Menkes disease (MD) is a X-linked genetic disorder of copper transport characterized by low brain copper that results in infantile neurodegeneration and premature death. MD is caused by mutations in a copper transporter gene, ATP7A. Current treatment is limited to subcutaneous copper injections and is especially effective in patients with mutant alleles that do not completely abrogate ATP7A function, and who are identified near birth (N Engl J Med 2008 358:605-614). For patients with complete loss-of-function mutations, copper delivered peripherally does not efficiently cross the blood-brain barrier. Thus, alternative treatment approaches are needed. In a murine model of classical MD (atp7amo-br) which cannot be rescued by intraperitoneal or intravenous copper, we are studying two brain-directed therapies: 1) early intracerebroventricular injection of copper chloride, and 2) early intracerebroventricular injection of a recombinant adeno-associated virus serotype 5 (AAV5) vector expressing a reduced size human ATP7A, rsATP7A-AAV. ? ? We developed a genotyping assay that identifies mutant pups before clinical signs, and administered 50 ng copper chloride to affected mice by intracerebroventricular injection within 3 days of birth. The dose was extrapolated from a maximum tolerated dose in adult rats that we determined previously (Molec Genet Metab 2007 91:30-36). Treatment modestly extended survival in mutant males and increased mean brain cortex copper levels in mutant mice . ? ? In an alternative approach, we are studying the expression and effects of rsATP7A-AAV delivered by intracerebroventricular injection. The transgene product begins at methionine 461 of the Menkes ATP7A and includes the fifth and sixth copper-binding domains. In mice receiving the AAV vector, we documented preliminary evidence of improved brain catechol ratios reflecting enhanced activity of dopamine-beta-hydroxylase, a copper-dependent enzyme. ? ? Our preliminary data indicate that intracerebroventricular delivery of copper and rsATP7A-AAV results in distribution throughout the atp7a
| Haddad, Marie Reine; Choi, Eun-Young; Zerfas, Patricia M et al. (2018) Cerebrospinal Fluid-Directed rAAV9-rsATP7A Plus Subcutaneous Copper Histidinate Advance Survival and Outcomes in a Menkes Disease Mouse Model. Mol Ther Methods Clin Dev 10:165-178 |
| Kaler, Stephen G (2016) Microbial peptide de-coppers mitochondria: implications for Wilson disease. J Clin Invest 126:2412-4 |
| Bandmann, Oliver; Weiss, Karl Heinz; Kaler, Stephen G (2015) Wilson's disease and other neurological copper disorders. Lancet Neurol 14:103-13 |
| 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 |
| Hicks, Julia D; Donsante, Anthony; Pierson, Tyler M et al. (2012) Increased frequency of congenital heart defects in Menkes disease. Clin Dysmorphol 21:59-63 |
| Huppke, Peter; Brendel, Cornelia; Korenke, Georg Christoph et al. (2012) Molecular and biochemical characterization of a unique mutation in CCS, the human copper chaperone to superoxide dismutase. Hum Mutat 33:1207-15 |
| Møller, Lisbeth B; Hicks, Julia D; Holmes, Courtney S et al. (2011) Diagnosis of copper transport disorders. Curr Protoc Hum Genet Chapter 17:Unit17.9 |
| Lem, Kristen E; Brinster, Lauren R; Tjurmina, Olga et al. (2007) Safety of intracerebroventricular copper histidine in adult rats. Mol Genet Metab 91:30-6 |
| Price, David J; Ravindranath, Thyyar; Kaler, Stephen G (2007) Internal jugular phlebectasia in Menkes disease. Int J Pediatr Otorhinolaryngol 71:1145-8 |
| Donsante, Anthony; Tang, Jingrong; Godwin, Sarah C et al. (2007) Differences in ATP7A gene expression underlie intrafamilial variability in Menkes disease/occipital horn syndrome. J Med Genet 44:492-7 |
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