Comprehensive Pharmacological Management of Wilson’s Disease: Mechanisms, Clinical Strategies, and Emerging Therapeutic Innovations

Abstract

Wilson’s disease is a rare autosomal recessive disorder of copper metabolism characterized by excessive copper accumulation in the liver, brain, and other tissues. This paper provides an overview of the primary pharmacological agents used in its treatment, including penicillamine, trientine, tetrathiomolybdate, and zinc. Their mechanisms of action, therapeutic applications, and side-effect profiles are examined, emphasizing how each agent helps reduce copper overload. Additionally, brief information is given on novel therapies such as gene therapy and artificial intelligence applications. Furthermore, information about the structural and chemical properties of these compounds is provided, highlighting the molecular features that enable them to chelate copper or reduce its intestinal absorption. By integrating pathophysiological insights with chemical and mechanistic perspectives, this paper offers a comprehensive review of existing treatment strategies for Wilson’s disease and stresses the importance of careful, patient-specific management to optimize long-term outcomes.

1. Introduction

Wilson’s disease is a rare autosomal recessive disorder caused by mutations in the ATP7B gene on chromosome 13, leading to defective copper metabolism [1]. Research on Wilson’s disease began in 1912 when Samuel Alexander Kinnier Wilson identified the role of copper overload in neurological conditions in 12 patients, four of whom he examined personally and six of whom were reported in the literature [2].

Normally, copper absorbed in the gastrointestinal tract is transported to the liver, where it is incorporated into ceruloplasmin and then excreted via bile [3]. In Wilson’s disease, this excretory mechanism is compromised, leading to the progressive accumulation of copper in various tissues, particularly the liver and brain. The clinical spectrum of Wilson’s disease is highly variable, and adults typically present with hepatic disease with or without neuropsychiatric symptoms [4,5]. According to the established diagnostic consensus, a serum ceruloplasmin level lower than 200,000 ng/mL is generally accepted as the principal diagnostic threshold in patients with Wilson’s disease [6]. However, up to 20% of children and adults with Wilson’s disease may have normal ceruloplasmin levels, as reported in patients carrying bi-allelic mutations of the ATP7B gene [5]. Therefore, the detection of disease-specific ATP7B mutations may be performed as part of a routine evaluation, particularly in individuals with a known family history of Wilson’s disease [4].

If left untreated, the disease can progress to severe hepatic injury, including cirrhosis and, in some cases, fulminant liver failure [4,5]. Neurologically, Wilson’s disease may present as tremors, impaired coordination, dysarthria, and psychiatric symptoms such as depression and personality changes. Kayser–Fleischer rings (copper deposits at the periphery of the cornea) are a distinctive clinical feature that aids in early diagnosis [5].

Adults typically require about 0.9 milligrams of copper per day, although needs can vary slightly based on factors like age and overall health [7]. The liver plays a central role in copper metabolism by incorporating copper into essential enzymes and then excreting any excess primarily through bile into the digestive tract, where it is ultimately eliminated in the feces (Figure 1). A smaller amount is also excreted in urine. This tight control helps maintain the right balance of copper in the body to support functions such as energy production, connective tissue formation, and antioxidant defense.

Pharmacological interventions for Wilson’s disease focus on removing excess copper from the body and reducing copper absorption from the diet. Key drugs used in treatment over the years have included penicillamine, trientine, tetrathiomolybdate, and zinc salts [5]. These medications vary in their chemical composition and mechanisms of action. Some bind copper to facilitate its elimination through urine, while others stimulate metallothionein production to prevent copper absorption in the intestines. Understanding the unique structural and chemical properties of these drugs is essential for explaining their effectiveness in treating copper overload. For example, penicillamine and trientine form stable complexes with copper to aid in its removal, while zinc promotes metallothionein synthesis to reduce copper absorption [8]. Despite their shared goal of reducing copper toxicity, each drug has its own advantages, drawbacks, and side effects that may make them more or less suitable based on a patient’s individual circumstances, especially when considering neurological symptoms, liver function, and other health conditions [4,5].

In addition to describing core therapies, researchers and clinicians are also exploring potential adjunctive or alternative treatments, such as novel chelators and combination therapies [9,10]. This research aims to further optimize outcomes for patients with severe manifestations or those who do not tolerate first-line agents well. Such investigations are crucial because Wilson’s disease, while rare, can have life-threatening consequences if not identified and managed early. Moreover, experimental findings in stem cell therapy [11,12] and vector-driven gene therapies [13,14,15] hold not only promise to be significant additions in therapy but also in the diagnostics [16] of Wilson’s disease.

Wilson’s disease is relatively rare, with an estimated worldwide prevalence of about 1 in 100,000 to 135 in 100,000 individuals, with a 1 in 90 calculated frequency of carriers, calculated according to the Hardy–Weinberg equilibrium and considering full penetrance [17]. Genetic variants vary among ethnic groups and geographical origins [18,19,20,21]. However, the exact frequency can vary between regions due to genetic factors and differences in population screening. Presently, nearly 4000 genetic variants are known in the ATP7B gene, of which approximately 700 are likely pathogenic [18].

Clinical guidelines emphasize the importance of prompt intervention, along with ongoing monitoring of copper levels, liver enzymes, and neuropsychiatric symptoms to ensure continued disease control and prevent relapse [4,5]. Since Wilson’s disease typically presents in late childhood, adolescence, or early adulthood, maintaining comprehensive oversight throughout a patient’s life is a critical aspect of care [22].

This overview systematically summarizes the major pharmacologic agents used in the treatment of Wilson’s disease. It highlights the key differences in their mechanisms of action, clinical applications, adverse effect profiles, and the importance of careful monitoring in patient management. The structures and chemical characteristics of these compounds are also discussed to illustrate how their inherent properties support their therapeutic effects. By integrating the pathophysiological understanding of Wilson’s disease with a detailed analysis of available pharmacotherapies, this review aims to guide clinicians and researchers towards more effective, patient-tailored approaches to counteract copper overload and safeguard organ function.

2. Overview of Wilson’s Disease Pathophysiology

Copper transport in the human body is a finely tuned process crucial for maintaining copper homeostasis. The ATP7B protein, primarily located in the liver, plays a vital role by facilitating the movement of copper from the cytoplasm into the trans-Golgi network (TGN), where it is incorporated into ceruloplasmin for systemic circulation (Figure 2). Additionally, ATP7B helps excrete excess copper into bile to prevent toxicity.

Wilson’s disease is caused by mutations in the ATP7B gene, which encodes a copper-transporting P-type ATPase primarily found in hepatocytes [23]. The normal function of this enzyme involves incorporating copper into ceruloplasmin and eliminating excess copper through bile by isomerizing between high-affinity (E1) and low-affinity (E2) conformational states [24,25]. However, in individuals with Wilson’s disease, the ATP7B protein is either impaired or absent, leading to a continuous buildup of copper in the liver.

As a result, the liver becomes overwhelmed with copper and begins releasing free copper into the bloodstream. The excess copper accumulates in tissues outside the liver, particularly in the basal ganglia of the brain and the corneas, causing progressive and severe damage to various organs [1].

