RARE DISEASE
Wilson disease
Wilson disease
Wilson disease
Synonyms: Hepatolenticular degeneration
Synonyms: Hepatolenticular degeneration
Synonyms: Hepatolenticular degeneration
Drug discovery
23
drugs
With orphan designations
Overview
Wilson disease is a rare autosomal recessive disorder caused by ATP7B gene mutations, impairing copper metabolism and leading to toxic copper accumulation in the liver, brain, and other organs. Clinical manifestations range from hepatic dysfunction (hepatitis, cirrhosis) to neuropsychiatric symptoms (tremors, psychiatric disturbances) and Kayser-Fleischer rings. Early diagnosis (via serum ceruloplasmin, urinary copper, genetic testing) and lifelong treatment with chelation therapy or zinc are critical to prevent irreversible organ damage [1][3][5][13].
Population
Prevalence: ~1:30,000–50,000 globally; higher in isolated populations (e.g., 1:15,000 in Crete) [2][6][14].
Age of onset: Typically 5–35 years, but ranges from infancy to late adulthood [2][14][17].
Risk factors: Consanguinity increases prevalence; neurological symptoms more common in males, hepatic presentations in females [2][8][14].
Burden
Clinical impact: Untreated cases progress to liver failure, severe neurological disability, or death [5][9][17].
Quality of life: Neuropsychiatric symptoms and treatment side effects (e.g., penicillamine toxicity) impair daily functioning [4][7][13].
Management challenges: Lifelong adherence to therapy required; multidisciplinary care (hepatology, neurology, psychiatry) essential [7][15][18].
Therapies
Chelation therapy: Penicillamine or trientine (removes excess copper), with zinc (blocks intestinal absorption) for maintenance [3][7][15].
Liver transplant: Curative for acute liver failure or end-stage cirrhosis [9][19].
Emerging therapies: Tetrathiomolybdate and gene therapy under investigation [4][18].
Categories: rare genetic diseases, rare hepatic diseases, rare inborn errors of metabolism, rare neurological diseases, rare ophthalmic disorders, rare renal diseases, rare transplant-related disorders
Research Papers
1,212 drug discovery papers about Wilson disease, with 3 first-in-class and 8 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,212 drug discovery papers about Wilson disease, with 3 first-in-class and 8 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
cell therapies
2026-07-08 | Mechanisms of multi-organ damage in Wilson disease from the gut-liver-brain axis perspective: copper metabolism, gut microbiota, and metabolite communication.
Wilson disease (WD) is an autosomal recessive disorder of copper metabolism caused by ATP7B mutations, leading to pathological copper deposition in the liver, brain, and cornea. Although the gut-liver-brain axis plays a role, direct copper accumulation in multiple organs remains the primary cause of tissue damage. Recent years have seen growing attention to the gut microbiota in WD pathogenesis. Copper imbalance remodels gut microbiota composition and function, while dysbiosis, in turn, affects copper absorption and excretion, forming a vicious cycle that exacerbates multi-organ damage. Copper-induced intestinal barrier disruption, lipopolysaccharide translocation, and systemic inflammation are key links connecting local copper accumulation to systemic injury. This review summarizes the genetic basis of WD, mechanisms of copper toxicity, gut microbiota alterations, and their roles in liver injury and neurodegeneration. It highlights microbiota-derived metabolites-short-chain fatty acids, tryptophan metabolites, bile acids, sulfur-containing amino acids, and branched-chain amino acids-in inter-organ communication. The bidirectional interaction between WD therapies (chelators, zinc salts, dietary interventions) and the gut microbiota is analyzed, along with microbiota-based personalized therapies. However, most current evidence derives from animal models or small cross-sectional studies; large-scale longitudinal human data are critically lacking. A deeper understanding of the gut-liver-brain axis in WD may reveal novel biomarkers and therapeutic targets.
2026-07-01 | Cognitive function and quality of life in Wilson disease: Implications for the timing of liver transplantation
Background Wilson's disease (WD) is a rare inherited disorder of copper metabolism that may lead to hepatic and neuropsychiatric impairment. The role of liver transplantation (LT) in improving cognitive outcomes and quality of life (QoL) in WD remains uncertain. Methods This single-center cross-sectional study compared cognitive function and QoL among 54 participants: 23 healthy controls, 16 post-LT WD, and 15 non-LT WD patients. Cognitive performance was assessed using the smartphone-based Stroop test (EncephalApp), while QoL was evaluated using a validated 20-item RAND survey. Rank-based ANCOVA adjusted for gender was applied for statistical analysis. Results Healthy controls demonstrated the fastest Stroop performance, followed by LT and non-LT WD groups. Although post-LT patients demonstrated numerically better cognitive outcomes than non-LT patients, the differences were not statistically significant (p > 0.05). However, LT patients reported significantly higher QoL in self-perceived health and perceived health parity with others (p = 0.017 and p = 0.014, respectively). Conclusion Post-LT WD patients exhibited a trend toward superior cognitive performance and significantly improved QoL compared to non-LT patients. These findings suggest that LT may confer neurocognitive and psychosocial benefits beyond hepatic recovery, underscoring the importance of timely transplantation and further multicenter studies to validate these outcomes
2026-05-30 | [Recent Advances in the Diagnosis and Management of Wilson's Disease].
This review summarizes recent developments in the genetics of Wilson's disease, highlights major diagnostic innovations, discusses novel aspects of therapeutic strategies, and outlines advances in treatment monitoring that are of particular relevance for clinical practice. Recent genetic population studies based on carrier frequencies of ATP7B mutations suggest that the prevalence of Wilson's disease is higher than estimates derived from clinical patient registries. Current evidence indicates that some ATP7B mutations are associated with milder disease phenotypes and reduced penetrance, supporting the concept of genotype-phenotype associations. A major advance in the diagnosis of Wilson's disease is the introduction of Relative Exchangeable Copper (REC). An additional diagnostic improvement is metallothionein immunohistochemistry in liver biopsy specimens. In cases of Wilson's disease-related acute liver failure, immediate listing for liver transplantation is generally recommended. Based on recent studies, bridging plasma exchange therapy should be considered in all patients and particularly in patients without advanced hepatic encephalopathy, and in selected cases with early treatment and mild encephalopathy transplantation may be avoided.
2026-03-01 | Immunomodulation by systemic administration of exosomes derived from induced pluripotent stem cell mesenchymal stem cells to alleviate liver inflammation and fibrosis in Wilson's disease.
Exosomes derived from mesenchymal stem cells (MSCs) are proposed to have anti-inflammatory and immunomodulatory effects. We sought to determine the therapeutic effects of human induced pluripotent stem cell-MSC derived exosomes (iPSC-MSC-Ex) on liver inflammation and fibrosis in Wilson's disease (WD). Exosomes derived from MSCs differentiated from iPSCs were administered intravenously into an ATPase Copper Transporting Beta (ATP7B) knockout mouse in-vivo model of WD. Hepatic function was then evaluated. iPSC-MSC-Ex treated mice showed attenuated liver injury, evidenced by enhanced liver functionality, decreased collagen accumulation, and reduced inflammation. Our results also revealed that treatment with iPSC-MSC-Ex regulated the immune response with reduced splenic inflammatory monocytes and NK cells and increased splenic Treg cells. Altered macrophage polarization was observed in mice that received iPSC-MSC-derived exosomes, accompanied by down-regulation of hepatic proinflammatory cytokines and up-regulation of hepatic anti-inflammatory cytokines. Our findings demonstrated that iPSC-MSC-derived exosomes could ameliorate hepatic fibrosis in a mouse model of WD via immunomodulation and macrophage polarization. These results support the development of iPSC-MSC-derived exosomes as a cell-free therapy for WD as well as other chronic liver diseases.
2025-12-31 | Study on the effect of mesenchymal stem cells on neural injury, inflammation and copper content in Wilson disease.
To investigate the effects of bone marrow mesenchymal stem cells (BMSCs) on extrapyramidal neural network of Wilson disease (WD). 27 6-month-old toxic milk mice (TX mice, WD animal model) and 15 C57 mice were selected. Corrected phase (CP) value on susceptibility weighted imaging (SWI), fractional anisotropy (FA) on diffusion tensor imaging (DTI) were performed. The volume of fiber connections was determined. BMSCs was transplanted though tail vein injection (1 × 106, 0.5 mL). The myelin basic protein (MBP), amyloid precursor protein (β-APP), nitric oxide (NO), glutathione (GSH) and interleukin (IL-1β) were determined at 1, 2, 4 and 8 weeks after transplantation. The CP value of TX mice increased at 4 (p = 0.029) and 8 weeks (p = 0.037) after transplantation. FA values (p = 0.026, 0.020, 0.037) and the volume of neural fibers (p = 0.016, 0.023, 0.018) increased at 2, 4 and 8 weeks after transplantation. The pathological indexes of demyelination (MBP) and axon injury (β-APP) improved after BMSCs transplantation. The brain copper content decreased at 4 and 8 weeks after transplantation (p = 0.024, 0.038). The indexes of oxidative stress (NO and GSH) and inflammation (IL-1β) of TX mice were improved after transplantation. BMSCs can ameliorate WD extrapyramidal neural network injury. The mechanism may be related to reducing copper deposition and alleviating oxidative stress and inflammatory response.
small molecules
2026-08-17 | A Dual-Function Guanidinium Scaffold for Copper sequestration and Redox Protection in Wilson disease Models.
