Wilson's disease (WD), albeit relatively rare, is an important genetic metabolic disease because of highly effective therapies that can be lifesaving. It is a great imitator and requires a high index of suspicion for correct and timely diagnosis. Neurologic, psychiatric and hepatologic problems in WD are very nonspecific, and we discuss the most common clinical phenotypes. The diagnosis remains laboratory based, and here we review the most important challenges and pitfalls in laboratory evaluation of WD, including the emerging role of genetic testing in WD diagnosis. WD is a monogenic disorder but has very high allelic heterogeneity with >500 disease-causing mutations identified, and new insights into phenotype-genotype correlations are also reviewed. The gold standard of therapy is chelation of excessive copper, but many unmet needs exist because of possible clinical deterioration in treated patients and potential adverse effects associated with currently available chelating medications. We also review the most promising novel therapeutic approaches, including chelators targeting specific cell types, cell transplantation and gene therapy.

/pdf/update-on-the-clinical-management-of-wilson-s-disease-3tpcmi0isr.pdf

Update on the clinical management of Wilson's disease.

Wilson disease (WD) is an autosomal recessive disorder of copper metabolism manifesting with hepatic, neurological and psychiatric symptoms. The limitations of the currently available therapy for WD (particularly in the management of neuropsychiatric disease), together with our limited understanding of key aspects of this illness (e.g. neurological vs. hepatic presentation) justify the ongoing need to study WD in suitable animal models. Four animal models of WD have been established: the Long-Evans Cinnamon rat, the toxic-milk mouse, the Atp7b knockout mouse and the Labrador retriever. The existing models of WD all show good similarity to human hepatic WD and have been helpful in developing an improved understanding of the human disease. As mammals, the mouse, rat and canine models also benefit from high homology to the human genome. However, important differences exist between these mammalian models and human disease, particularly the absence of a convincing neurological phenotype. This review will first provide an overview of our current knowledge of the orthologous genes encoding ATP7B and the closely related ATP7A protein in C. elegans, Drosophila and zebrafish (Danio rerio) and then summarise key characteristics of rodent and larger mammalian models of ATP7B-deficiency.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/jnc.14323

Animal models of Wilson disease.

Wilson disease (WD) is a genetic disorder caused by pathological tissue copper accumulation with secondary damage of affected organs (mainly, but not limited to, the liver and brain). The main clinical symptoms of WD are, in concordance with the pathogenesis, hepatic and/or neuropsychiatric. Current treatment options for WD, based on drugs leading to negative copper body balance like chelators or zinc salts, were introduced more than 40 years ago and are generally effective in the majority of WD cases if used lifelong. However, especially in neurological patients, treatment may lead to neurological deterioration, which is often irreversible. Further, almost 50% of neurologically affected WD patients present with persistent neurological deficits despite the use of anti-copper treatment. In addition, up to 30% of patients treated with the widely used drug, d-penicillamine, present with adverse events related to treatment, which often leads to treatment discontinuation. Finally, almost 25% of WD patients do not adhere with anti-copper treatment, partially due to drug-related adverse events and complex treatment regimens (3 times daily, before meals, etc.). These limitations with current treatments have led to the search for other WD treatment possibilities. Currently, research is mainly focused on: (I) new agents with better safety profiles and less neurological deterioration properties compared with traditional chelators, e.g., tetrathiomolybdate salts or central nervous system—penetrable trientine, with the aim to provide more effective copper removal from brain tissue; (II) other non-chelating drugs that lead to removal of copper from cells [e.g., methanobactin (currently in preclinical studies)]; (III) cell and gene therapy. In this article, current research on future treatments for WD is reviewed.

https://atm.amegroups.com/article/viewFile/23192/pdf

Wilson disease-treatment perspectives.

