Therapeutic Management of Menkes Disease and Related Copper Transport Disorders

The only currently available treatment for Menkes disease, subcutaneous copper histidinate injections, is successful only in patients with ATP7A gene mutations that do not completely corrupt ATP7A copper transport function (estimated 20-25% of affected patients) and when started at a very early age (first month of life). The combination of viral gene therapy with copper injections provides working copies of the ATP7A copper transporter into the brain, together with a source of the substrate (copper)  needed for proper brain growth and clinical neurodevelopment.

Codon-optimized nucleic acids encoding a reduced-size ATP7A protein and compositions of AAV vectors were discovered by NICHD researchers  along with methods of administering this therapy. Human P-type ATPase copper-transporting ATPase 1 (ATP7A) transports copper from enterocytes (where it is taken up from dietary copper) into the blood. ATP7A also mediates passage of copper across the blood-cerebrospinal fluid (CSF) barrier and the blood-brain barrier. In Menkes disease and occipital horn syndrome (OHS), copper accumulates in intestinal cells and less copper is absorbed into the blood, resulting in restricted copper supply to other tissues, particularly the brain. Death in infancy or early childhood is a common consequence. Therapeutic delivery of the copper transport protein via an AAV vector, combined with subcutaneous copper histidinate treatment will relieve the copper deficiency to the brain and permit normal neurological development and function.