Wilson disease (WD) is caused due to mutations in the copper ATPase gene ATP7B, resulting in accumulation of copper and the consequent disruption of cellular redox balance through reactive oxygen species generation. Current therapies mainly depend on copper chelation to lower metal burden which sometimes also strip copper from cuproproteins and disturb key physiological copper-dependent processes. It also does not directly suppress pathological copper reactivity i.e., free radical generation, a major driver of WD progression. To overcome these limitations, we have rationally designed Gua-Cu-3, a C3-symmetric guanidinium-based non-toxic molecule that can chelate labile copper without metal stripping from cuproproteins due to moderate binding affinity and it has intrinsic antioxidant activity within a single nanosheet-forming supramolecular self-assembly. Spectroscopic, calorimetric, and computational analyses revealed multivalent copper coordination (Kd = 95.4μM) while radical-scavenging and hydroxyl-radical inhibition assays revealed redox-regulatory activity. In copper loaded hepatocytes, Gua-Cu-3 reduces ATP7B trafficking from trans-Golgi network, confirming effective intracellular copper sequestration. This was accompanied by a marked reduction in oxidative stress readouts, i.e., translocation of Nrf2 in nucleus and of HO-1 expression, thereby limiting lipid peroxidation and restoration of ER and mitochondrial health. Gua-Cu-3 attenuates oxidative stress in ATP7B-homolog-deficient Caenorhabditis elegans and rescues copper-induced developmental defects in zebrafish, outperforming D-penicillamine, which is currently in use for WD management. These findings establish Gua-Cu-3 with a therapeutic potential that couples-controlled copper sequestration with redox regulation and provides a framework for treating WD and other disorders associated with metal dyshomeostasis and oxidative stress.
2026-08-09 | Copper homeostasis and cuproptosis: New perspectives on the diagnosis and treatment of metabolic diseases.
Cuproptosis is a recently identified form of regulated cell death driven by the direct binding of Cu⁺ to the lipoyl moiety of mitochondrial tricarboxylic acid (TCA) cycle enzymes, leading to dihydrolipoamide S-acetyltransferase (DLAT) oligomerisation, iron-sulfur cluster (Fe-S) protein depletion, and proteotoxic stress, and is uniquely dependent on mitochondrial respiration. This review critically synthesises current evidence on the role of cuproptosis in type 2 diabetes mellitus (T2DM), metabolic dysfunction-associated steatotic liver disease (MASLD), and obesity. In T2DM, three causally validated pathways of copper transporter dysregulation converge on ferredoxin 1 (FDX1)-dependent DLAT oligomerisation, with substantial FDX1 reduction in diabetic skeletal muscle providing quantitative evidence of cuproptotic commitment; however, β-cell-specific knockout studies remain critically absent. In MASLD, indirect reactive oxygen species (ROS)-mediated insulin resistance is favoured over direct copper-receptor interactions. We propose the metabolic threshold hypothesis, positing that cuproptosis represents failed adaptation to chronic lipid overload, triggered when copper influx exceeds the combined buffering capacity of ATPase copper transporting beta (ATP7B)-mediated efflux, metallothionein sequestration, and glutathione (GSH) chelation. The serum Cu/Zn ratio cannot distinguish cuproptosis from ferroptosis; precise identification requires combined detection of FDX1, DLAT, lipoic acid synthase (LIAS), and lipoyltransferase 1 (LIPT1) with mitochondrial copper content, with immunohistochemistry (IHC) for DLAT oligomerisation as the most clinically accessible surrogate marker. Copper chelators including tetrathiomolybdate and merestinib are primary agents for metabolic tissue preservation, whereas ionophores such as elesclomol are restricted to oncology, with lipid nanoparticle-based delivery platforms essential to overcome the blood-brain barrier challenge, as underscored by the neurological worsening documented in D-penicillamine-treated Wilson disease patients. The interplay between cuproptosis and ferroptosis, sharing GSH depletion but diverging at lipoylated protein aggregation versus glutathione peroxidase 4 (GPX4)-dependent lipid peroxidation, suggests dual-pathway inhibition may be necessary. Future priorities include validation of the metabolic threshold hypothesis, β-cell-specific knockout studies, standardised DLAT oligomerisation diagnostics, tissue-targeted copper modulator delivery, and integration of cuproptosis biomarkers with multi-omics and artificial intelligence for clinically stratified precision medicine.
2026-07-14 | Prognosis of pediatric hepatic Wilson disease with ATP7B loss of function variants.
Genotype-phenotype correlations in Wilson disease (WD) have so far been inconclusive. ATP7B variants with loss of function (LOF) may have a different trajectory. Since genotypes in Asia differ from the West, we aimed to correlate LOF variants of ATP7B with the severity and outcome of hepatic WD. Patients with a confirmed diagnosis of WD (Leipzig criteria ≥4) were prospectively enrolled. Genetic sequencing of ATP7Bmutations was assessed by Whole-exome sequencing. For patients with variants of uncertain significance, Sanger sequencing was additionally performed on their parents to identify the inherited variants. In silico analyses were used to predict the pathogenicity of variants. Mutations that resulted in at least one truncation (nonsense, frameshift, splice site, deletions) and nontruncation (missense, synonymous) protein were defined as LOF and no LOF (NLF) respectively. Phenotypes, biochemical parameters, and outcomes were analyzed. One hundred sixteen hepatic WD children (84 boys, median age at diagnosis 8.9±3.3 years) with biallelic ATP7B mutations (62 different variants) were enrolled. The most common LOF (n=79) and NLF (n=37) variants were c.813C>A and c.3809A>G. Advanced liver disease (76% vs. 4%, P=0.004), portal hypertension (44% vs. 24%, P=0.03), neurological (39% vs. 16%, P=0.01) and renal involvement (44% vs. 13%, P=0.01) were significantly higher in LOF than in NLF. c.813C>A had higher serum exchangeable copper (6.8±4.4 μmol/L vs. 1.4±3.5 μmol/L, P=0.04) and lower disappearance of the Kayser-Fleischer ring (4% vs. 49%, P= 0.01) than c.3809A>G variants. Over a follow-up of 6.1±4.7 years, a single LOF variant did not show a poorer liver or overall outcomes in comparison to ≥2 LOF variants. A single ATP7B LOF variant, especially c.813C>A was associated with advanced liver disease, portal hypertension, and extrahepatic involvement. LOF variants did not affect liver or overall outcomes.
2026-07-08 | A 31-Year-Old Woman With Liver Cirrhosis Due to Wilson Disease and the Double Impact of Active Tuberculosis and Anti-Tuberculosis Therapy Resulting in Acute Liver Injury.
BACKGROUND In some patients with Wilson disease, there can be a combined impact of active tuberculosis (TB) and anti-tuberculosis therapy (ATT), a "double hit", due to drug-induced liver injury that can accelerate Wilson cirrhosis and result in acute liver failure. This report presents the case of a 31-year-old woman with liver cirrhosis due to Wilson disease and the combined impact of active TB and ATT resulting in acute liver injury. CASE REPORT A 31-year-old woman with genetically confirmed Wilson disease and Child-Pugh B liver cirrhosis presented in July 2025 with acute hepatic decompensation. Investigation revealed a positive QuantiFERON-TB Gold test result, lymphocytic exudative ascites, and a clinical picture consistent with extrapulmonary TB. Empiric ATT was initiated with rifampicin and isoniazid. Within 2 months, she re-presented with severe anti-TB drug-induced liver injury, which manifested as acute-on-chronic liver failure. The hepatotoxic regimen was immediately discontinued, and intensive supportive care was administered, resulting in gradual stabilization of liver function and clinical improvement. CONCLUSIONS This case demonstrates the critical "double-hit" vulnerability in Wilson disease, in which copper-mediated glutathione depletion leaves the liver unable to detoxify standard anti-TB drugs. Clinicians managing TB in patients with decompensated Wilson cirrhosis should avoid standard rifampicin-isoniazid regimens and use hepatosafe alternatives instead. A high index of suspicion for TB is warranted in all cirrhotic patients with fever, lymphocytic exudative ascites, and unexplained decompensation.
2026-07-02 | The gut-liver-kidney-brain axis in Wilson disease: copper speciation-flux and barrier-mediated organ crosstalk.
Wilson disease (WD) has long been framed as a hepatocentric disorder of copper accumulation. That view is now giving way to a broader model centered on the gut-liver-kidney-brain axis. In WD, copper is not simply stored in tissues as an inert burden. It circulates in dynamic, bioactive pools-particularly relative exchangeable copper (REC)-that disrupt barrier structures, including the intestinal epithelium and blood-brain barrier, and spread toxicity through measurable biochemical mediators. Major pathogenic processes include copper-induced suppression of autophagy, disruption of FXR-regulated bile acid signaling, and direct injury to the intestinal barrier. Gut dysbiosis, supported by fecal microbiota transplantation (FMT) studies in ATP7B-deficient mice, further amplifies hepatic inflammation and favors copper retention. Renal tubular dysfunction and neurotoxicity appear to reflect copper species-dependent passage across biological barriers together with secondary metabolic disturbances, including the recently described pathway of cuproptosis. In the clinic, this shift has been accompanied by greater use of copper-species biomarkers such as ceruloplasmin oxidase activity and REC, along with advanced imaging approaches such as 64Cu-PET/CT. Treatment is also moving beyond conventional chelation alone, with increasing attention to biliary copper excretion, epithelial barrier repair, and microbiome-directed interventions. Viewed in this way, the axis model helps explain the marked phenotypic heterogeneity of WD and offers a mechanistic basis for more precise interventions aimed at breaking pathogenic feedback loops across organs.
proteins
2026-06-11 | Wilson disease in children: Recent update on pathophysiology and management
Wilson's disease (WD) is an autosomal recessive disease caused by mutations in the ATP7B gene, which plays a fundamental role in copper metabolism, leading to the accumulation of copper in the liver and other vital organs.Major functions of ATP7B are the incorporation of copper into apoceruloplasmin and the excretion of copper into bile.From simple asymptomatic elevation of liver enzymes to acute liver failure, as well as chronic hepatitis, portal hypertension may be the initial presentation of this disease.Approximately 800 different mutations of the ATP7B gene have been recognized.WD has wide phenotypic disease expressions.Genotypic expression does not always correlate with phenotypic disease expression or disease severity.Environmental and epigenetic factors may play a role in disease expression.No single test is diagnostic for WD.Initial testing includes ocular slit-lamp examination, 24-hour urinary copper excretion, and serum ceruloplasmin.The Leipzig scoring system for diagnosis is widely used.Relative exchangeable copper is the new noninvasive biomarker for WD.It gives a quick result before awaiting genetic testing.Timely diagnosis of WD is important, as it can halt the clinical progression of the liver and neurological disease.D-penicillamine and trientine remain the main chelators for WD treatment.Patients need lifelong chelation therapy until liver transplantation.Research on new treatment modalities, such as methanobactin, is ongoing for further human use.This review discusses the genetic aspects of WD, copper metabolism, a new diagnostic method, and a research molecule for future management of WD.
