ATP7A Gene Addition to the Choroid Plexus Results in Long-term Rescue of the Lethal Copper Transport Defect in a Menkes Disease Mouse Model

• Published in: Molecular therapy Vol. 19; no. 12; pp. 2114 - 2123
• Main Authors: Donsante, Anthony, Yi, Ling, Zerfas, Patricia M, Brinster, Lauren R, Sullivan, Patricia, Goldstein, David S, Prohaska, Joseph, Centeno, Jose A, Rushing, Elisabeth, Kaler, Stephen G
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-12-2011; Elsevier Limited; Nature Publishing Group
• Subjects: Adeno-associated virus; Adenosine Triphosphatases - physiology; Amino Acid Sequence; Amino acids; Animals; Armed forces; Behavior, Animal; Biological Transport; Blotting, Western; Brain - enzymology; Brain - pathology; Cation Transport Proteins - physiology; Cells, Cultured; Childrens health; Choroid Plexus - enzymology; Choroid Plexus - pathology; Copper; Copper - pharmacokinetics; Copper-transporting ATPases; Dependovirus - genetics; Disease Models, Animal; Dopamine; Dopamine beta-Hydroxylase - genetics; Dopamine beta-Hydroxylase - metabolism; Enzymes; Female; Gene therapy; Genetic Complementation Test; Humans; Immunoenzyme Techniques; Kidney - cytology; Kidney - metabolism; Localization; Male; Menkes Kinky Hair Syndrome - enzymology; Menkes Kinky Hair Syndrome - genetics; Menkes Kinky Hair Syndrome - therapy; Metabolism; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Molecular Sequence Data; Mutation; Neuropsychological Tests; Original; Pathology; Phenotype; Real-Time Polymerase Chain Reaction; RNA, Messenger - genetics; Saccharomyces cerevisiae; Sequence Homology, Amino Acid; Tissue Distribution; Yeast; Washington DC; United States > US; Maryland
• ISSN: 1525-0016; 1525-0024
• DOI: 10.1038/mt.2011.143

Menkes disease is a lethal infantile neurodegenerative disorder of copper metabolism caused by mutations in a P-type ATPase, ATP7A. Currently available treatment (daily subcutaneous copper injections) is not entirely effective in the majority of affected individuals. The mottled-brindled (mo-br) mouse recapitulates the Menkes phenotype, including abnormal copper transport to the brain owing to mutation in the murine homolog, Atp7a, and dies by 14 days of age. We documented that mo-br mice on C57BL/6 background were not rescued by peripheral copper administration, and used this model to evaluate brain-directed therapies. Neonatal mo-br mice received lateral ventricle injections of either adeno-associated virus serotype 5 (AAV5) harboring a reduced-size human ATP7A (rsATP7A) complementary DNA (cDNA), copper chloride, or both. AAV5-rsATP7A showed selective transduction of choroid plexus epithelia and AAV5-rsATP7A plus copper combination treatment rescued mo-br mice; 86% survived to weaning (21 days), median survival increased to 43 days, 37% lived beyond 100 days, and 22% survived to the study end point (300 days). This synergistic treatment effect correlated with increased brain copper levels, enhanced activity of dopamine-β-hydroxylase, a copper-dependent enzyme, and correction of brain pathology. Our findings provide the first definitive evidence that gene therapy may have clinical utility in the treatment of Menkes disease.