1. ATP7A gene therapy in murine models of Menkes disease. Menkes disease is a lethal infantile neurodegenerative disorder of copper metabolism caused by mutations in a P-type ATPase, ATP7A. Currently available treatment is ineffective in a majority of affected individuals and mortality is high. 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-beta-hydroxylase, a copper-dependent enzyme, and correction of brain pathology. These findings provide the first definitive evidence that gene therapy may have clinical utility in the treatment of Menkes disease. Further preclinical proof-of-concept investigations involving AAV serotypes with the capacity to cross the blood-brain barrier after systemic administration (AAV9, AAVrh10) are under investigation. 2. Novel molecular defects associated with disordered copper metabolism. In collaboration with others, we characterized patients from five families with an unknown disorder of copper metabolism. We documented defects in in SLC33A1 that encodes a highly conserved acetylCoA transporter (AT-1), required for acetylation of multiple gangliosides and glycoproteins. The mutations were found to cause reduced or absent AT-1 expression and abnormal intracellular localization of the protein. We showed that AT-1 knockdown in HepG2 cells led to reduced ceruloplasmin secretion. The finding revealed an essential role for AT-1 in proper post-translational modification of numerous proteins, without which normal brain development is interrupted.

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Yi, Ling; Kaler, Stephen (2014) ATP7A trafficking and mechanisms underlying the distal motor neuropathy induced by mutations in ATP7A. Ann N Y Acad Sci 1314:49-54
Graper, Mary L; Huster, Dominik; Kaler, Stephen G et al. (2014) Introduction to Human Disorders of Copper Metabolism. Ann N Y Acad Sci 1314:v-vi
Haddad, Marie Reine; Patel, Keyur D; Sullivan, Patricia H et al. (2014) Molecular and biochemical characterization of Mottled-dappled, an embryonic lethal Menkes disease mouse model. Mol Genet Metab 113:294-300
Kaler, Stephen G (2014) Translational research investigations on ATP7A: an important human copper ATPase. Ann N Y Acad Sci 1314:64-8
Kaler, Stephen G (2013) Inborn errors of copper metabolism. Handb Clin Neurol 113:1745-54
Donsante, Anthony; Sullivan, Patricia; Goldstein, David S et al. (2013) L-threo-dihydroxyphenylserine corrects neurochemical abnormalities in a Menkes disease mouse model. Ann Neurol 73:259-65
Desai, V; Donsante, A; Swoboda, K J et al. (2011) Favorably skewed X-inactivation accounts for neurological sparing in female carriers of Menkes disease. Clin Genet 79:176-82
Goldstein, David S; Holmes, Courtney S; Kaler, Stephen G (2009) Relative efficiencies of plasma catechol levels and ratios for neonatal diagnosis of menkes disease. Neurochem Res 34:1464-8
Kaler, Stephen G; Tang, Jingrong; Donsante, Anthony et al. (2009) Translational read-through of a nonsense mutation in ATP7A impacts treatment outcome in Menkes disease. Ann Neurol 65:108-13
Tang, Jingrong; Donsante, Anthony; Desai, Vishal et al. (2008) Clinical outcomes in Menkes disease patients with a copper-responsive ATP7A mutation, G727R. Mol Genet Metab 95:174-81

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