2023-09-01 | A co-opted endogenous retroviral envelope promotes cell survival by controlling CTR1-mediated copper transport and homeostasis
Copper is a critical element for eukaryotic life involved in numerous cellular functions, including redox balance, but is toxic in excess. Therefore, tight regulation of copper acquisition and homeostasis is essential for cell physiology and survival. Here, we identify a different regulatory mechanism for cellular copper homeostasis that requires the presence of an endogenous retroviral envelope glycoprotein called Refrex1. We show that cells respond to elevated extracellular copper by increasing the expression of Refrex1, which regulates copper acquisition through interaction with the main copper transporter CTR1. Downmodulation of Refrex1 results in intracellular copper accumulation leading to reactive oxygen species (ROS) production and subsequent apoptosis, which is prevented by copper chelator treatment. Our results show that Refrex1 has been co-opted for its ability to regulate copper entry through CTR1 in order to limit copper excess, redox imbalance, and ensuing cell death, strongly suggesting that other endogenous retroviruses may have similar metabolic functions among vertebrates.
2022-10-27 | ATP7B-Deficient Hepatocytes Reveal the Importance of Protein Misfolding Induced at Low Copper Concentration
Copper is a transition metal essential for human life. Its homeostasis is regulated in the liver, which delivers copper to the whole body and excretes its excess outside the organism in the feces through the bile. These functions are regulated within hepatocytes, and the ATP7B copper transporter is central to making the switch between copper use and excretion. In Wilson disease, the gene coding for ATP7B is mutated, leading to copper overload, firstly, in the liver and the brain. To better understand the role of ATP7B in hepatocytes and to provide a smart tool for the development of novel therapies against Wilson disease, we used the CrispR/Cas9 tool to generate hepatocyte cell lines with the abolished expression of ATP7B. These cell lines revealed that ATP7B plays a major role at low copper concentrations starting in the micromolar range. Moreover, metal stress markers are induced at lower copper concentrations compared to parental cells, while redox stress remains not activated. As shown recently, the main drawback induced by copper exposure is protein unfolding that is drastically exacerbated in ATP7B-deficient cells. Our data enabled us to propose that the zinc finger domain of DNAJ-A1 would serve as a sensor of Cu stress. Therefore, these Wilson-like hepatocytes are of high interest to explore in more detail the role of ATP7B.
2022-05-10 | Suppression of ATG4B by copper inhibits autophagy and involves in Mallory body formation.
Autophagy is an evolutionarily conserved self-protecting mechanism implicated in cellular homeostasis. ATG4B plays a vital role in autophagy process via undertaking priming and delipidation of LC3. Chemical inhibitors and regulative modifications such as oxidation of ATG4B have been demonstrated to modulate autophagy function. Whether and how ATG4B could be regulated by metal ions is largely unknown. Copper is an essential trace metal served as static co-factors in redox reactions in physiology process. Excessive accumulation of copper in ATP7B mutant cells leads to pathology progression such as insoluble Mallory body (MB) in Wilson disease (WD). The clearance of MB via autophagy pathway was thought as a promising strategy for WD. Here, we discovered that copper ion instead of other ions could inhibit the activity of ATG4B followed by autophagy suppression. In addition, copper could induce ATG4B oligomers depending on cysteine oxidation which could be abolished in reduced condition. Copper also promotes the formation of insoluble ATG4B aggregates, as well as p62-and ubiquitin-positive aggregates, which is consistent with the components of MB caused by copper overload in WD cell model. Importantly, overexpression of ATG4B could partially reduce the formation of MB and rescue impaired autophagy. Taken together, our results uncovered for the first time a new damage mechanism mediated by copper and implied new insights of the crosstalk between the toxicity of copper and autophagy in the pathogenesis of WD.
2018-08-16 | A Luminal Loop of Wilson Disease Protein Binds Copper and Is Required for Protein Activity
The copper-transporting ATPase ATP7B is essential for loading of copper ions to copper-dependent enzymes in the secretory pathway; its inactivation results in Wilson disease. In contrast to copper-ion uptake by the cytoplasmic domains, ATP7B-mediated copper-ion release in the Golgi has not been explored yet. We demonstrate here that a luminal loop in ATP7B, rich in histidine/methionine residues, binds reduced copper (Cu(I)) ions, and identified copper-binding residues play an essential role in ATP7B-mediated metal ion release. NMR experiments on short-peptide models demonstrate that three methionine and two histidine residues are specifically involved in Cu(I) ion binding; with these residues replaced by alanines, no Cu(I) ion interaction is detected. Although more than one Cu(I) ion can interact with the wild-type peptide, removing either all histidine or all methionine residues reduces the stoichiometry to one Cu(I) ion binding per peptide. Using a yeast complementation assay, we show that for efficient copper transport by full-length ATP7B, the complete set of histidine and methionine residues in the lumen loop are required. The replacement of histidine/methionine residues by alanines does not perturb overall ATP7B structure, as the localization of ATP7B variants in yeast cells matches that of the wild-type protein. Thus, in similarity to ATP7A, ATP7B also appears to have a luminal "exit" copper ion site.
gene therapies
2026-08-15 | Recent advances in research on high-frequency mutations in the ATP7B gene associated with Wilson disease in the Chinese population: from genetic evolution to precision medicine.
Wilson disease (WD) is a hereditary disorder of copper metabolism caused by mutations in the ATP7B gene; the Chinese population exhibits a unique, high-frequency mutation profile centered on the R778L and P992L mutations. This article provides a narrative review of the genetic evolution, molecular pathogenic mechanisms, phenotypic heterogeneity, and precision diagnosis and treatment strategies for high-frequency ATP7B mutations in the Chinese WD population. The high-frequency enrichment of R778L and P992L is speculated to arise from the combined effects of CpG mutation hotspots and the founder effect supported by East Asian haplotype data, with distinct geographical distributions and relatively conserved haplotypes observed in existing cohorts. Functional studies indicate that the R778L variant disrupts the transmembrane domain and induces severe protein misfolding associated with an early-onset hepatic phenotype, whereas the P992L mutation partially retains catalytic function and tends to present neurological manifestations in many clinical cohorts, though individual phenotypic variation remains substantial. Preclinical molecular chaperone and gene editing strategies offer potential mechanistic targets for mutation-specific intervention, yet their clinical translation remains at an immature stage with insufficient human trial data. In the future, it will be necessary to establish multicenter cohorts, advance mutation-targeted therapies, and develop a precision diagnosis and treatment system covering the entire disease lifecycle.
2026-08-14 | Liver Organoids: From Disease Modelling to Regenerative Medicine.
Liver organoids are three-dimensional miniature liver models that recapitulate the complex architecture and key functions of the human liver in vitro, offering powerful platforms for both fundamental research and translational applications. This review systematically summarises current fabrication strategies, disease-modelling utilities and regenerative potentials of liver organoids, alongside the major challenges and future directions. In recent years, the field has witnessed several breakthroughs. Through endothelial co-culture approaches, vascularised and metabolically zonated liver organoids have been successfully generated, achieving endothelial coverage exceeding 85%. Prime editing enables precise correction of pathogenic mutations in patient-derived organoids, with no off-target effects detected at the genome-wide level. In disease modelling, iPSC-derived liver organoids faithfully recapitulate the pathological progression of metabolic dysfunction-associated steatotic liver disease (MASLD) and verify the lipid-lowering efficacy of semaglutide. Macrophage-integrated organoid models support the full life cycles of HEV, SARS-CoV-2 and dengue virus, providing new tools for antiviral drug screening. Large-scale patient-derived tumour organoid biobanks successfully preserve the heterogeneity and clinical drug-resistance signatures of liver cancers. In regenerative medicine, encapsulated hepatocyte organoids and the UTOpiA bioartificial liver system have effectively rescued acute liver failure in animal models, while gene-edited autologous organoids offer potential curative strategies for genetic disorders such as Wilson disease. Nevertheless, insufficient hepatocyte functional maturity, difficulties in constructing vascular networks, and the lack of standardised culture protocols remain major obstacles to clinical translation. By bridging fundamental liver biology and clinical practice, liver organoid technology lays a solid foundation for precision hepatology and regenerative therapies. Continued interdisciplinary efforts are still required to overcome current limitations and facilitate its clinical adoption.
2026-07-29 | From one-size-fits-all to on-demand: personalized crispr gene editing for rare genetic liver diseases.