The toxicity of excess copper is partly due to its role in generating reactive oxygen species (ROS) that can damage cell membranes, mitochondria, and other cellular structures [26]. Excessive copper ions can participate in Fenton redox cycling, continuously cycling from a reduced Cu⁺ state to an oxidized Cu²⁺ state [27], thereby generating ROS such as hydroxyl radicals. These radicals damage proteins, lipids, and DNA, leading to the activation of stress-response signaling pathways. One key pathway involves nuclear factor kappa B (NF-κB), a transcription factor that regulates the expression of pro-inflammatory cytokines and interacts with many other important pathways [28]. Elevated cytokine levels cause an influx of immune cells, exacerbating inflammation and perpetuating tissue damage by triggering apoptosis or necrosis, contributing to progressive organ dysfunction. Moreover, some of these inflammatory cytokines, such as interleukin-1 (IL-1), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6), can further stimulate ROS generation [29]. The stimulation of cytokine expression by ROS and NF-κB, combined with the ability of several cytokines to drive ROS production further, creates a dangerous cycle of escalating inflammation, oxidative stress, and cell death, particularly in the liver.

Hepatocyte injury can lead to elevated transaminases, fibrosis, and, in acute cases, fulminant hepatic failure [1]. Chronic hepatic involvement often results in cirrhosis and complications related to portal hypertension. The release of copper into the systemic circulation accelerates further tissue deposition, especially in the central nervous system. This affects the basal ganglia and can disrupt dopaminergic and other neurotransmitter pathways [30,31,32,33]. Neurological symptoms can vary in severity, including tremors, ataxia, dysarthria, and various psychiatric symptoms like behavioral changes, depression, and psychosis [33].

A distinct sign of copper overload appears in the eyes as Kayser–Fleischer rings, which result from copper deposition in Descemet’s membrane of the cornea and can often be detected in pre-symptomatic cases of Wilson’s disease [34]. These rings are detectable through slit-lamp examination and serve as an important diagnostic indicator, particularly in patients displaying neurological or psychiatric manifestations. While many patients develop symptoms in adolescence or young adulthood, the penetrance and pattern of disease progression vary widely [4,5]. Some individuals present mainly with hepatic dysfunction, such as jaundice, elevated liver enzymes, or acute liver failure, even in the absence of overt neurological involvement, whereas others initially develop psychiatric symptoms (e.g., depression, anxiety, or personality changes) and neurological signs (e.g., tremor, dysarthria, or ataxia) before experiencing significant liver injury [4].

Since Wilson’s disease follows an autosomal recessive inheritance pattern, individuals must inherit two defective copies of the ATP7B gene to manifest clinical symptoms. Carriers with a single mutated allele are typically asymptomatic but can occasionally exhibit subtle biochemical changes, such as borderline reductions in serum ceruloplasmin levels or mildly elevated urinary copper excretion [4,5]. However, Wilson’s disease has a highly variable clinical penetrance and genetic heterogeneity, posing a significant challenge for diagnosis, disease prognosis, and genetic counseling. Even siblings who are homozygote carriers of ATP7B mutations can have a phenotype ranging from asymptomatic without hepatic copper storage to fulminant hepatic failure and cirrhosis [35]. Nevertheless, early identification of pre-symptomatic siblings or relatives through genetic testing and biochemical screening (e.g., serum ceruloplasmin, 24-h urinary copper, and slit-lamp examination by an experienced ophthalmologist) is crucial to initiate prompt chelation therapy if necessary, thereby averting irreversible organ damage [5].

In summary, the main cause of Wilson’s disease is the disruption of the ATP7B-mediated copper export mechanism, leading to excessive copper accumulation primarily in the liver but also in other organs such as the brain, cornea, and kidney. This ultimately causes toxicity and a range of clinical manifestations. Cellular damage, inflammation, and oxidative stress are responsible for the range of symptoms seen in patients, such as liver dysfunction, neuropsychiatric disturbances, and ocular changes. Understanding these underlying mechanisms is crucial for developing successful treatment approaches, whether through copper chelation or inhibiting its absorption in the intestines. It is also important to monitor patients regularly to prevent complications and slow down disease progression throughout their lives.

3. Pharmacological Management

The management of Wilson’s disease often relies on a variety of drugs designed to reduce copper accumulation or mitigate its toxic effects. These therapies typically include chelating agents that bind copper for excretion, medications that block intestinal copper absorption, and supportive treatments targeting inflammation and oxidative stress. In the following sections, an overview of these pharmacological strategies, their underlying mechanisms, efficacy, and potential side effects will be discussed.

3.1. British Anti-Lewisite

British anti-lewisite (BAL), also known as dimercaprol, was discovered by British scientists during World War II as an emergency antidote to the arsenic-based warfare agent lewisite. In 1951, D. Denny-Brown and H. Porter proposed its use for Wilson’s disease [36]. However, severe side effects, such as injection site reactions, elevated blood pressure, neurological aggravation, nausea, vomiting, and a burning sensation in the lips, mouth, and throat [37], limited BAL’s widespread adoption. Although BAL forms stable, water-soluble complexes with heavy metals, including arsenic, gold, lead, and mercury (

Table 1. British anti-lewisite: Chemical properties, mechanism of action and therapeutic uses.

Chemical Name	2,3-Dimercapto-1-propanol (Dimercaprol, Dithioglycerin), commonly referred to as British anti-lewisite (BAL)
CAS No.	59-52-9
Chemical Formula	C3H8O2S2
Structure
Basic Description	A colorless or slightly yellow liquid with two sulfhydryl (–SH) groups, originally developed as an antidote to the chemical warfare agent lewisite.
Mechanism of Action	Forms stable, water-soluble complexes with heavy metals such as arsenic, gold, lead, and mercury. Although not a primary treatment for Wilson’s disease, BAL can chelate copper in acute settings.
Solubility	In water, BAL is slightly soluble and often unstable in aqueous solutions. However, in organic solvents or oils, it is more soluble, and typically formulated in peanut oil for intramuscular injection.
Therapeutic Use in Wilson’s Disease	The primary indication for BAL is an antidote for acute heavy metal poisoning (e.g., arsenic, gold, mercury, lead). In cases of Wilson’s disease, BAL has historically been considered in acute or special scenarios, but is rarely used today due to significant side effects and the availability of better chelators (e.g., penicillamine, trientine). The dosage range for BAL is commonly between 2.5 and 5 mg/kg via intramuscular injection, with frequency guided by clinical protocols and the severity of poisoning.
Adverse Effects and Monitoring	Common side effects include hypertension, tachycardia, gastrointestinal distress, headache, and local injection site reactions. Monitoring of vital signs, complete blood count, and serum metal levels (where applicable) is necessary to prevent under- or overtreatment and detect toxicity.
Other relevant information	The clinical use of BAL has declined in favor of newer agents with fewer adverse effects. Treatment with BAL requires careful medical supervision due to its potential toxicity and the complexity of managing acute heavy metal exposures.

), it is rarely recommended today, given the availability of safer, more effective chelators for both oral and parenteral administration.

3.2. D-Penicillamine

D-Penicillamine, originally discovered in the mid-20th century as a byproduct of penicillin fermentation derived from Penicillium cultures, gained attention for its copper-chelating properties through the work of physician John M. Walshe. In early laboratory experiments, Walshe tested the ability of penicillamine to bind copper in vitro and observed significant increases in urinary copper excretion when given to patients with suspected copper overload. In 1956, Walshe first suggested this drug for therapeutics in Wilson’s disease [38]. This discovery came after initial investigations with other agents, like BAL, which had limited success and notable toxicity concerns. Penicillamine, however, showed a more favorable therapeutic profile, leading to a series of small-scale clinical studies in the late 1950s where patients with Wilson’s disease were treated with penicillamine while closely monitoring their biochemical and clinical responses. The results of these trials indicated substantial improvements in liver function and neurological symptoms, ultimately establishing penicillamine as the first major pharmacological treatment for Wilson’s disease. Over time, as physicians gained experience with dosing and patient monitoring, penicillamine became a standard of care, giving rise to further refinements in copper-chelation strategies and establishing the foundation for subsequent therapies in managing this rare but serious condition. It is important to note that penicillamine also has chelating properties for other metals, making this sulfur-containing amino acid derivative an effective option for treating lead poisoning when other chelating agents are not available (

Table 2. D-Penicillamine: Chemical properties, mechanism of action and therapeutic uses.

