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 (Fig. 1) 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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Bhattacharjee, Ashima; Yang, Haojun; Duffy, Megan et al. (2016) The Activity of Menkes Disease Protein ATP7A Is Essential for Redox Balance in Mitochondria. J Biol Chem 291:16644-58
Kaler, Stephen G (2016) Microbial peptide de-coppers mitochondria: implications for Wilson disease. J Clin Invest 126:2412-4
Choi, Eun-Young; Patel, Keyur; Haddad, Marie Reine et al. (2015) Tandem Duplication of Exons 1-7 Neither Impairs ATP7A Expression Nor Causes a Menkes Disease Phenotype. JIMD Rep 20:57-63
Bandmann, Oliver; Weiss, Karl Heinz; Kaler, Stephen G (2015) Wilson's disease and other neurological copper disorders. Lancet Neurol 14:103-13
Kotzbauer, David; Kaler, Stephen G (2015) Persistent lethargy, hypothermia, and failure to thrive in a neonate. Hosp Pediatr 5:234-7
Yi, Ling; Kaler, Stephen G (2015) Direct interactions of adaptor protein complexes 1 and 2 with the copper transporter ATP7A mediate its anterograde and retrograde trafficking. Hum Mol Genet 24:2411-25
Burgemeister, Anna Lena; Zirn, Birgit; Oeffner, Frank et al. (2015) Menkes disease with discordant phenotype in female monozygotic twins. Am J Med Genet A :
Kaler, Stephen G (2014) Neurodevelopment and brain growth in classic Menkes disease is influenced by age and symptomatology at initiation of copper treatment. J Trace Elem Med Biol 28:427-30
Wada, Takahito; Haddad, Marie Reine; Yi, Ling et al. (2014) A novel two-nucleotide deletion in the ATP7A gene associated with delayed infantile onset of Menkes disease. Pediatr Neurol 50:417-20
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

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