Rare genetic liver diseases collectively affect millions of individuals worldwide and encompass a heterogeneous group of monogenic disorders including Wilson disease, alpha-1 antitrypsin deficiency, glycogen storage diseases, urea cycle disorders, progressive familial intrahepatic cholestasis, and acute hepatic porphyrias. While conventional management relies on dietary modification, pharmacotherapy, and ultimately liver transplantation, the advent of clustered regularly interspaced short palindromic repeats (CRISPR)-based gene editing has opened transformative therapeutic avenues. This review provides a comprehensive and critical appraisal of the current landscape of CRISPR-based therapies for genetic liver diseases, from preclinical proof-of-concept studies to landmark clinical trials. We examine the evolution from conventional Cas9 nuclease-mediated editing to precision tools including base editors and prime editors, which enable single-nucleotide corrections without inducing double-strand DNA breaks. The role of lipid nanoparticle delivery systems in achieving efficient hepatocyte-targeted delivery is discussed, alongside emerging challenges in pediatric dosing and immunogenicity. We highlight the paradigm shift toward personalized, patient-specific CRISPR therapies, exemplified by the first-in-human bespoke gene editing treatment delivered in 2025. Competing nucleic acid technologies, including RNA interference and antisense oligonucleotides, are compared in terms of durability, safety, and cost-effectiveness. Finally, we critically evaluate the evolving regulatory landscape and propose a priority framework for selecting genetic liver diseases most amenable to CRISPR-based correction. This review underscores that CRISPR gene editing is transitioning from experimental promise to clinical reality for genetic liver diseases, with personalized approaches poised to redefine the treatment paradigm.
2026-07-23 | From Copper Accumulation to Personalized Medicine: Understanding Wilson Disease and Looking Ahead to Future Directions
Wilson disease (WD) is an autosomal recessive hereditary disorder of copper metabolism caused by mutations in the ATP7B gene on chromosome 13. This paper systematically reviews the complete research landscape of WD, covering its discovery history, pathogenic mechanisms, epidemiology, clinical subtypes, current therapeutic strategies, and future advances in personalized medicine. Epidemiological data reveal an uneven global distribution of WD, with a markedly higher prevalence in Asia than in Europe and North America. The disease primarily onsets between the ages of 5 and 35, and is clinically categorized into three major subtypes: hepatic, neurological, and psychiatric. Multi-system involvement frequently leads to missed or misdiagnosis. Loss-of-function mutations in ATP7B impair hepatic copper transport and biliary excretion, resulting in massive copper accumulation in the liver. Excess copper triggers overproduction of reactive oxygen species (ROS), which initiates lipid peroxidation, protein and nucleic acid damage, mitochondrial dysfunction, cuproptosis, inflammatory cascades, and hepatic fibrosis. Copper subsequently leaks into systemic circulation and deposits in the brain, cornea, kidneys, myocardium, and other organs, causing multi-organ lesions. Current clinical management relies on long-term copper elimination therapy, including low-copper dietary modification, copper chelators (D-penicillamine and trientine), and zinc salts. Liver transplantation is reserved for patients with end-stage liver disease. Nevertheless, conventional treatments are limited by adverse drug reactions, irreversible neurological damage, and lifelong medication requirements. Future personalized medicine strategies center on curative gene therapies such as AAV-mediated gene repair, CRISPR gene editing, and stem cell therapy. Newborn screening combining dried blood spot ATP7B peptide detection and genomic sequencing enables early diagnosis. At present, gene therapy faces multiple bottlenecks including limited vector packaging capacity, host immune rejection, diminished efficacy in pediatric patients due to liver proliferation, and off-target effects. As a classic research model for copper metabolism disorders, Wilson disease also serves as a critical paradigm for rare monogenic diseases advancing toward early screening, precise stratification, and curative gene-based individualized therapy.
2026-04-15 | CRISPR/Cas9-mediated gene correction of Wilson disease H1069Q point mutation in patient-specific induced pluripotent stem cells.
The innovative clustered regularly interspaced short palindromic repeats (CRISPR) associated nuclease 9 (Cas9) gene editing technique may represent a suitable therapeutic opportunity for the treatment of inherited diseases such as Wilson disease (WD). This monogenetic liver disease is based on a mutation of the ATP7B gene and leads to a functional deterioration in copper (Cu) excretion. Excess Cu accumulations in organs such as the liver and brain lead to severe cytotoxicity, followed by acute or chronic liver failure and/or neurological symptoms, and even death, which makes cellular Cu excretion indispensable for any potential WD therapy, e.g., gene therapy. A life-long treatment with zinc or chelators such as D-penicillamine may improve the course of the disease, but serious side effects have been observed in a significant portion of patients. In this study, isolated urinary epithelial cells from a WD patient carrying the ATP7B H1069Q mutation were reprogrammed into induced pluripotent stem cells (iPSCs). Using the CRISPR/Cas9 technology, ATP7B H1069Q was corrected by the additional use of single-stranded oligo DNA nucleotides (ssODNs). After differentiation into hepatocyte-like cells (HLCs), a high resistance to Cu was observed, plus a recovery of ATP7B trafficking. This is the first study to confirm that CRISPR/Cas9-mediated correction of the ATP7B point mutation H1069Q is possible and could open new possibilities for future applications.
other
2026-03-18 | Multiscale computational genomics in Wilson disease: from atomic dynamics to clinical prediction.
Wilson disease (WD) is an autosomal recessive disorder caused by pathogenic variants in the ATP7B gene, leading to toxic copper accumulation. The integration of computational genomics approaches is now essential for deciphering the complex genotype-phenotype relationships and advancing towards targeted therapies. This review synthesizes how multiscale computational strategies are transforming WD research. At the atomic level, molecular dynamics (MD) simulations reveal the conformational dynamics of the ATP7B protein, the functional impact of mutations, and the detailed copper transport cycle. At the systems level, machine learning (ML) models integrate genomic, epigenomic, transcriptomic, and clinical data to classify variant pathogenicity, predict disease subtypes, and forecast clinical outcomes such as cirrhosis or neurological deterioration. Furthermore, multi-omics network analyses uncover disease-associated regulatory modules, elucidate the role of epigenetic dysregulation, and implicate emerging pathways like cuproptosis in WD pathogenesis. Critically, these computational insights are increasingly guiding therapeutic innovation, including the in silico design of allosteric modulators (e.g., nanobodies) and pharmacological chaperones to correct ATP7B folding. By bridging scales from molecular structure to patient phenotypes, computational genomics provides a powerful, integrative framework that holds the potential to accelerate the development of dynamic, mechanism-based therapies and pave the way for personalized medicine in Wilson disease.
2025-11-16 | Clinical case: combination of ulcerative colitis and Wilson – Konovalov disease – challenges of diagnostics and treatment
Wilson – Konovalov disease (WKD) or hepatolenticular degeneration is a rare genetic disorder associated with a defect in copper metabolism, which in turn leads to liver dysfunction and degenerative changes in the basal ganglia of the brain. In the presented clinical case, the patient had a combination of symptoms of ulcerative colitis and WKD in the form of liver failure and neurological symptoms. There is no evidence in the world literature of a common genetic background between ulcerative colitis and Wilson's disease, but high copper levels are present in both diseases. The diagnosis of WKD was diagnosed a year after the onset of ulcerative colitis symptoms. UC did not respond to treatment with hormones and cytostatics. Regression of clinical symptoms was observed after the addition of biological therapy.
2024-06-27 | Gandouling induces GSK3β promoter methylation to improve cognitive impairment in Wilson's disease.
Cognitive impairment is a serious clinical manifestation of Wilson's disease (WD) in the nervous system. Gandouling (GDL) is a hospital preparation of the First Affiliated Hospital of Anhui University of Chinese Medicine. Previous studies have found that GDL has an ameliorative effect on cognitive impairment in WD. We aimed to explore the molecular-level regulatory mechanisms underlying cognitive impairment in WD, and provide evidence supporting GDL as a promising candidate drug for the treatment of cognitive impairment in WD. We found that GSK3β was significantly up-regulated in the brain tissue of C3He-Atp7Btx-J/J (tx-j) mice in the WD gene mutant model, and the monomer components of GDL could combine well with GSK3β. Therefore, in this work, we used Behavioral tests, Hematoxylin and eosin (H&E), Nissl and Terminal deoxynucleotidyl transferase dUTP-biotin nick end labeling(TUNEL) staining, Ultrastructural morphological observation by Transmission electron microscopy (TEM), bisulfite sequencing (BSP), Quantitative real-time polymerase chain reaction (RT-qPCR), Western blot, immunofluorescence, network pharmacology, molecular docking, and related methods to study the effects of GDL in tx-j mice and HT22 cell to clarify the effect of GDL on cognitive impairment in WD. In this study, MWM, NOR, H&E, Nissl TUNEL and TEM results showed that GDL could promote the repair of learning and memory function, improve the morphological damage to hippocampal neurons, and maintain mitochondria integrity. In the HT22 cell experiment, the CCK-8 method showed that GDL increased the viability of copper-overloaded cell models. The study found that GSK3β may be a target of GDL for the treatment of WD cognitive impairment through network pharmacology. Western blot and qRT-PCR results confirmed that GDL significantly increased the expression of proteins and mRNA in DNMT1, Nrf2, and HO-1. BSP showed that GSK3β promoter methylation was lower in the Model group than in the control group, and the promoter methylation of GSK3β was further reduced after intraperitoneal injection with decitabine, and GDL could ameliorate this pathology. GDL demonstrates a protective role by inducing GSK3β promoter methylatio, regulating the GSK3β/Nrf2 signaling pathway in WD.
