This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Our past research has led to the development of an FDA approval of zinc for maintenance therapy of Wilson's disease. Zinc can now replace penicillamine and trientine, which have much more toxicity. Zinc is too slow acting for treating Wilson's disease patients when they first present with acute copper toxicity illness. These patients may be acutely ill from brain damage or liver damage. For the patients presenting with brain (neurologic) development, we are well along on developing a new drug, tetrathiomolybdate (TM), which is safe, fast-acting, and effective. However, approximately 12% of patients develop symptoms of copper deficiency (anemia, leukopenia), and 12% of patients develop mild elevations in transaminase enzymes under the current dose regimen. Both of these minor side effects are readily reversible by reducing the TM dose. We have developed this double-blind protocol to test a new dose regimen, which gives a lower dose of TM over a longer period of time than the standard regimen, in the hope of eliminating these side effects while preserving the efficacy of the treatment. We will include all patients (including children), both males and females, all ethnic groups in this study. They will be randomly assigned either the standard TM regimen or the modified TM dose regimen. All patients will receive zinc as well. Patients will be in the General Clinical Research Center of University of Michigan Hospital for about 6 weeks, then receive the drugs at home for another 10 weeks. Blood will be drawn every two weeks at home for continuing evaluation. After 16 weeks of therapy, patients will return to UM for a follow-up visit. Patients receiving the traditional TM dose will be kept on zinc maintenance therapy after 8 weeks of TM. They will receive a TM-placebo with the zinc until week 16. Patients on the new TM regimen will be transitioned to zinc maintenance therapy after 16 weeks of TM treatment. If this study shows the new TM dose regimen to be a superior treatment for this kind of patient, it will decrease the incidence of overtreatment and transaminase enzyme elevations, while preserving the neurologic function of patients.
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