Chemical Name	D-Penicillamine (3-Mercapto-D-valine; 3,3-Dimethyl-D-cysteine)
CAS No.	52-67-5
Chemical Formula	C5H11NO2S
Structure
Basic Description	A sulfur-containing amino acid derivative historically related to penicillin, though lacking antibiotic properties.
Mechanism of Action	It primarily functions as a copper-chelating agent, binding free copper ions and promoting their excretion in urine. It also has some chelating activity for other metals (e.g., lead, mercury) and is occasionally used for rheumatoid arthritis.
Solubility	Penicillamine is moderately to freely soluble in water (depending on pH) and sparingly soluble in ethanol. In an aqueous alkaline solution (e.g., 1N sodium hydroxide), it is readily soluble.
Therapeutic Use in Wilson’s Disease	The typical dosage range for adults is 750–1500 mg per day, divided into two or three doses and given orally as capsules or tablets. It should be administered on an empty stomach, at least 1 h before meals and 2 h after meals. Concentration in therapeutic use varies among individuals, but dosing is generally titrated based on clinical response and copper-level monitoring.
Adverse Effects and Monitoring	Common side effects include gastrointestinal discomfort, skin rash, bone marrow suppression (e.g., thrombocytopenia, leukopenia), renal impairment, diarrhea, loss of appetite, and, in rare cases, a lupus-like syndrome. Regular blood counts, liver function tests, and 24-h urinary copper levels are essential for monitoring to balance effective copper chelation with the risk of toxicity.
Other relevant information	Initiation of therapy may temporarily worsen neurologic symptoms in some patients with Wilson’s disease; careful initiation and monitoring are recommended. Patients often require lifelong therapy to maintain adequate copper control and prevent accumulation. Adequate dietary measures (e.g., reduced copper intake) may complement medical treatment. Penicillamine is sold under the trade name Cuprimine and used in the therapy of cystinuria, rheumatoid arthritis, scleroderma, and lead poisoning if no other preferred chelating agents are available. However, it is contraindicated in patients with a previous history of penicillamine-related aplastic anemia, penicillin allergy, or renal insufficiency.

).

3.3. Trientine

Trientine, also known chemically as triethylenetetramine (TETA), emerged in the 1960s as a synthetic copper-chelating agent when researchers, led by Walshe and others, sought reliable alternatives to penicillamine. Initially recognized for its ability to bind metals in industrial processes, trientine garnered attention for possible medical applications, prompting a series of in vitro trials that demonstrated significant copper-chelating properties and a comparatively favorable side effect profile. Early small-scale clinical investigations in twenty individuals conducted by Walshe showed that trientine effectively lowered copper levels in patients with Wilson’s disease, ameliorating hepatic and neurological symptoms in individuals intolerant or unresponsive to penicillamine therapy [39]. Rigorous evaluations of trientine’s pharmacokinetics and dosing regimens cemented its position as a second-line or adjunctive therapy, expanding the therapeutic options for Wilson’s disease and continuing the progress toward safer and more precise copper chelation strategies [40]. Common side effects include gastrointestinal discomfort, iron deficiency anemia (due to chelation of iron), and hypersensitivity reactions (

Table 3. Trientine: Chemical properties, mechanism of action and therapeutic uses.

Chemical Name	Triethylenetetramine dihydrochloride (commonly referred to as Trientine, TETA)
CAS No.	38260-01-4 (Dihydrochloride), 4961-40-4 (Tetrahydrochloride)
Chemical Formula	C6H18N4 × 2HCl (for the dihydrochloride salt)
Structure
Basic Description	A polyamine compound designed to chelate copper ions and aid in their excretion. It shares a similar therapeutic indication to penicillamine but is structurally distinct.
Mechanism of Action	It binds copper ions in the bloodstream and tissues, forming complexes that are excreted via the urine. It is particularly useful for patients with Wilson’s disease who experience intolerance or adverse effects with penicillamine.
Solubility	Trientine is freely soluble in water, while having limited solubility in common organic solvents.
Therapeutic Use in Wilson’s Disease	The typical dosage range is 750–1500 mg per day (divided doses) for adults, though some regimens may go up to 2 g per day depending on clinical requirements. The drug is usually administered in an oral formulation (capsule) for convenience and consistent dosing. The goal is to maintain a therapeutic schedule that effectively lowers copper load while minimizing adverse effects.
Adverse Effects and Monitoring	Common side effects include gastrointestinal discomfort, iron deficiency anemia (due to chelation of iron), and possible hypersensitivity reactions.
	In therapy monitoring, regular measures of 24-h urinary copper excretion and serum free copper are suggested to assess treatment effectiveness, along with periodic blood counts to check for anemia and other cytopenias.
Other relevant information	It is typically regarded as a second-line option for patients who cannot tolerate penicillamine or require alternative chelation therapy. Long-term therapy is often necessary to keep copper levels controlled, with patient compliance and close medical follow-up being paramount. Dietary counseling to limit excessive copper intake (e.g., avoiding copper-rich foods) can further support therapeutic goals. Trientine tetrahydrochloride has been sold under the brand name Cuprior in Europe since 2019 and under the brand name Cuvrior in the US since 2022. Trientine has been found to reduce serum iron levels, and iron supplements may be necessary in case of iron deficiency anemia. The combination of trientine with zinc is not recommended.

).

3.4. Tetrathiomolybdate

Tetrathiomolybdate (TTM), initially studied in the 1970s as a substance to reduce copper levels in livestock feed, quickly gained attention for its potential effectiveness in treating human copper overload disorders. Intravenous administration of ammonium-TTM given in three doses on alternate days was also shown to be an effective means to cure the acute phase of copper toxicity in sheep and reduce the mortality rate in animals that had developed hemolytic crisis [41,42]. Early preclinical experiments showed its strong copper-chelating ability and relatively mild side effect profile, prompting further research into its use in treating Wilson’s disease. Clinical investigations, led by George J. Brewer and others, demonstrated that ammonium-TTM effectively reduced free serum copper levels and alleviated neurological and hepatic symptoms, making it a promising alternative or additional therapy for patients who cannot tolerate or do not respond to standard chelation treatments like penicillamine and trientine [43]. However, although TTM is an excellent Cu-sequestering drug, the therapeutic application of TTM in Wilson’s disease with neurological disorders is limited by the fact that the negatively charged TTM is unable to pass through the blood-brain barrier [44]. Details about the chemical properties and therapeutic uses of this drug are summarized in

Table 4. Tetrathiomolybdate: Chemical properties, mechanism of action and therapeutic uses.

