Bis‐choline Tetrathiomolybdate as Old Drug in a New Design for Wilson’s Disease: Good for Brain and Liver?

Stremmel, Wolfgang

doi:10.1002/hep.30130

Cited by 22 publications

(13 citation statements)

References 3 publications

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“…TTM had the advantages of being fast-acting and did not lead to neurological deterioration in WD patients. It can restore normal copper balance without increasing serum “free copper” within several weeks compared to other copper chelators or zinc salts requiring several months [ 285 ]. However, the ammonium formulation has been proven too unstable for routine use, so clinical experience with them remains limited.…”

Section: Therapeutics To Tackle Copper Ions In Admentioning

confidence: 99%

Copper Toxicity Links to Pathogenesis of Alzheimer’s Disease and Therapeutics Approaches

Ejaz

Wang

Lang

2020

IJMS

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Alzheimer’s disease (AD) is an irreversible, age-related progressive neurological disorder, and the most common type of dementia in aged people. Neuropathological lesions of AD are neurofibrillary tangles (NFTs), and senile plaques comprise the accumulated amyloid-beta (Aβ), loaded with metal ions including Cu, Fe, or Zn. Some reports have identified metal dyshomeostasis as a neurotoxic factor of AD, among which Cu ions seem to be a central cationic metal in the formation of plaque and soluble oligomers, and have an essential role in the AD pathology. Cu-Aβ complex catalyzes the generation of reactive oxygen species (ROS) and results in oxidative damage. Several studies have indicated that oxidative stress plays a crucial role in the pathogenesis of AD. The connection of copper levels in AD is still ambiguous, as some researches indicate a Cu deficiency, while others show its higher content in AD, and therefore there is a need to increase and decrease its levels in animal models, respectively, to study which one is the cause. For more than twenty years, many in vitro studies have been devoted to identifying metals’ roles in Aβ accumulation, oxidative damage, and neurotoxicity. Towards the end, a short review of the modern therapeutic approach in chelation therapy, with the main focus on Cu ions, is discussed. Despite the lack of strong proofs of clinical advantage so far, the conjecture that using a therapeutic metal chelator is an effective strategy for AD remains popular. However, some recent reports of genetic-regulating copper transporters in AD models have shed light on treating this refractory disease. This review aims to succinctly present a better understanding of Cu ions’ current status in several AD features, and some conflicting reports are present herein.

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Section: Therapeutics To Tackle Copper Ions In Admentioning

confidence: 99%

Copper Toxicity Links to Pathogenesis of Alzheimer’s Disease and Therapeutics Approaches

Ejaz

Wang

Lang

2020

IJMS

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“…Liver injury may occur but is dose dependent. Phase III clinical trials are underway to assess efficacy and safety in patients (>18 years) with WD 35–37…”

Section: Neuropsychiatric Manifestationsmentioning

confidence: 99%

Wilson disease in children and adolescents

et al. 2020

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Wilson disease (WD) is a rare, recessively inherited disorder of copper metabolism mainly affecting liver and brain. In childhood, it is known to have a predominant hepatic phenotype. It is likely that the low awareness for WD-associated neuropsychiatric signs and symptoms in this age group means that neurological Wilson’s disease is underdiagnosed in children and young people. Practitioners should be alert for this complication in children with or without liver disease. Management of children with WD requires a dedicated multidisciplinary approach involving hepatologists, geneticists, neurologists and psychiatrists to ensure subtle neuropsychiatric symptoms are identified early and addressed appropriately. This review highlights recent advances in hepatic and neuropsychiatric symptoms of WD in childhood, specific diagnostic tools and pitfalls and summarises existing and potential future treatment options.

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“…In initial clinical trials, bis-choline-tetrathiomolybdate (TTM) is currently evaluated (49). It acts like a copper chelator, operating within the cells by binding copper associated to proteins in stable complexes which are excreted via bile (50,51). It also seems to be taken-up into neurons for recovery from copper induced cell damage by binding of excess protein bound copper.…”

Section: Drug Therapy Of Wilson Diseasementioning

confidence: 99%

“…It also seems to be taken-up into neurons for recovery from copper induced cell damage by binding of excess protein bound copper. In blood it binds albumin-bound copper (50). The consequent disposal remains open.…”

Section: Drug Therapy Of Wilson Diseasementioning

confidence: 99%

Therapeutic strategies in Wilson disease: pathophysiology and mode of action

Stremmel¹,

Weiskirchen²

2021

Ann Transl Med

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Wilson disease is a copper overload disease treatable with the chelators D-penicillamine and trientine to enhance urinary excretion or with zinc which predominantly inhibits absorption. By lifelong treatment a normal life expectancy and significant improvement of hepatic injury as well as neurologic manifestation is achievable. Here we evaluate the mode of action for effective therapy of Wilson disease.We postulate that there is no quantitative removal of copper from the liver possible. The therapeutic goal is the removal of toxic free copper (non-ceruloplasmin, but albumin bound copper). This is achievable by the induction of metallothionein which is accomplished by chelators and in particular by zinc. For control of therapy the option of a direct measurement of free copper would be preferable over the less reliable calculation of this fraction. A therapeutic challenge is still the full restoration of neurological deficits which can hardly be reached by the available chelators. Whether bis-choline-tetrathiomolybdate as intracellular copper chelator is an option has to be awaited. It is concluded that the goal of actual drug therapy in Wilson disease is the normalization of free copper in serum.

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Bis‐choline Tetrathiomolybdate as Old Drug in a New Design for Wilson’s Disease: Good for Brain and Liver?

Cited by 22 publications

References 3 publications

Copper Toxicity Links to Pathogenesis of Alzheimer’s Disease and Therapeutics Approaches

Copper Toxicity Links to Pathogenesis of Alzheimer’s Disease and Therapeutics Approaches

Wilson disease in children and adolescents

Therapeutic strategies in Wilson disease: pathophysiology and mode of action

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