulting impairments in cellular oxygen consumption are especially felt in the brain, which consumes close to 20% of all oxygen that humans breathe.5
ENX-103 is a copper-transporting small molecule that has the unique ability to deliver copper across biological membranes into mitochondria, which is especially crucial for brain health and development.6
In preclinical studies, ENX-103 was able to rescue Menkes mutant mice from neonatal death, prolonging survival and supporting the achievement of neurodevelopmental milestones. Engrail is rapidly advancing ENX-103 into clinical studies.6
Menkes disease causes copper deficiencies that are ultimately fatal1 — new approaches to effectively transport copper may change the course of care
1. Horn N & Wittung-Stafshede P. Biomedicines. 2021;9:391. 2. NORD. Menkes Disease. Accessed June 1, 2022. https://rarediseases.org/rare-diseases/menkes-disease/. 3. Bhattacharjee A, et al. J Biol Chem. 2016;291:16644–16658. 4. Vairo FPE, et al. Mol Genet Metab. 2019;126:6–13. 5. National Institutes of Health (US); Biological Sciences Curriculum Study. NIH Curriculum Supplement Series [Internet]. Bethesda (MD): National Institutes of Health (US); 2007. Information about the Brain. 6. Engrail Therapeutics. Data on file.