Chemical Name	Tetrathiomolybdate (typically used in the form of ammonium tetrathiomolybdate, TTM)
CAS No.	15060-55-6 (Ammonium tetrathiomolybdate)
Chemical Formula	(NH4)2MoS4
Structure	(Molybdate)
Basic Description	A molybdenum-sulfide compound that forms strong complexes with copper, reducing copper availability in the body.
Mechanism of Action	It binds free copper in the blood and tissues, promoting the formation of excretable complexes and reducing intestinal copper absorption by forming insoluble copper complexes in the gastrointestinal tract.
Solubility	In water, it is soluble, with solubility varying depending on pH and salt form. In organic solvents, it generally has poor solubility.
Therapeutic Use in Wilson’s Disease	The typical dosage is often initiated in research or compassionate-use protocols with regimens varying but ranging from about 60 to 120 mg/day in divided doses, depending on disease severity and patient response. It is particularly considered for patients with neurological involvement or those intolerant to other chelators. Sometimes used in short-term “de-coppering” protocols, long-term approaches exist in specific clinical trial settings.
Adverse Effects and Monitoring	Potential side effects include overcorrection leading to copper deficiency (e.g., anemia, neutropenia), gastrointestinal disturbances, and possible bone marrow suppression. Close monitoring of hematological parameters, serum copper levels, and clinical response is crucial to prevent inadequate or excessive copper depletion.
Other relevant information	Availability varies and can be limited outside of research settings. Continued investigation aims to clarify optimal dosing, duration of therapy, and long-term safety. Patient compliance and a multidisciplinary care plan, including dietary counseling, play critical roles in successful management. TTM for oral application in Wilson’s disease is sold under the brand name Coprexa. Dihydrogentetramolybdate (tiomobibdic acid) is sold under the trade name Decuprate. The bis-choline complexed form of tetramolybdate, also known as WTX-101 or ALXN1840, is an effective drug that targets hepatic intracellular copper and reduces nonceruloplasmin-bound copper by forming tripartite complexes with albumin and increasing biliary copper excretion [45].

.

3.5. Dimcercaptosuccinic Acid

Dimercaptosuccinic acid (DMSA) was synthesized in the mid-20th century as a water-soluble derivative of dimercaprol with the goal of reducing adverse effects associated with BAL. Initially approved for the treatment of heavy metal poisoning, especially lead, mercury, and arsenic poisoning [46,47,48,49], DMSA demonstrated a more favorable risk-benefit profile compared to its parent compound. Subsequent studies investigated its ability to chelate copper in Wilson’s disease, with early trials conducted in China indicating that it can enhance copper excretion and alleviate some clinical symptoms, although direct comparisons with first-line agents are limited [50]. The oral bioavailability and relatively mild side effect profile of DMSA make it a viable option for patients who cannot tolerate penicillamine or trientine, reflecting the broader trend towards personalized and less toxic treatment for copper overload disorders. Additionally, DMSA forms complexes with several other divalent cations, including Cd²⁺, Pb²⁺, Fe²⁺, Hg²⁺, Zn²⁺, and Ni²⁺ (

Table 5. Dimercaptosuccinic acid: Chemical properties, mechanism of action and therapeutic uses.

Chemical Name	2,3-Dimercaptosuccinic acid (Meso-2,3-dimercaptosuccinic acid), commonly referred to as DMSA, sometimes called Dimercaptosuccinate in certain contexts
CAS No.	304-55-2
Chemical Formula	C4H6O4S2
Structure
Basic Description	This water-soluble dithiol-containing chelator with two sulfhydryl (–SH) groups is capable of binding heavy metals such as lead, mercury, and arsenic. Commercially available forms include the disodium salt (more soluble) and the free acid.
Mechanism of Action	It chelates metal ions by forming stable, water-soluble complexes that are primarily excreted via the kidneys. Widely recognized for its use in managing lead poisoning, it also shows efficacy against other heavy metals.
Solubility	The free acid form is sparingly soluble in water, while salt forms (e.g., disodium salt) have better solubility in water, which can be advantageous for oral dosing.
Therapeutic Use in Wilson’s Disease	Its primary indication is the oral treatment of children and adults with elevated blood lead levels (succimer). In addition to Pb2+, it forms complexes with several other divalent cations, including Cd2+, Fe2+, Hg2+, Zn2+, and Ni2+. It also shows chelating activity against mercury and arsenic. While not a standard agent for Wilson’s disease, it is commonly managed with penicillamine, trientine, or zinc. The typical dosage for lead poisoning is 10 mg/kg orally every eight hours for five days, with specific protocols varying by region and clinical practice.
Adverse Effects and Monitoring	Common side effects include gastrointestinal discomfort, mild skin rash, and transient elevated liver enzymes in some cases.Monitoring should include periodic blood counts, renal function tests, and metal levels (e.g., lead) to ensure effective chelation and avoid overcorrection.
Other relevant information	It is safe and effective for outpatient management of moderate lead toxicity, especially in children. It is less lipid-soluble than some older chelators (e.g., Dimercaprol/BAL), resulting in fewer central nervous system side effects. Compliance and adherence to dosing schedules are crucial for successful chelation therapy, often combined with environmental controls (e.g., removing the source of lead). It is absorbed rapidly but incompletely after oral administration. DMSA in plasma is mainly albumin-bound, with only a very small amount present as a free drug.

) [49,51]. DMSA in combination with zinc was shown to significantly improve the neurological symptoms in neurological Wilson’s disease patients who had a history of penicillamine-induced allergy or early neurological deterioration [52].

3.6. Ethylenediaminetetraacetic Acid

Ethylenediaminetetraacetic acid (EDTA) was first synthesized in 1935 by the German chemist Ferdinand Münz [53]. It quickly gained traction for its ability to bind and sequester various metals. Nowadays, EDTA is widely used in formulations such as shampoos and shower gels because it can reduce water hardness [53]. Initially used in industrial processes to soften water and prevent metal corrosion, EDTA soon found therapeutic applications due to its chelating potential. Early investigations explored its effectiveness in treating lead and other heavy metal poisonings, during which researchers noted its ability to disrupt abnormal metal deposits in tissues. While its use in Wilson’s disease has been more limited compared to penicillamine or trientine, sporadic clinical studies have investigated oral and intravenous formulations of EDTA for lowering copper levels in patients. However, concerns about EDTA’s affinity and potential to displace essential trace elements have confined its role primarily to experimental or adjunctive settings, requiring careful monitoring of electrolyte imbalances and renal function during treatment. Nevertheless, EDTA infusions are now being discussed as an effective therapy for the treatment of manganese storage disorders resulting from autosomal recessively inherited mutations in the manganese transporter gene SLC30A10, also known as the “new Wilson’s disease” [54,55]. It is important to note that in the clinical setting, EDTA is administered intravenously or intramuscularly. Due to its potential nephrotoxicity and its capacity to provoke electrolyte disturbances, it is necessary to regularly monitor kidney function, electrolytes, and blood lead levels (

Table 6. Ethylenediaminetetraacetic acid: Chemical properties, mechanism of action and therapeutic uses.

Chemical Name	Ethylenediaminetetraacetic acid (EDTA)
CAS No.	60-00-4
Chemical Formula	C10H16N2O8
Structure
Basic Description	EDTA is a chelating agent with four carboxyl groups and two amine groups, forming stable complexes with many metal ions.
Mechanism of Action	It binds divalent and trivalent metal ions (e.g., Pb2+, Ca2+, Fe3+) to form water-soluble complexes that are excreted, primarily via the kidneys. It is used clinically in the form of calcium disodium EDTA (CaNa2EDTA) when treating certain heavy metal toxicities, such as lead poisoning.
Solubility	In water, EDTA is moderately soluble, and its solubility is enhanced by converting it to a sodium or calcium disodium salt.In other solvents, it is generally sparingly soluble in many organic solvents.
Therapeutic Use in Wilson’s Disease	A common indication for EDTA is the management of lead poisoning, often given alongside dimercaprol in severe cases. It is typically administered intravenously or intramuscularly in a hospital setting. The dosage for lead poisoning in adults is often 1000 mg/m2 per day (or around 30 mg/kg/day) as a continuous intravenous infusion or in divided doses. Exact regimens vary by age, body weight, and clinical protocols.
Adverse Effects and Monitoring	Potential side effects of EDTA include nephrotoxicity (especially at higher doses or prolonged administration), electrolyte disturbances (e.g., hypocalcemia), and local injection site irritation. Monitoring kidney function, electrolytes, and blood lead levels is routinely conducted to assess therapeutic efficacy and minimize the risk of toxicity.
Other relevant information	EDTA is utilized in laboratory settings as an anticoagulant in blood collection tubes and in specific industrial applications due to its potent metal-chelating properties. In medical contexts, it is crucial to differentiate between calcium disodium EDTA (used for lead chelation) and disodium EDTA (which can chelate calcium more aggressively, posing a greater risk of hypocalcemia if used incorrectly). Treatment for heavy metal poisoning is tailored to the particular metal, the clinical status of the patient, and any coexisting medical issues, often necessitating close consultation with toxicology specialists. Intravenous chelation therapy with disodium EDTA reduces the likelihood of adverse cardiovascular outcomes, such as atherosclerosis, by scavenging calcium found in fatty, atherosclerotic deposits [56,57]. EDTA is also known as edetic acid, Titriplex II, Trilon B, Idranal II, Edathamil (EDTA tetrasodium dehydrate), Chelaplex III (EDTA disodium salt), and Versene (EDTA solution in phosphate-buffered saline).

