Wilson’s disease: Prospective developments towards new therapies

Abstract

Wilson’s disease (WD) is an autosomal recessive disorder of copper metabolism, caused by mutations in the ATP7B gene. A clear demand for novel WD treatment strategies has emerged. Although therapies using zinc salts and copper chelators can effectively cure WD, these drugs exhibit limitations in a substantial pool of WD patients who develop intolerance and/or severe side effects. Several lines of research have indicated intriguing potential for novel strategies and targets for development of new therapies. Here, we review these new approaches, which comprise correction of ATP7B mutants and discovery of new compounds that circumvent ATP7B-deficiency, as well as cell and gene therapies. We also discuss whether and when these new therapeutic strategies will be translated into clinical use, according to the key requirements for clinical trials that remain to be met. Finally, we discuss the hope for the current rapidly developing research on molecular mechanisms underlying WD pathogenesis and for the related potential therapeutic targets to provide a solid foundation for the next generation of WD therapies that may lead to an effective, tolerable and safe cure.

Recent advances in understanding liver fibrosis: bridging basic science and individualized treatment concepts

“…Elevated iron concentrations are the characteristic result in hereditary hemochromatosis provoked by mutations within the HFE gene or other genes ( SLC40A1 , TFR2 , HAMP , and HJV ) controlling iron homeostasis 7 . Likewise, hepatic damage in Wilson's disease affecting the uptake and clearance of ingested copper is induced by mutations within the ATP7B gene 8 . Genetic disorders associated with functional alterations of ATP-binding cassette (ABC) transporters utilizing the energy of ATP binding and hydrolysis in the participation of hepatobiliary transport of metabolites, phospholipids, and cholesterol and different bile acid translocation of various substrates across cellular membranes can provoke fibrosis when failing to protect the cells from endogenously produced toxic compounds and metabolites.…”

DPM-1001 decreased copper levels and ameliorated deficits in a mouse model of Wilson's disease

“…There are two approaches to reducing copper levels. Zinc salts, such as zinc acetate, are a first line of therapy, particularly for asymptomatic patients, and are also important as a maintenance therapy for long-term management of Wilson's disease after treatment with chelators (Ranucci et al 2017). Zinc decreases absorption of copper from the gut by inducing expression of metallothionein in intestinal cells, which then traps both metals, leading to excretion as the mucosal cells are sloughed off and removed in the feces (Brewer 2001).…”

“…Clearly, new approaches are required to treat Wilson's disease. Strategies involving cell and gene therapy to target nonfunctional mutant forms of ATP7B are being considered (Gupta 2014;Jaber et al 2017;Ranucci et al 2017) and may bear fruit in the longer term. In this study, we took the approach of characterizing copper binding by a small molecule that is distinct from the known chelators; it may offer an improved strategy for decreasing copper levels that is more immediate.…”

Wilson disease in children and adolescents

“…Correction of dysfunctional ATP7B mutant function and/or less toxic suppression of copper import is being explored, following the model of modulators already widely explored in cystic fibrosis 44…”