Pilot Clinical Study Showing Abnormal Copper Metabolism in Healthy Wilson Disease Heterozygote Subjects

Wilson Disease (WD) is a rare, potentially debilitating and life-threatening disorder of copper (Cu) metabolism, considered to be inherited in an autosomal recessive manner, since heterozygotes are healthy. The disease is due to mutations in ATP7B, a hepatic Cu transporting P-type ATPase responsible for the dual role of regulating Cu homeostasis by eliminating excess Cu into the feces and transferring Cu for biosynthetic incorporation into Cu-dependent enzymes. We conducted a single center open-label pilot clinical study in 3 healthy volunteers (HV) and 3 WD heterozygotes (HTZ) who received an intravenous dose of 64Cu. 64Cu cumulative fecal and therefore biliary Cu excretion over 72 h showed a mean reduction of 3.8-fold in WD HTZ compared to HV. Studies have demonstrated that ATP7B can form dimers in vitro and in cells. The abnormal Cu metabolism observed in WD HTZ can represent a reduction in ATP7B function in biliary copper excretion if the mutant: normal dimer has a dominant negative effect on the ATP7B transporter proteins, so that only healthy: healthy dimers may be fully active in vivo. Therefore, when considering gene therapy for WD, production of a high number of mRNA transcripts may be necessary to overcome potential dimerization of ATP7B with mutant protein that might exert a negative effect and limit the efficacy of the therapy. Further studies are needed to validate these hypotheses, and attention should be paid to the particular ATP7B mutations present in individuals with WD being considered for gene therapy or gene repair therapies.