).

3.7. Bis-Choline Tetrathiomolybdate

Bis-choline-TTM is a second-generation derivative of TTM, designed to improve upon the efficacy and tolerability profile of its predecessor [45]. Emerging from efforts to refine copper-chelating treatments for Wilson’s disease, researchers synthesized bis-choline-TTM by combining TTM with choline molecules, aiming to enhance bioavailability and minimize gastrointestinal side effects. The bis-choline moiety is a major advance because it increases stability, forming a tripartite complex consisting of TTM, copper, and albumin [45]. Early laboratory assays affirmed its robust capacity to bind free copper, spurring pilot clinical trials that demonstrated reductions in serum free copper and improvements in hepatic function with a simple once-daily dosing regimen [45]. Interestingly, bis-choline-TTM does not facilitate biliary copper excretion but instead reduces intestinal copper uptake in humans [58]. In contrast to older agents, bis-choline-TTM appears to exhibit a more controlled release mechanism, theoretically reducing the risk of abrupt copper shifts that can precipitate neurological complications. Ongoing investigations strive to pinpoint optimal dosing strategies and evaluate long-term safety, with the goal of integrating this agent into established treatment protocols (

Table 7. Bis-choline tetrathiomolybdate: Chemical properties, mechanism of action and therapeutic uses.

Chemical Name	Bis-choline tetrathiomolybdate (commonly referred to as WTX101). Also known under synonym ATN-224; bis-choline-TTM)
CAS No.	649749-10-0
Chemical Formula	C10H30N2O8
Structure
Basic Description	A new formulation of TTM bound to choline moieties designed to improve oral bioavailability and tolerability compared to previous versions of TTM.
Mechanism of Action	It binds free copper ions in the bloodstream and gastrointestinal tract, forming complexes that reduce copper absorption and facilitate excretion, keeping “free” or nonceruloplasmin-bound copper at safe levels, thus helping prevent the toxic effects of copper overload.
Solubility	Primarily designed for oral administration, this choline-based composition offers sufficient solubility in aqueous environments for gastrointestinal absorption. Specific solubility may vary depending on the formulation and pH.
Therapeutic Use in Wilson’s Disease	This investigation agent is mainly being studied in clinical trials for the treatment of Wilson’s disease. Study protocols have examined different oral doses, typically in the tens of milligrams per day range, which are based on therapeutic response and copper-level monitoring. The drug is used to rapidly reduce and sustain low levels of exchangeable (free) copper without causing copper deficiency.
Adverse Effects and Monitoring	Possible side effects include the risk of inducing copper deficiency (e.g., anemia, leukopenia), gastrointestinal discomfort, and other mild to moderate events depending on the dosage. Close monitoring of free copper, total serum copper, ceruloplasmin, and blood counts is crucial. Patients should be evaluated for any hepatic or hematologic changes.
Other relevant information	Intended to offer a more convenient and potentially safer alternative to other copper-chelating regimens, although long-term effectiveness and safety are still being assessed. It is typically incorporated into a comprehensive management plan for Wilson’s disease, which may involve dietary recommendations to reduce copper intake. Availability may be limited to clinical trials or regulated programs until final regulatory approvals are obtained. Collaboration with toxicology specialists is often necessary.

).

3.8. Zinc

Zinc therapy emerged in the second half of the 20th century as an alternative approach to managing Wilson’s disease by reducing intestinal copper absorption rather than mobilizing tissue-bound copper. Early clinical investigations, notably led by the Dutch investigator Gerrit Schouwink in 1961, showed that zinc effectively blocked copper absorption [59]. Later, the group of George Brewer demonstrated in a rat model that oral zinc salts induce the production of the endogenous copper-binding protein metallothionein within intestinal cells, which sequesters copper in a nontoxic form [60]. This protein effectively sequesters copper in the enterocytes, which are then shed as part of normal mucosal turnover, thus reducing the net copper uptake into the bloodstream. Through careful monitoring of dietary intake and copper balances, zinc therapy became a valuable option for long-term maintenance, especially in asymptomatic patients or those intolerant to chelating agents. Over time, refinements in formulations and dosing regimens contributed to zinc’s acceptance as a well-tolerated, cost-effective solution for certain patient populations. The drug is often formulated in capsules or tablets as hydrated zinc acetate or zinc sulfate. Zinc therapy, employed as an alternative to chelation, works by reducing the levels of circulating nonceruloplasmin-bound copper. It matches the effectiveness of other anticopper agents in reducing hepatic and neurological Wilson’s disease symptoms, and offers a very low toxicity profile with minimal side effects, supported by its long-standing, safe, and cost-effective use [8,61] (

Table 8. Zinc: Chemical properties, mechanism of action and therapeutic uses.

Chemical Name	Zinc is an element, typically administered as zinc acetate or zinc sulfate in clinical settings
CAS No.	Zinc (element): CAS No. 7440-66-6; zinc acetate: CAS No. 557-34-6 (commonly used for Wilson’s disease therapy); zinc sulfate: CAS No. 7733-02-0
Chemical Formula	Zn(CH3COO)2 (often formulated as zinc acetate dihydrate in capsules or tablets)
Structure	Zn2+                     Zn2+                                                                                   Zinc acetate (water free)               Zinc sulfate (water free)
Basic Description	Zinc, when administered as a salt, is an oral supplement used to block the absorption of copper.
Mechanism of Action	Induction of metallothionein: Zinc triggers the production of intestinal metallothionein, which specifically binds to copper, reducing its absorption and promoting its excretion through feces.
Solubility	Zinc acetate dissolves readily in water, with its solubility affected by formulation and pH. Zinc sulfate, also water-soluble, is commonly found in supplement form.
Therapeutic Use in Wilson’s Disease	Typically, a daily dose of 150 mg of elemental zinc is recommended (often taken as 50 mg three times a day), although dosing may vary depending on clinical response and local guidelines. Standard formulations are oral capsules or tablets that should be taken on an empty stomach for optimal effectiveness.
Adverse Effects and Monitoring	Possible side effects of zinc include gastrointestinal discomfort (nausea, stomach irritation), a metallic taste, and occasional headaches.
Other relevant information	Long-term treatment is often continued indefinitely to prevent copper re-accumulation. Zinc acetate is approved for treating Wilson’s disease under the brand names Galzin in the US and Wilzin in Europe.

).

3.9. Summary of Pharmacological Agents

The field of pharmacological therapeutics for Wilson’s disease is constantly evolving. The nine compounds listed here are either currently in use or have been historically used to manage the condition.

Table 9. Summary of major pharmacological treatment for Wilson’s disease.