ATP7B gene therapy of autologous reprogrammed hepatocytes alleviates copper accumulation in a mouse model of Wilson’s disease

Wilson’s disease (WD) is an inherited metabolic disease arising from ATPase copper transporting beta gene (ATP7B) mutation. Orthotoropic liver transplantation is the only radical treatment of fulminant WD, although appropriate donors are lacking at the onset of emergency. Given the hepatogenic capacity and tissue-integration/reconstruction ability in the liver of stem cells from human exfoliated deciduous teeth (SHED), SHED have been proposed as a source for curing liver diseases. We hypothesized the therapeutic potential of SHED and SHED-converted hepatocyte-like- cells (SHED-Heps) for fulminant WD. SHED and SHED-Heps were transplanted into WD model Atp7b-mutated Long-Evans Cinnamon (LEC) rats received copper overloading to induce a lethal fulminant liver failure. Due to the superior copper tolerance via ATP7B, SHED-Hep transplantation gave more prolonged life-span of fulminant LEC rats than SHED transplantation. The integrated ATP7B-expressing SHED-Heps showed more therapeutic effects on to restoring the hepatic dysfunction and tissue damages in the recipient liver than the integrated naive SHED without ATP7B expression. Moreover, SHED-Heps could reduce copper-induced oxidative stress via ATP7B- independent stanniocalcin 1 secretion in the fulminant LEC rats, suggesting a possible role for paracrine effect of the integrated SHED-Heps. Taken together, SHED-Heps offer a potential of functional restoring, bridging, and preventive approaches for treating fulminant WD.

/pdf/therapeutic-potential-of-hepatocyte-like-cells-converted-1tlljxa2sm.pdf

Therapeutic potential of hepatocyte-like-cells converted from stem cells from human exfoliated deciduous teeth in fulminant Wilson's disease.

Background 
Recent studies have demonstrated that transplantation of ATP7B-transduced hepatocytes ameliorates disease progression in LEC (Long-Evans Cinnamon) rats, a model of Wilson's disease (WD). However, the inability of transplanted cells to proliferate in a normal liver hampers long-term treatment. In the current study, we investigated whether transplantation of ATP7B-transduced bone marrow mesenchymal stem cells (BM-MSCs) could decrease copper overload in LEC rats.
Materials and Methods 
The livers of LEC rats were preconditioned with radiation (RT) and/or ischemia-reperfusion (IRP) before portal vein infusion of ATP7B-transduced MSCs (MSCsATP7B). The volumes of MSCsATP7B or saline injected as controls were identical. The expression of ATP7B was analyzed by real-time quantitative polymerase chain reaction (RT-PCR) at 4, 12 and 24 weeks post-transplantation. MSCATP7B repopulation, liver copper concentrations, serum ceruloplasmin levels, and alanine transaminase (ALT) and aspartate transaminase (AST) levels were also analyzed at each time-point post-transplantation.
Results 
IRP-plus-RT preconditioning was the most effective strategy for enhancing the engraftment and repopulation of transplanted MSCsATP7B. This strategy resulted in higher ATP7B expression and serum ceruloplasmin, and lower copper concentration in this doubly preconditioned group compared with the saline control group, the IRP group, and the RT group at all three time-points post-transplantation (p<0.05 for all). Moreover, 24 weeks post-transplantation, the levels of ALT and AST in the IRP group, the RT group, and the IRP-plus-RT group were all significantly decreased compared to those of the saline group (p<0.05 compared with the IRP group and RT group, p<0.01 compared with IRP-plus-RT group); ALT and AST levels were significantly lower in the IRP-plus-RT group compared to either the IRP group or the RT group (p<0.01 and p<0.05. respectively).
Conclusions 
These results demonstrate that transplantation of MSCsATP7B into IRP-plus-RT preconditioned LEC rats decreased copper overload and was associated with an increase in MSC engraftment and repopulation.

/pdf/transplantation-of-atp7b-transduced-bone-marrow-mesenchymal-20a5drux0s.pdf

Transplantation of ATP7B-transduced bone marrow mesenchymal stem cells decreases copper overload in rats.

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Transplantation of ATP7B-transduced bone marrow mesenchymal stem cells decreases copper overload in rats.