2023-09-26 | An RNA foundation model enables discovery of disease mechanisms and candidate therapeutics
Abstract Accurately modeling and predicting RNA biology has been a long-standing challenge, bearing significant clinical ramifications for variant interpretation and the formulation of tailored therapeutics. We describe a foundation model for RNA biology, “BigRNA”, which was trained on thousands of genome-matched datasets to predict tissue-specific RNA expression, splicing, microRNA sites, and RNA binding protein specificity from DNA sequence. Unlike approaches that are restricted to missense variants, BigRNA can identify pathogenic non-coding variant effects across diverse mechanisms, including polyadenylation, exon skipping and intron retention. BigRNA accurately predicted the effects of steric blocking oligonucleotides (SBOs) on increasing the expression of 4 out of 4 genes, and on splicing for 18 out of 18 exons across 14 genes, including those involved in Wilson disease and spinal muscular atrophy. We anticipate that BigRNA and foundation models like it will have widespread applications in the field of personalized RNA therapeutics.
2023-06-19 | Wilson disease complicated by Crohn disease: A case report and literature review.
Wilson disease (WD), also known as hepatolenticular degeneration, is an autosomal-recessive hereditary disease with abnormal copper metabolism. Crohn disease (CD) is a chronic inflammatory gastrointestinal disease, which belongs to inflammatory bowel disease, all segments of the gastrointestinal tract can be affected, especially the terminal ileum and colon, accompanied by extraintestinal manifestations and related immune disorders. WD complicated by ulcerative colitis has been reported before, but WD complicated by CD has not been reported so far. We presented the first report of a young patient with WD complicated by CD, who was admitted to the hospital because of repeated low fever, elevated C-reactive protein for 3 years, and anal fistula for 6 months. In this complicated disease, Ustekinumab is safe and effective. We conclude that copper metabolism and oxidative stress play important roles in WD and CD.
cell therapies
2026-07-08 | Mechanisms of multi-organ damage in Wilson disease from the gut-liver-brain axis perspective: copper metabolism, gut microbiota, and metabolite communication.
Wilson disease (WD) is an autosomal recessive disorder of copper metabolism caused by ATP7B mutations, leading to pathological copper deposition in the liver, brain, and cornea. Although the gut-liver-brain axis plays a role, direct copper accumulation in multiple organs remains the primary cause of tissue damage. Recent years have seen growing attention to the gut microbiota in WD pathogenesis. Copper imbalance remodels gut microbiota composition and function, while dysbiosis, in turn, affects copper absorption and excretion, forming a vicious cycle that exacerbates multi-organ damage. Copper-induced intestinal barrier disruption, lipopolysaccharide translocation, and systemic inflammation are key links connecting local copper accumulation to systemic injury. This review summarizes the genetic basis of WD, mechanisms of copper toxicity, gut microbiota alterations, and their roles in liver injury and neurodegeneration. It highlights microbiota-derived metabolites-short-chain fatty acids, tryptophan metabolites, bile acids, sulfur-containing amino acids, and branched-chain amino acids-in inter-organ communication. The bidirectional interaction between WD therapies (chelators, zinc salts, dietary interventions) and the gut microbiota is analyzed, along with microbiota-based personalized therapies. However, most current evidence derives from animal models or small cross-sectional studies; large-scale longitudinal human data are critically lacking. A deeper understanding of the gut-liver-brain axis in WD may reveal novel biomarkers and therapeutic targets.
2026-07-01 | Cognitive function and quality of life in Wilson disease: Implications for the timing of liver transplantation
Background Wilson's disease (WD) is a rare inherited disorder of copper metabolism that may lead to hepatic and neuropsychiatric impairment. The role of liver transplantation (LT) in improving cognitive outcomes and quality of life (QoL) in WD remains uncertain. Methods This single-center cross-sectional study compared cognitive function and QoL among 54 participants: 23 healthy controls, 16 post-LT WD, and 15 non-LT WD patients. Cognitive performance was assessed using the smartphone-based Stroop test (EncephalApp), while QoL was evaluated using a validated 20-item RAND survey. Rank-based ANCOVA adjusted for gender was applied for statistical analysis. Results Healthy controls demonstrated the fastest Stroop performance, followed by LT and non-LT WD groups. Although post-LT patients demonstrated numerically better cognitive outcomes than non-LT patients, the differences were not statistically significant (p > 0.05). However, LT patients reported significantly higher QoL in self-perceived health and perceived health parity with others (p = 0.017 and p = 0.014, respectively). Conclusion Post-LT WD patients exhibited a trend toward superior cognitive performance and significantly improved QoL compared to non-LT patients. These findings suggest that LT may confer neurocognitive and psychosocial benefits beyond hepatic recovery, underscoring the importance of timely transplantation and further multicenter studies to validate these outcomes
2026-05-30 | [Recent Advances in the Diagnosis and Management of Wilson's Disease].
This review summarizes recent developments in the genetics of Wilson's disease, highlights major diagnostic innovations, discusses novel aspects of therapeutic strategies, and outlines advances in treatment monitoring that are of particular relevance for clinical practice. Recent genetic population studies based on carrier frequencies of ATP7B mutations suggest that the prevalence of Wilson's disease is higher than estimates derived from clinical patient registries. Current evidence indicates that some ATP7B mutations are associated with milder disease phenotypes and reduced penetrance, supporting the concept of genotype-phenotype associations. A major advance in the diagnosis of Wilson's disease is the introduction of Relative Exchangeable Copper (REC). An additional diagnostic improvement is metallothionein immunohistochemistry in liver biopsy specimens. In cases of Wilson's disease-related acute liver failure, immediate listing for liver transplantation is generally recommended. Based on recent studies, bridging plasma exchange therapy should be considered in all patients and particularly in patients without advanced hepatic encephalopathy, and in selected cases with early treatment and mild encephalopathy transplantation may be avoided.
2026-03-01 | Immunomodulation by systemic administration of exosomes derived from induced pluripotent stem cell mesenchymal stem cells to alleviate liver inflammation and fibrosis in Wilson's disease.
Exosomes derived from mesenchymal stem cells (MSCs) are proposed to have anti-inflammatory and immunomodulatory effects. We sought to determine the therapeutic effects of human induced pluripotent stem cell-MSC derived exosomes (iPSC-MSC-Ex) on liver inflammation and fibrosis in Wilson's disease (WD). Exosomes derived from MSCs differentiated from iPSCs were administered intravenously into an ATPase Copper Transporting Beta (ATP7B) knockout mouse in-vivo model of WD. Hepatic function was then evaluated. iPSC-MSC-Ex treated mice showed attenuated liver injury, evidenced by enhanced liver functionality, decreased collagen accumulation, and reduced inflammation. Our results also revealed that treatment with iPSC-MSC-Ex regulated the immune response with reduced splenic inflammatory monocytes and NK cells and increased splenic Treg cells. Altered macrophage polarization was observed in mice that received iPSC-MSC-derived exosomes, accompanied by down-regulation of hepatic proinflammatory cytokines and up-regulation of hepatic anti-inflammatory cytokines. Our findings demonstrated that iPSC-MSC-derived exosomes could ameliorate hepatic fibrosis in a mouse model of WD via immunomodulation and macrophage polarization. These results support the development of iPSC-MSC-derived exosomes as a cell-free therapy for WD as well as other chronic liver diseases.
2025-12-31 | Study on the effect of mesenchymal stem cells on neural injury, inflammation and copper content in Wilson disease.
To investigate the effects of bone marrow mesenchymal stem cells (BMSCs) on extrapyramidal neural network of Wilson disease (WD). 27 6-month-old toxic milk mice (TX mice, WD animal model) and 15 C57 mice were selected. Corrected phase (CP) value on susceptibility weighted imaging (SWI), fractional anisotropy (FA) on diffusion tensor imaging (DTI) were performed. The volume of fiber connections was determined. BMSCs was transplanted though tail vein injection (1 × 106, 0.5 mL). The myelin basic protein (MBP), amyloid precursor protein (β-APP), nitric oxide (NO), glutathione (GSH) and interleukin (IL-1β) were determined at 1, 2, 4 and 8 weeks after transplantation. The CP value of TX mice increased at 4 (p = 0.029) and 8 weeks (p = 0.037) after transplantation. FA values (p = 0.026, 0.020, 0.037) and the volume of neural fibers (p = 0.016, 0.023, 0.018) increased at 2, 4 and 8 weeks after transplantation. The pathological indexes of demyelination (MBP) and axon injury (β-APP) improved after BMSCs transplantation. The brain copper content decreased at 4 and 8 weeks after transplantation (p = 0.024, 0.038). The indexes of oxidative stress (NO and GSH) and inflammation (IL-1β) of TX mice were improved after transplantation. BMSCs can ameliorate WD extrapyramidal neural network injury. The mechanism may be related to reducing copper deposition and alleviating oxidative stress and inflammatory response.
small molecules
2026-08-17 | A Dual-Function Guanidinium Scaffold for Copper sequestration and Redox Protection in Wilson disease Models.
Wilson disease (WD) is caused due to mutations in the copper ATPase gene ATP7B, resulting in accumulation of copper and the consequent disruption of cellular redox balance through reactive oxygen species generation. Current therapies mainly depend on copper chelation to lower metal burden which sometimes also strip copper from cuproproteins and disturb key physiological copper-dependent processes. It also does not directly suppress pathological copper reactivity i.e., free radical generation, a major driver of WD progression. To overcome these limitations, we have rationally designed Gua-Cu-3, a C3-symmetric guanidinium-based non-toxic molecule that can chelate labile copper without metal stripping from cuproproteins due to moderate binding affinity and it has intrinsic antioxidant activity within a single nanosheet-forming supramolecular self-assembly. Spectroscopic, calorimetric, and computational analyses revealed multivalent copper coordination (Kd = 95.4μM) while radical-scavenging and hydroxyl-radical inhibition assays revealed redox-regulatory activity. In copper loaded hepatocytes, Gua-Cu-3 reduces ATP7B trafficking from trans-Golgi network, confirming effective intracellular copper sequestration. This was accompanied by a marked reduction in oxidative stress readouts, i.e., translocation of Nrf2 in nucleus and of HO-1 expression, thereby limiting lipid peroxidation and restoration of ER and mitochondrial health. Gua-Cu-3 attenuates oxidative stress in ATP7B-homolog-deficient Caenorhabditis elegans and rescues copper-induced developmental defects in zebrafish, outperforming D-penicillamine, which is currently in use for WD management. These findings establish Gua-Cu-3 with a therapeutic potential that couples-controlled copper sequestration with redox regulation and provides a framework for treating WD and other disorders associated with metal dyshomeostasis and oxidative stress.