Compound	Mechanism	Efficacy	Dosing	Side Effects	Monitoring	Clinical Indication
British anti-lewisite (BAL, Dimercaprol)	Chelates arsenic and various heavy metals (including Cu), forming stable complexes.	Historically used for WD, but it is much less effective and not recommended as a routine therapy today.	Typically administered intramuscularly. The exact regimens vary, and BAL is not used for long-term management of WD.	Injection site reactions, elevated blood pressure, possible neurological worsening, GI discomfort.	Blood pressure, neurological status, basic labs; if used, monitor Cu levels to assess response.	Blood pressure, neurological status, basic labs; if used, monitor Cu levels to assess response.
D-Penicillamine	Forms soluble complexes with Cu and aids its excretion in urine.	Widely considered a first-line agent, particularly effective in symptomatic patients with hepatic and/or neurological symptoms.	Commonly 750–1500 mg/day (20 mg/kg/day) in divided doses; dosage can be increased (up to ~2 g/day) in severe cases.	Hypersensitivity reactions, bone marrow suppression, lupus-like syndrome, renal impairment, connective tissue disorders; nausea, hair loss, diarrhea, risk of neurological deterioration upon initiation, and many others.	CBC, renal function, LFTs, 24-h urinary Cu excretion, and clinical status.	Primary therapy for WD, although some patients switch to alternatives (e.g., trientine) due to side effects.
Trientine	Chelates Cu by forming complexes excreted in urine; lacks some reactive sulfur groups found in penicillamine.	Considered equally effective to D-penicillamine for many patients and is often used if there is penicillamine intolerance.	Typically 750–2000 mg/day (20 mg/kg/day) in divided doses. The exact dose depends on the clinical response.	Generally fewer side effects than penicillamine, but can cause iron deficiency anemia, GI irritation, skin rash, arthralgia, or neurological worsening in rare cases.	CBC, iron parameters (ferritin), 24-h urinary Cu excretion, LFTs, clinical status.	CBC, iron parameters (ferritin), 24-h urinary Cu excretion, LFTs, clinical status.
Tetrathiomolybdate (TTM)	Binds Cu in the gut and bloodstream, reducing absorption and free Cu levels.	Especially useful in neurological WD, as it may reduce the risk of initial neurological worsening compared to other chelators.	Approximately 120 mg/day in divided doses with meals (regimens vary in research and clinical practice).	Risk of Cu deficiency (overtreatment), bone marrow suppression (anemia, neutropenia), and potential toxicity if dosed incorrectly.	Serum Cu indices (free Cu and ceruloplasmin), CBC, and clinical signs of Cu deficiency.	Investigational or second-line in some regions; can be first-line for neurological manifestations in specific protocols.
Dimercaptosuccinic Acid (DMSA, Succimer)	A water-soluble chelator that binds various heavy metals (commonly used for lead poisoning); also has Cu-chelating capabilities.	Not a standard first-line agent for WD and is occasionally used off-label or in investigational studies.	Often ~30 mg/kg/day in divided doses for heavy metal poisoning; protocols for WD are not well-established.	GI discomfort, rash, and potential elevation in liver enzymes.	CBC, LFTs, Cu indices, clinical response.	Primarily indicated for lead poisoning; role in WD is limited and not widely adopted.
Ethylenediaminetetraacetic Acid (EDTA)	Chelates multiple metals; extensively used for lead and some other heavy metal toxicities.	Not considered effective enough for routine WD treatment.	Typically administered parenterally (IV); there is no standardized regimen for WD.	Nephrotoxicity, electrolyte imbalances, and hypotension, if infused too rapidly.	Renal function, electrolytes, and vital signs.	Standard therapy for lead poisoning; not recommended for WD.
Bis-choline Tetrathiomolybdate	Similar to TTM; forms complexes with Cu and reduces absorption, lowering free Cu in serum.	Early studies suggest it may reduce the risk of neurological deterioration, potentially being as effective or superior to older chelators.	Trial protocols often use ~120 mg/day in divided doses; exact regimens are still being refined.	Cu deficiency, bone marrow suppression (cytopenias), GI disturbances.	Cu deficiency, bone marrow suppression (cytopenias), GI disturbances.	Investigational or emerging therapy for WD; focus on neurological protection.
Zinc	Induces metallothionein in enterocytes, which binds Cu and prevents its absorption.	Useful as maintenance therapy or in presymptomatic/mild cases; often combined or used after initial chelation in symptomatic patients.	Commonly, 50 mg of elemental zinc taken thrice daily on an empty stomach when body weight is over 50 kg; should be lowered to 25 mg when body weight is under 50 kg.	GI irritation, reduced iron absorption (leading to anemia if unmonitored).	Full clinical assessment, Cu indices (serum Cu/ceruloplasmin), iron status (ferritin), LFTs.	Maintenance or monotherapy in mild or presymptomatic WD, as well as patients intolerant to more potent chelators.

Abbreviations used are: CBC, Complete blood count; Cu, copper; GI, gastrointestinal; LFT(s), liver function test(s) WD, Wilson’s disease.

provides a brief overview of important details for each treatment, including mechanism of action, effectiveness, recommended dosage (if applicable), notable side effects, key monitoring parameters, and typical clinical indications. This information serves as a quick reference, but treatment plans, dosages, and monitoring may vary based on regional guidelines, drug availability, patient condition, and emerging clinical evidence.

3.10. Combination Therapy with Antioxidants and Anti-Inflammatory

Combination therapies in Wilson’s disease can target multiple pathological processes at once, such as copper accumulation, oxidative stress, and chronic inflammation. By co-administering different drugs (e.g., chelators, antioxidants, and anti-inflammatory agents), each agent can often be employed at a lower concentration, potentially reducing side effects. However, it should be critically noted that the combination of some Wilson’s disease drugs, such as penicillamine and zinc, resulted in significantly higher mortality rates, while other chelators combined with zinc treatment were superior to zinc monotherapy [62,63]. Moreover, combination therapies in Wilson’s disease increase the complexity of therapy at the expense of adherence, cost, and parental stress, with the potential to result in poorer chelation than what could be achieved with chelator monotherapy [64]. This suggests that the efficacy of each combination requires careful monitoring.

Nevertheless, building on the proven efficacy of copper chelators, newer treatment approaches for Wilson’s disease increasingly recognize the strong interplay between copper overload, oxidative stress, and inflammation, which has been recognized for many years [65]. As discussed, excess free copper triggers ROS production, leading to direct cellular damage and copper-dependent cell death (cuproptosis), perpetuating an inflammatory response in the liver and other tissues [66]. While conventional chelators help remove copper from circulation, thereby lowering total body copper burden, they do not always address the lingering oxidative injury and immune-mediated processes that can persist even after copper levels begin to normalize.

By integrating antioxidants such as vitamin C, vitamin E, N-acetylcysteine, or α-lipoic acid (Figure 3), alongside standard chelators, these combination treatments aim to neutralize ROS more directly [9]. Antioxidants can stabilize cellular membranes and preserve mitochondrial function, potentially mitigating the progression of liver and neurological damage [67]. Potential beneficial drugs include sulfur-containing antioxidants (glutathione, N-acetyl-L-cysteine, S-Nitroso-N-acetylcysteine, S-allocysteine, S-adenosyl-L-methionine), bucillamine, lipoic acid, taurine, α-tocopherol, ascorbic acid, melatonin, caffeic acid, rosmarinic acid, nicotinic acid, naturally occurring flavones (genistein, luteolin, quercetin, apigenin, naringenin), and many other polyphenolic compounds that have shown general hepatoprotective effects in animal disease models [68]. It was shown that trans-retinoids were effective in rescuing ceruloplasmin secretion, reducing ROS formation, and lipid accumulation in Wilson-specific hepatocytes treated with oleic acid [68].

Anti-inflammatory agents, whether traditional nonsteroidal drugs or newer agents that target specific cytokines, may help to control the immunological cascade that occurs in response to copper-induced tissue injury [67]. The speculative synergy arises from treating the condition along multiple pathophysiological pathways: chelation to reduce copper load, antioxidants to prevent or repair oxidative damage, and anti-inflammatory drugs to downregulate harmful immune activation. Nowadays, there is knowledge of a relationship between copper, inflammation, and immunity that might explain the variability of symptoms, clinical courses, and responses to therapies in Wilson’s disease [69]. Although clinical studies on these newer regimens and combinatorial therapies remain limited, promising preliminary data suggest that carefully calibrated combination therapies hold promise for enhanced efficacy and a broader protective effect compared to chelation alone [9].

Figure 3. Representative antioxidants with potential benefits in treating Wilson’s disease. Depicted here are glutathione, lipoic acid, vitamin C, N-acetylcysteine, caffeic acid, taurine, α-tocopherol, and melatonin. The figure shows each compound’s chemical structure, molecular composition, molecular weight, Chemical Abstracts Service (CAS) registry number, and PubChem Compound ID (CID). All structures were taken from the PubChem Compound Repository [70]. For additional information, refer to the text.

Figure 3. Representative antioxidants with potential benefits in treating Wilson’s disease. Depicted here are glutathione, lipoic acid, vitamin C, N-acetylcysteine, caffeic acid, taurine, α-tocopherol, and melatonin. The figure shows each compound’s chemical structure, molecular composition, molecular weight, Chemical Abstracts Service (CAS) registry number, and PubChem Compound ID (CID). All structures were taken from the PubChem Compound Repository [70]. For additional information, refer to the text.

3.11. Emerging/Adjunct Therapies

Emerging and adjunct therapies for Wilson’s disease focus on improving existing chelation strategies, reducing adverse effects, and exploring new mechanisms of action that target copper homeostasis from multiple angles [9,10]. One such strategy involves combination protocols, where relatively low doses of established chelators (e.g., penicillamine, trientine) are paired with zinc supplementation or newer agents, such as second-generation forms of TTM, to optimize the balance between efficacy and tolerability [8]. However, the safety of these therapies is under critical discussion [62]. Therefore, it is necessary to further clarify the side effects of each regimen used in Wilson’s disease therapy. This is important because there are reports showing that some patients experienced neurological worsening after receiving chelator therapy [71]. Additionally, researchers are exploring the potential of antioxidant and anti-inflammatory compounds to reduce the oxidative damage and tissue inflammation caused by excess copper deposits. Novel formulations, including nanoparticle-based or sustained-release drug delivery systems, aim to minimize systemic toxicity while achieving more precise diagnostics and modulation of copper metabolism [72,73].

Nanoparticles can be engineered to encapsulate copper-chelating agents or other therapeutic compounds [74,75], or to incorporate CRISPR/Cas9 plasmids into hepatic cells [76]. These nanoparticles can then be directed to specific tissues or cells affected by copper accumulation, minimizing off-target effects and improving the bioavailability of the drug. This provides effective medication delivery methods for the future [77]. Furthermore, these formulations can address the limitations associated with conventional therapies, such as a lack of copper selectivity, reduced biocompatibility, and inability to penetrate the blood–brain barrier. For example, a study demonstrated that a colloidal carrier system in which TETA was encapsulated into surface-modified liposomes showed up to a 16-fold higher brain uptake of TETA compared to free TETA [78]. Therefore, such carriers could be extremely beneficial for patients with cerebral symptoms.

Beyond pharmacological interventions, gene therapy has emerged as a promising frontier. It leverages viral or nonviral vectors to deliver functional ATP7B genes into hepatocytes, potentially offering a direct molecular correction of the genetic defect underlying Wilson’s disease [79]. Although still in the early stages of development, initial preclinical data suggest that restoring ATP7B expression can produce measurable gains in controlling copper balance, mitigating tissue damage, and stacking the deck in favor of long-term remission. This approach may also represent a safer alternative to classic gene replacement strategies [79].

Various novel therapeutic agents are being explored (Figure 4). These include DPM-1001 (a highly selective, orally bioavailable copper chelator that also possesses anti-diabetic properties and acts as a noncompetitive protein-tyrosine phosphatase inhibitor) [80], Chel1 (a liver-targeted Cu⁺ chelator) [81,82], 8-hydroxyquinoline (a highly specific copper chelator) [83], methanobactin (a bacterial peptide with high copper affinity) [84], curcumin (an antioxidant that enhances copper transport in liver cells) [85], 4-phenylbutyric acid (a chaperone that boosts the expression of heat-shock proteins and partially promotes the proper folding of ATP7B mutants) [86], oxidative stress-induced peptide 108 (OSIP108, a plant-derived decapeptide with the sequence MLCVLQGLRE that inhibits copper-induced apoptosis) [87], T0901317 (an LXR agonist with anti-inflammatory and anti-fibrotic properties that affects lipid metabolism but does not act as a copper chelator or prevent copper accumulation) [88], and thiol-containing glycocyclopeptide (a highly efficient Cu⁺ chelator) [89]. Many of these and other compounds are currently under investigation and have already been tested for their applicability in suitable in vitro and animal models [82] (Figure 4).

Furthermore, recent findings indicate that the prion protein promotes copper toxicity in cell and animal models of Wilson’s disease, suggesting that strategies aimed at targeting the cellular prion protein may help reduce copper toxicity in Wilson’s disease [90]. Future clinical trials will likely provide more insight into the feasibility, safety, and cost-effectiveness of these advanced strategies. The ultimate goal is to establish therapies that are more tolerable, specific to each patient, and capable of preventing the irreversible complications associated with copper accumulation.

4. Monitoring and Follow-Up

Monitoring and follow-up are essential components of long-term management in Wilson’s disease, ensuring that therapeutic interventions remain effective, tolerable, and that severe complications such as hepatocellular carcinoma are prevented [91]. A comprehensive, multiparameter approach typically includes regular assessments of total serum copper levels, serum ceruloplasmin, and especially serum free (nonceruloplasmin-bound) copper, along with 24-h urinary copper excretion to confirm active copper mobilization and gauge treatment adherence [4,5]. Liver function tests (e.g., bilirubin, aminotransferases, coagulation factors) are performed periodically to detect medication-induced toxicity or progression toward cirrhosis, while neuroimaging (often MRI) and annual or semiannual neurological evaluations help identify treatment-responsive changes or potential deterioration [92]. Hematological parameters, such as complete blood counts, are monitored closely to uncover adverse effects like bone marrow suppression, and renal function tests help detect possible chelator-related impairment [4,5,93]. Patients on zinc therapy require additional surveillance of iron status, given zinc’s interference with iron absorption [94]. Psychological and psychiatric evaluations, along with attention to diet, compliance, and clinical symptoms, are also vital, as neuropsychiatric manifestations can fluctuate and signs of copper deficiency (e.g., anemia, leukopenia, iron deficiency, or peripheral neuropathy) may surface if therapy is overly aggressive [95,96,97]. In recent years, artificial intelligence tools have augmented these diagnostic and monitoring strategies by leveraging pattern recognition to detect subtle shifts in laboratory or imaging findings, potentially refining therapeutic decisions and encouraging customized care [3].