2026-08-09 | Copper homeostasis and cuproptosis: New perspectives on the diagnosis and treatment of metabolic diseases.
Cuproptosis is a recently identified form of regulated cell death driven by the direct binding of Cu⁺ to the lipoyl moiety of mitochondrial tricarboxylic acid (TCA) cycle enzymes, leading to dihydrolipoamide S-acetyltransferase (DLAT) oligomerisation, iron-sulfur cluster (Fe-S) protein depletion, and proteotoxic stress, and is uniquely dependent on mitochondrial respiration. This review critically synthesises current evidence on the role of cuproptosis in type 2 diabetes mellitus (T2DM), metabolic dysfunction-associated steatotic liver disease (MASLD), and obesity. In T2DM, three causally validated pathways of copper transporter dysregulation converge on ferredoxin 1 (FDX1)-dependent DLAT oligomerisation, with substantial FDX1 reduction in diabetic skeletal muscle providing quantitative evidence of cuproptotic commitment; however, β-cell-specific knockout studies remain critically absent. In MASLD, indirect reactive oxygen species (ROS)-mediated insulin resistance is favoured over direct copper-receptor interactions. We propose the metabolic threshold hypothesis, positing that cuproptosis represents failed adaptation to chronic lipid overload, triggered when copper influx exceeds the combined buffering capacity of ATPase copper transporting beta (ATP7B)-mediated efflux, metallothionein sequestration, and glutathione (GSH) chelation. The serum Cu/Zn ratio cannot distinguish cuproptosis from ferroptosis; precise identification requires combined detection of FDX1, DLAT, lipoic acid synthase (LIAS), and lipoyltransferase 1 (LIPT1) with mitochondrial copper content, with immunohistochemistry (IHC) for DLAT oligomerisation as the most clinically accessible surrogate marker. Copper chelators including tetrathiomolybdate and merestinib are primary agents for metabolic tissue preservation, whereas ionophores such as elesclomol are restricted to oncology, with lipid nanoparticle-based delivery platforms essential to overcome the blood-brain barrier challenge, as underscored by the neurological worsening documented in D-penicillamine-treated Wilson disease patients. The interplay between cuproptosis and ferroptosis, sharing GSH depletion but diverging at lipoylated protein aggregation versus glutathione peroxidase 4 (GPX4)-dependent lipid peroxidation, suggests dual-pathway inhibition may be necessary. Future priorities include validation of the metabolic threshold hypothesis, β-cell-specific knockout studies, standardised DLAT oligomerisation diagnostics, tissue-targeted copper modulator delivery, and integration of cuproptosis biomarkers with multi-omics and artificial intelligence for clinically stratified precision medicine.
2026-07-14 | Prognosis of pediatric hepatic Wilson disease with ATP7B loss of function variants.
Genotype-phenotype correlations in Wilson disease (WD) have so far been inconclusive. ATP7B variants with loss of function (LOF) may have a different trajectory. Since genotypes in Asia differ from the West, we aimed to correlate LOF variants of ATP7B with the severity and outcome of hepatic WD. Patients with a confirmed diagnosis of WD (Leipzig criteria ≥4) were prospectively enrolled. Genetic sequencing of ATP7Bmutations was assessed by Whole-exome sequencing. For patients with variants of uncertain significance, Sanger sequencing was additionally performed on their parents to identify the inherited variants. In silico analyses were used to predict the pathogenicity of variants. Mutations that resulted in at least one truncation (nonsense, frameshift, splice site, deletions) and nontruncation (missense, synonymous) protein were defined as LOF and no LOF (NLF) respectively. Phenotypes, biochemical parameters, and outcomes were analyzed. One hundred sixteen hepatic WD children (84 boys, median age at diagnosis 8.9±3.3 years) with biallelic ATP7B mutations (62 different variants) were enrolled. The most common LOF (n=79) and NLF (n=37) variants were c.813C>A and c.3809A>G. Advanced liver disease (76% vs. 4%, P=0.004), portal hypertension (44% vs. 24%, P=0.03), neurological (39% vs. 16%, P=0.01) and renal involvement (44% vs. 13%, P=0.01) were significantly higher in LOF than in NLF. c.813C>A had higher serum exchangeable copper (6.8±4.4 μmol/L vs. 1.4±3.5 μmol/L, P=0.04) and lower disappearance of the Kayser-Fleischer ring (4% vs. 49%, P= 0.01) than c.3809A>G variants. Over a follow-up of 6.1±4.7 years, a single LOF variant did not show a poorer liver or overall outcomes in comparison to ≥2 LOF variants. A single ATP7B LOF variant, especially c.813C>A was associated with advanced liver disease, portal hypertension, and extrahepatic involvement. LOF variants did not affect liver or overall outcomes.
2026-07-08 | A 31-Year-Old Woman With Liver Cirrhosis Due to Wilson Disease and the Double Impact of Active Tuberculosis and Anti-Tuberculosis Therapy Resulting in Acute Liver Injury.
BACKGROUND In some patients with Wilson disease, there can be a combined impact of active tuberculosis (TB) and anti-tuberculosis therapy (ATT), a "double hit", due to drug-induced liver injury that can accelerate Wilson cirrhosis and result in acute liver failure. This report presents the case of a 31-year-old woman with liver cirrhosis due to Wilson disease and the combined impact of active TB and ATT resulting in acute liver injury. CASE REPORT A 31-year-old woman with genetically confirmed Wilson disease and Child-Pugh B liver cirrhosis presented in July 2025 with acute hepatic decompensation. Investigation revealed a positive QuantiFERON-TB Gold test result, lymphocytic exudative ascites, and a clinical picture consistent with extrapulmonary TB. Empiric ATT was initiated with rifampicin and isoniazid. Within 2 months, she re-presented with severe anti-TB drug-induced liver injury, which manifested as acute-on-chronic liver failure. The hepatotoxic regimen was immediately discontinued, and intensive supportive care was administered, resulting in gradual stabilization of liver function and clinical improvement. CONCLUSIONS This case demonstrates the critical "double-hit" vulnerability in Wilson disease, in which copper-mediated glutathione depletion leaves the liver unable to detoxify standard anti-TB drugs. Clinicians managing TB in patients with decompensated Wilson cirrhosis should avoid standard rifampicin-isoniazid regimens and use hepatosafe alternatives instead. A high index of suspicion for TB is warranted in all cirrhotic patients with fever, lymphocytic exudative ascites, and unexplained decompensation.
2026-07-02 | The gut-liver-kidney-brain axis in Wilson disease: copper speciation-flux and barrier-mediated organ crosstalk.
Wilson disease (WD) has long been framed as a hepatocentric disorder of copper accumulation. That view is now giving way to a broader model centered on the gut-liver-kidney-brain axis. In WD, copper is not simply stored in tissues as an inert burden. It circulates in dynamic, bioactive pools-particularly relative exchangeable copper (REC)-that disrupt barrier structures, including the intestinal epithelium and blood-brain barrier, and spread toxicity through measurable biochemical mediators. Major pathogenic processes include copper-induced suppression of autophagy, disruption of FXR-regulated bile acid signaling, and direct injury to the intestinal barrier. Gut dysbiosis, supported by fecal microbiota transplantation (FMT) studies in ATP7B-deficient mice, further amplifies hepatic inflammation and favors copper retention. Renal tubular dysfunction and neurotoxicity appear to reflect copper species-dependent passage across biological barriers together with secondary metabolic disturbances, including the recently described pathway of cuproptosis. In the clinic, this shift has been accompanied by greater use of copper-species biomarkers such as ceruloplasmin oxidase activity and REC, along with advanced imaging approaches such as 64Cu-PET/CT. Treatment is also moving beyond conventional chelation alone, with increasing attention to biliary copper excretion, epithelial barrier repair, and microbiome-directed interventions. Viewed in this way, the axis model helps explain the marked phenotypic heterogeneity of WD and offers a mechanistic basis for more precise interventions aimed at breaking pathogenic feedback loops across organs.
proteins
2026-06-11 | Wilson disease in children: Recent update on pathophysiology and management
Wilson's disease (WD) is an autosomal recessive disease caused by mutations in the ATP7B gene, which plays a fundamental role in copper metabolism, leading to the accumulation of copper in the liver and other vital organs.Major functions of ATP7B are the incorporation of copper into apoceruloplasmin and the excretion of copper into bile.From simple asymptomatic elevation of liver enzymes to acute liver failure, as well as chronic hepatitis, portal hypertension may be the initial presentation of this disease.Approximately 800 different mutations of the ATP7B gene have been recognized.WD has wide phenotypic disease expressions.Genotypic expression does not always correlate with phenotypic disease expression or disease severity.Environmental and epigenetic factors may play a role in disease expression.No single test is diagnostic for WD.Initial testing includes ocular slit-lamp examination, 24-hour urinary copper excretion, and serum ceruloplasmin.The Leipzig scoring system for diagnosis is widely used.Relative exchangeable copper is the new noninvasive biomarker for WD.It gives a quick result before awaiting genetic testing.Timely diagnosis of WD is important, as it can halt the clinical progression of the liver and neurological disease.D-penicillamine and trientine remain the main chelators for WD treatment.Patients need lifelong chelation therapy until liver transplantation.Research on new treatment modalities, such as methanobactin, is ongoing for further human use.This review discusses the genetic aspects of WD, copper metabolism, a new diagnostic method, and a research molecule for future management of WD.