For example, digital pill systems that incorporate ingestible sensors and point-of-care (PoC) testing systems can track real-time medication ingestion data. This data can be analyzed by machine learning algorithms to provide targeted adherence interventions [98]. Smartphone applications and wearable devices also support adherence through automated reminders, chatbots, and patient-specific feedback loops. In terms of disease progression [98], AI-driven predictive models for Wilson’s disease now integrate laboratory metrics, imaging findings, and longitudinal patient data to forecast clinical outcomes, inform dosing adjustments, and alert healthcare providers about potential exacerbations [3]. These tools can significantly optimize treatment plans, reduce adverse events, and guide follow-up strategies. A recent review provides a comprehensive overview of these developments, highlighting both the current landscape and future opportunities for AI-assisted monitoring and predictive modeling in Wilson’s disease [3].

Once patients reach a stable state with controlled copper levels, monitoring intervals may be extended. However, lifelong vigilance remains critical to prevent both recurrent copper overload and inadvertent copper deficiency.

5. Guidelines and Recommendations

5.1. General Guidelines

Guidelines issued by leading hepatology societies, such as the European Association for the Study of the Liver (EASL) and the American Association for the Study of Liver Diseases (AASLD), provide a standardized framework for the diagnosis and management of Wilson’s disease [4,5]. These recommendations emphasize early identification of at-risk individuals through clinical, biochemical (ceruloplasmin levels, 24-h urinary copper excretion), and ophthalmologic assessments (Kayser–Fleischer rings), followed by prompt initiation of therapy [4,5]. First-line treatment typically includes chelating agents like penicillamine or trientine, with zinc therapy often used as an alternative or adjunct based on patient tolerance and clinical presentation. The guidelines stress the importance of regular monitoring, covering liver function, neurological status, and copper metabolism markers, to detect treatment failure or adverse events. Additionally, they highlight the need for lifelong adherence to therapy, underscoring that a personalized approach and close follow-up are crucial for preventing long-term complications in patients with Wilson’s disease [4,5]. Official sources and updated clinical guidelines should be consulted for the most current recommendations on Wilson’s disease management, as ongoing research and new therapeutic developments continually refine diagnostic strategies and treatment protocols to ensure optimal patient outcomes. In this context, nonprofit organizations such as the Wilson Disease Association (WDA), Wilson’s Disease Support Group UK (WDSG-UK), or the German Morbus Wilson e.V., which are dedicated to improving the lives of individuals affected by Wilson’s disease, provide education, raise public awareness, support research, and offer patient and family resources. Their websites regularly feature announcements of new diagnostic tools, treatment innovations, and clinical trials, fostering awareness and promoting advancements in Wilson’s disease management.

5.2. Management Considerations for Pediatric Patients

Wilson’s disease often presents in childhood or adolescence, and managing pediatric patients involves unique considerations compared to adults [99,100]. For example, the dosing of chelators in children is usually based on weight, necessitating careful adjustments to minimize liver and neurological complications. It is essential to closely monitor growth and development because medications like D-penicillamine or trientine can suppress bone marrow, nutritional status, and overall growth [101,102,103,104]. In growing children, maintaining proper copper levels must be balanced with the risk of excessive chelation, which could result in copper deficiency and related issues. Additionally, adherence to treatment may be more challenging in pediatric patients or adolescents, who may require specialized counseling and family support to ensure long-term compliance. This challenge may be particularly pronounced in developing countries [103]. Regular follow-up with a multidisciplinary team, including pediatric hepatologists, dietitians, and mental health professionals, is crucial to safeguard both medical outcomes and psychosocial well-being in pediatric patients.

6. Future Directions

New strategies in the management of Wilson’s disease focus on exploring combinatorial therapies, emerging drugs, and ongoing clinical investigations to improve both efficacy and safety. One notable approach involves combining moderate doses of established chelators (such as D-penicillamine or trientine) with zinc or second-generation TTM formulations. These combinations could potentially reduce side effects while effectively controlling copper levels. Additionally, novel investigative agents like bis-choline-TTM and other synthetic copper-binding molecules are undergoing rigorous evaluation to confirm improved pharmacokinetic profiles and tolerability. Researchers are also conducting trials that integrate antioxidant and neuroprotective agents to address the damage caused by excess copper, especially in nervous system tissues. Beyond pharmacological advances, cell-based and gene-based therapies are gaining attention for correcting the ATP7B mutation, with clinical studies exploring viral and nonviral delivery systems [11,12,13,14,15,16]. In particular, the previous work of my lab has shown that gene therapy is a promising strategy for treating Wilson’s disease by targeting the root cause (lack of functional ATP7B genes) in experimental settings (Figure 5).

Research primarily focuses on delivering functional copies of the gene into hepatocytes using viral or nonviral vectors, allowing the restored ATP7B protein to regulate copper levels. However, hepatic inflammation arising during vector therapy can result in hepatocellular turnover and dilution of the transfected transgenes or proteins [106]. Preclinical studies in animal models have shown promising results, with gene therapy successfully reducing toxic copper accumulation and improving liver function and neurological symptoms [13,14,15]. However, challenges remain, such as ensuring consistent and long-lasting gene expression, minimizing immune responses to vectors, limited amount of genetic information that can be packed into virus vectors, and refining delivery methods for broader patient applicability [106]. Collaborative efforts between industry and academic centers are exploring gene editing tools like CRISPR/Cas9 and innovative delivery mechanisms with the goal of providing durable, potentially curative solutions that reduce reliance on lifelong chelation therapy [12]. These emerging strategies highlight the field’s dedication to developing more precise, individualized tailored treatments for Wilson’s disease, with the ultimate goal of minimizing or eliminating lifelong chelation regimens.

Moreover, artificial intelligence (AI) is emerging as a valuable tool in the management and diagnosis of Wilson’s disease by analyzing large sets of clinical, laboratory, and imaging data with unprecedented speed and accuracy [3]. Machine learning algorithms can detect subtle patterns, such as small fluctuations in serum copper levels, early changes in liver enzymes, or slight alterations in neuroimaging, that may be less apparent to human observers, potentially enabling earlier intervention and more precise prognostic assessments. Advanced AI-driven models can also integrate patient-specific variables, such as genetic background and comorbidities, to guide individualized chelation strategies and monitor for adverse effects or therapeutic failures. In this way, AI and machine learning approaches bolster clinicians’ decision-making, helping to optimize treatment regimens, minimize complications, and tailor follow-up intervals [3,107]. Although the field is still evolving and the availability of large datasets remains a challenge, ongoing research and collaboration between clinical experts, data scientists, and industry partners promise to enhance patient outcomes and broaden AI’s role in Wilson’s disease care.

Though novel treatments for Wilson’s disease show considerable promise, they also bring challenges related to cost, accessibility, and ethics. Advanced chelators, gene therapies, and AI-assisted monitoring tools often require substantial resources, and their high expense may restrict availability in low-resource settings or for underinsured patients. Furthermore, ensuring equal access across diverse regions remains a priority, highlighting the importance of public and private partnerships to improve affordability and distribution. Ethical considerations arise in balancing innovative research with patient safety, the fairness of clinical trial recruitment, and the protection of personal health data. Addressing these issues will be essential for integrating emerging breakthroughs into widely accessible and ethically sound treatment pathways.

7. Conclusions

Wilson’s disease requires a personalized therapeutic approach to reduce copper buildup and prevent organ damage. The main pharmacological treatments include copper chelators (such as penicillamine, trientine, and TTM) to increase copper excretion through urine, and zinc to inhibit copper absorption in the intestines. Each treatment has unique mechanisms of action, benefits, and potential side effects, highlighting the need for comprehensive patient evaluation and customized care. Ongoing research is continually improving current therapies and exploring new ones, as well as developing strategies to restore ATP7B protein expression through genetic approaches, providing optimism for individuals with this rare but treatable condition.