2023-09-01 | A co-opted endogenous retroviral envelope promotes cell survival by controlling CTR1-mediated copper transport and homeostasis
Copper is a critical element for eukaryotic life involved in numerous cellular functions, including redox balance, but is toxic in excess. Therefore, tight regulation of copper acquisition and homeostasis is essential for cell physiology and survival. Here, we identify a different regulatory mechanism for cellular copper homeostasis that requires the presence of an endogenous retroviral envelope glycoprotein called Refrex1. We show that cells respond to elevated extracellular copper by increasing the expression of Refrex1, which regulates copper acquisition through interaction with the main copper transporter CTR1. Downmodulation of Refrex1 results in intracellular copper accumulation leading to reactive oxygen species (ROS) production and subsequent apoptosis, which is prevented by copper chelator treatment. Our results show that Refrex1 has been co-opted for its ability to regulate copper entry through CTR1 in order to limit copper excess, redox imbalance, and ensuing cell death, strongly suggesting that other endogenous retroviruses may have similar metabolic functions among vertebrates.
2022-10-27 | ATP7B-Deficient Hepatocytes Reveal the Importance of Protein Misfolding Induced at Low Copper Concentration
Copper is a transition metal essential for human life. Its homeostasis is regulated in the liver, which delivers copper to the whole body and excretes its excess outside the organism in the feces through the bile. These functions are regulated within hepatocytes, and the ATP7B copper transporter is central to making the switch between copper use and excretion. In Wilson disease, the gene coding for ATP7B is mutated, leading to copper overload, firstly, in the liver and the brain. To better understand the role of ATP7B in hepatocytes and to provide a smart tool for the development of novel therapies against Wilson disease, we used the CrispR/Cas9 tool to generate hepatocyte cell lines with the abolished expression of ATP7B. These cell lines revealed that ATP7B plays a major role at low copper concentrations starting in the micromolar range. Moreover, metal stress markers are induced at lower copper concentrations compared to parental cells, while redox stress remains not activated. As shown recently, the main drawback induced by copper exposure is protein unfolding that is drastically exacerbated in ATP7B-deficient cells. Our data enabled us to propose that the zinc finger domain of DNAJ-A1 would serve as a sensor of Cu stress. Therefore, these Wilson-like hepatocytes are of high interest to explore in more detail the role of ATP7B.
2022-05-10 | Suppression of ATG4B by copper inhibits autophagy and involves in Mallory body formation.
Autophagy is an evolutionarily conserved self-protecting mechanism implicated in cellular homeostasis. ATG4B plays a vital role in autophagy process via undertaking priming and delipidation of LC3. Chemical inhibitors and regulative modifications such as oxidation of ATG4B have been demonstrated to modulate autophagy function. Whether and how ATG4B could be regulated by metal ions is largely unknown. Copper is an essential trace metal served as static co-factors in redox reactions in physiology process. Excessive accumulation of copper in ATP7B mutant cells leads to pathology progression such as insoluble Mallory body (MB) in Wilson disease (WD). The clearance of MB via autophagy pathway was thought as a promising strategy for WD. Here, we discovered that copper ion instead of other ions could inhibit the activity of ATG4B followed by autophagy suppression. In addition, copper could induce ATG4B oligomers depending on cysteine oxidation which could be abolished in reduced condition. Copper also promotes the formation of insoluble ATG4B aggregates, as well as p62-and ubiquitin-positive aggregates, which is consistent with the components of MB caused by copper overload in WD cell model. Importantly, overexpression of ATG4B could partially reduce the formation of MB and rescue impaired autophagy. Taken together, our results uncovered for the first time a new damage mechanism mediated by copper and implied new insights of the crosstalk between the toxicity of copper and autophagy in the pathogenesis of WD.
2018-08-16 | A Luminal Loop of Wilson Disease Protein Binds Copper and Is Required for Protein Activity
The copper-transporting ATPase ATP7B is essential for loading of copper ions to copper-dependent enzymes in the secretory pathway; its inactivation results in Wilson disease. In contrast to copper-ion uptake by the cytoplasmic domains, ATP7B-mediated copper-ion release in the Golgi has not been explored yet. We demonstrate here that a luminal loop in ATP7B, rich in histidine/methionine residues, binds reduced copper (Cu(I)) ions, and identified copper-binding residues play an essential role in ATP7B-mediated metal ion release. NMR experiments on short-peptide models demonstrate that three methionine and two histidine residues are specifically involved in Cu(I) ion binding; with these residues replaced by alanines, no Cu(I) ion interaction is detected. Although more than one Cu(I) ion can interact with the wild-type peptide, removing either all histidine or all methionine residues reduces the stoichiometry to one Cu(I) ion binding per peptide. Using a yeast complementation assay, we show that for efficient copper transport by full-length ATP7B, the complete set of histidine and methionine residues in the lumen loop are required. The replacement of histidine/methionine residues by alanines does not perturb overall ATP7B structure, as the localization of ATP7B variants in yeast cells matches that of the wild-type protein. Thus, in similarity to ATP7A, ATP7B also appears to have a luminal "exit" copper ion site.
gene therapies
2026-08-15 | Recent advances in research on high-frequency mutations in the ATP7B gene associated with Wilson disease in the Chinese population: from genetic evolution to precision medicine.
Wilson disease (WD) is a hereditary disorder of copper metabolism caused by mutations in the ATP7B gene; the Chinese population exhibits a unique, high-frequency mutation profile centered on the R778L and P992L mutations. This article provides a narrative review of the genetic evolution, molecular pathogenic mechanisms, phenotypic heterogeneity, and precision diagnosis and treatment strategies for high-frequency ATP7B mutations in the Chinese WD population. The high-frequency enrichment of R778L and P992L is speculated to arise from the combined effects of CpG mutation hotspots and the founder effect supported by East Asian haplotype data, with distinct geographical distributions and relatively conserved haplotypes observed in existing cohorts. Functional studies indicate that the R778L variant disrupts the transmembrane domain and induces severe protein misfolding associated with an early-onset hepatic phenotype, whereas the P992L mutation partially retains catalytic function and tends to present neurological manifestations in many clinical cohorts, though individual phenotypic variation remains substantial. Preclinical molecular chaperone and gene editing strategies offer potential mechanistic targets for mutation-specific intervention, yet their clinical translation remains at an immature stage with insufficient human trial data. In the future, it will be necessary to establish multicenter cohorts, advance mutation-targeted therapies, and develop a precision diagnosis and treatment system covering the entire disease lifecycle.
2026-08-14 | Liver Organoids: From Disease Modelling to Regenerative Medicine.
Liver organoids are three-dimensional miniature liver models that recapitulate the complex architecture and key functions of the human liver in vitro, offering powerful platforms for both fundamental research and translational applications. This review systematically summarises current fabrication strategies, disease-modelling utilities and regenerative potentials of liver organoids, alongside the major challenges and future directions. In recent years, the field has witnessed several breakthroughs. Through endothelial co-culture approaches, vascularised and metabolically zonated liver organoids have been successfully generated, achieving endothelial coverage exceeding 85%. Prime editing enables precise correction of pathogenic mutations in patient-derived organoids, with no off-target effects detected at the genome-wide level. In disease modelling, iPSC-derived liver organoids faithfully recapitulate the pathological progression of metabolic dysfunction-associated steatotic liver disease (MASLD) and verify the lipid-lowering efficacy of semaglutide. Macrophage-integrated organoid models support the full life cycles of HEV, SARS-CoV-2 and dengue virus, providing new tools for antiviral drug screening. Large-scale patient-derived tumour organoid biobanks successfully preserve the heterogeneity and clinical drug-resistance signatures of liver cancers. In regenerative medicine, encapsulated hepatocyte organoids and the UTOpiA bioartificial liver system have effectively rescued acute liver failure in animal models, while gene-edited autologous organoids offer potential curative strategies for genetic disorders such as Wilson disease. Nevertheless, insufficient hepatocyte functional maturity, difficulties in constructing vascular networks, and the lack of standardised culture protocols remain major obstacles to clinical translation. By bridging fundamental liver biology and clinical practice, liver organoid technology lays a solid foundation for precision hepatology and regenerative therapies. Continued interdisciplinary efforts are still required to overcome current limitations and facilitate its clinical adoption.
2026-07-29 | From one-size-fits-all to on-demand: personalized crispr gene editing for rare genetic liver diseases.
Rare genetic liver diseases collectively affect millions of individuals worldwide and encompass a heterogeneous group of monogenic disorders including Wilson disease, alpha-1 antitrypsin deficiency, glycogen storage diseases, urea cycle disorders, progressive familial intrahepatic cholestasis, and acute hepatic porphyrias. While conventional management relies on dietary modification, pharmacotherapy, and ultimately liver transplantation, the advent of clustered regularly interspaced short palindromic repeats (CRISPR)-based gene editing has opened transformative therapeutic avenues. This review provides a comprehensive and critical appraisal of the current landscape of CRISPR-based therapies for genetic liver diseases, from preclinical proof-of-concept studies to landmark clinical trials. We examine the evolution from conventional Cas9 nuclease-mediated editing to precision tools including base editors and prime editors, which enable single-nucleotide corrections without inducing double-strand DNA breaks. The role of lipid nanoparticle delivery systems in achieving efficient hepatocyte-targeted delivery is discussed, alongside emerging challenges in pediatric dosing and immunogenicity. We highlight the paradigm shift toward personalized, patient-specific CRISPR therapies, exemplified by the first-in-human bespoke gene editing treatment delivered in 2025. Competing nucleic acid technologies, including RNA interference and antisense oligonucleotides, are compared in terms of durability, safety, and cost-effectiveness. Finally, we critically evaluate the evolving regulatory landscape and propose a priority framework for selecting genetic liver diseases most amenable to CRISPR-based correction. This review underscores that CRISPR gene editing is transitioning from experimental promise to clinical reality for genetic liver diseases, with personalized approaches poised to redefine the treatment paradigm.
2026-07-23 | From Copper Accumulation to Personalized Medicine: Understanding Wilson Disease and Looking Ahead to Future Directions
Wilson disease (WD) is an autosomal recessive hereditary disorder of copper metabolism caused by mutations in the ATP7B gene on chromosome 13. This paper systematically reviews the complete research landscape of WD, covering its discovery history, pathogenic mechanisms, epidemiology, clinical subtypes, current therapeutic strategies, and future advances in personalized medicine. Epidemiological data reveal an uneven global distribution of WD, with a markedly higher prevalence in Asia than in Europe and North America. The disease primarily onsets between the ages of 5 and 35, and is clinically categorized into three major subtypes: hepatic, neurological, and psychiatric. Multi-system involvement frequently leads to missed or misdiagnosis. Loss-of-function mutations in ATP7B impair hepatic copper transport and biliary excretion, resulting in massive copper accumulation in the liver. Excess copper triggers overproduction of reactive oxygen species (ROS), which initiates lipid peroxidation, protein and nucleic acid damage, mitochondrial dysfunction, cuproptosis, inflammatory cascades, and hepatic fibrosis. Copper subsequently leaks into systemic circulation and deposits in the brain, cornea, kidneys, myocardium, and other organs, causing multi-organ lesions. Current clinical management relies on long-term copper elimination therapy, including low-copper dietary modification, copper chelators (D-penicillamine and trientine), and zinc salts. Liver transplantation is reserved for patients with end-stage liver disease. Nevertheless, conventional treatments are limited by adverse drug reactions, irreversible neurological damage, and lifelong medication requirements. Future personalized medicine strategies center on curative gene therapies such as AAV-mediated gene repair, CRISPR gene editing, and stem cell therapy. Newborn screening combining dried blood spot ATP7B peptide detection and genomic sequencing enables early diagnosis. At present, gene therapy faces multiple bottlenecks including limited vector packaging capacity, host immune rejection, diminished efficacy in pediatric patients due to liver proliferation, and off-target effects. As a classic research model for copper metabolism disorders, Wilson disease also serves as a critical paradigm for rare monogenic diseases advancing toward early screening, precise stratification, and curative gene-based individualized therapy.
2026-04-15 | CRISPR/Cas9-mediated gene correction of Wilson disease H1069Q point mutation in patient-specific induced pluripotent stem cells.
The innovative clustered regularly interspaced short palindromic repeats (CRISPR) associated nuclease 9 (Cas9) gene editing technique may represent a suitable therapeutic opportunity for the treatment of inherited diseases such as Wilson disease (WD). This monogenetic liver disease is based on a mutation of the ATP7B gene and leads to a functional deterioration in copper (Cu) excretion. Excess Cu accumulations in organs such as the liver and brain lead to severe cytotoxicity, followed by acute or chronic liver failure and/or neurological symptoms, and even death, which makes cellular Cu excretion indispensable for any potential WD therapy, e.g., gene therapy. A life-long treatment with zinc or chelators such as D-penicillamine may improve the course of the disease, but serious side effects have been observed in a significant portion of patients. In this study, isolated urinary epithelial cells from a WD patient carrying the ATP7B H1069Q mutation were reprogrammed into induced pluripotent stem cells (iPSCs). Using the CRISPR/Cas9 technology, ATP7B H1069Q was corrected by the additional use of single-stranded oligo DNA nucleotides (ssODNs). After differentiation into hepatocyte-like cells (HLCs), a high resistance to Cu was observed, plus a recovery of ATP7B trafficking. This is the first study to confirm that CRISPR/Cas9-mediated correction of the ATP7B point mutation H1069Q is possible and could open new possibilities for future applications.
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2026-03-18 | Multiscale computational genomics in Wilson disease: from atomic dynamics to clinical prediction.
Wilson disease (WD) is an autosomal recessive disorder caused by pathogenic variants in the ATP7B gene, leading to toxic copper accumulation. The integration of computational genomics approaches is now essential for deciphering the complex genotype-phenotype relationships and advancing towards targeted therapies. This review synthesizes how multiscale computational strategies are transforming WD research. At the atomic level, molecular dynamics (MD) simulations reveal the conformational dynamics of the ATP7B protein, the functional impact of mutations, and the detailed copper transport cycle. At the systems level, machine learning (ML) models integrate genomic, epigenomic, transcriptomic, and clinical data to classify variant pathogenicity, predict disease subtypes, and forecast clinical outcomes such as cirrhosis or neurological deterioration. Furthermore, multi-omics network analyses uncover disease-associated regulatory modules, elucidate the role of epigenetic dysregulation, and implicate emerging pathways like cuproptosis in WD pathogenesis. Critically, these computational insights are increasingly guiding therapeutic innovation, including the in silico design of allosteric modulators (e.g., nanobodies) and pharmacological chaperones to correct ATP7B folding. By bridging scales from molecular structure to patient phenotypes, computational genomics provides a powerful, integrative framework that holds the potential to accelerate the development of dynamic, mechanism-based therapies and pave the way for personalized medicine in Wilson disease.
2025-11-16 | Clinical case: combination of ulcerative colitis and Wilson – Konovalov disease – challenges of diagnostics and treatment
Wilson – Konovalov disease (WKD) or hepatolenticular degeneration is a rare genetic disorder associated with a defect in copper metabolism, which in turn leads to liver dysfunction and degenerative changes in the basal ganglia of the brain. In the presented clinical case, the patient had a combination of symptoms of ulcerative colitis and WKD in the form of liver failure and neurological symptoms. There is no evidence in the world literature of a common genetic background between ulcerative colitis and Wilson's disease, but high copper levels are present in both diseases. The diagnosis of WKD was diagnosed a year after the onset of ulcerative colitis symptoms. UC did not respond to treatment with hormones and cytostatics. Regression of clinical symptoms was observed after the addition of biological therapy.
2024-06-27 | Gandouling induces GSK3β promoter methylation to improve cognitive impairment in Wilson's disease.
Cognitive impairment is a serious clinical manifestation of Wilson's disease (WD) in the nervous system. Gandouling (GDL) is a hospital preparation of the First Affiliated Hospital of Anhui University of Chinese Medicine. Previous studies have found that GDL has an ameliorative effect on cognitive impairment in WD. We aimed to explore the molecular-level regulatory mechanisms underlying cognitive impairment in WD, and provide evidence supporting GDL as a promising candidate drug for the treatment of cognitive impairment in WD. We found that GSK3β was significantly up-regulated in the brain tissue of C3He-Atp7Btx-J/J (tx-j) mice in the WD gene mutant model, and the monomer components of GDL could combine well with GSK3β. Therefore, in this work, we used Behavioral tests, Hematoxylin and eosin (H&E), Nissl and Terminal deoxynucleotidyl transferase dUTP-biotin nick end labeling(TUNEL) staining, Ultrastructural morphological observation by Transmission electron microscopy (TEM), bisulfite sequencing (BSP), Quantitative real-time polymerase chain reaction (RT-qPCR), Western blot, immunofluorescence, network pharmacology, molecular docking, and related methods to study the effects of GDL in tx-j mice and HT22 cell to clarify the effect of GDL on cognitive impairment in WD. In this study, MWM, NOR, H&E, Nissl TUNEL and TEM results showed that GDL could promote the repair of learning and memory function, improve the morphological damage to hippocampal neurons, and maintain mitochondria integrity. In the HT22 cell experiment, the CCK-8 method showed that GDL increased the viability of copper-overloaded cell models. The study found that GSK3β may be a target of GDL for the treatment of WD cognitive impairment through network pharmacology. Western blot and qRT-PCR results confirmed that GDL significantly increased the expression of proteins and mRNA in DNMT1, Nrf2, and HO-1. BSP showed that GSK3β promoter methylation was lower in the Model group than in the control group, and the promoter methylation of GSK3β was further reduced after intraperitoneal injection with decitabine, and GDL could ameliorate this pathology. GDL demonstrates a protective role by inducing GSK3β promoter methylatio, regulating the GSK3β/Nrf2 signaling pathway in WD.
2023-09-26 | An RNA foundation model enables discovery of disease mechanisms and candidate therapeutics
Abstract Accurately modeling and predicting RNA biology has been a long-standing challenge, bearing significant clinical ramifications for variant interpretation and the formulation of tailored therapeutics. We describe a foundation model for RNA biology, “BigRNA”, which was trained on thousands of genome-matched datasets to predict tissue-specific RNA expression, splicing, microRNA sites, and RNA binding protein specificity from DNA sequence. Unlike approaches that are restricted to missense variants, BigRNA can identify pathogenic non-coding variant effects across diverse mechanisms, including polyadenylation, exon skipping and intron retention. BigRNA accurately predicted the effects of steric blocking oligonucleotides (SBOs) on increasing the expression of 4 out of 4 genes, and on splicing for 18 out of 18 exons across 14 genes, including those involved in Wilson disease and spinal muscular atrophy. We anticipate that BigRNA and foundation models like it will have widespread applications in the field of personalized RNA therapeutics.
2023-06-19 | Wilson disease complicated by Crohn disease: A case report and literature review.
Wilson disease (WD), also known as hepatolenticular degeneration, is an autosomal-recessive hereditary disease with abnormal copper metabolism. Crohn disease (CD) is a chronic inflammatory gastrointestinal disease, which belongs to inflammatory bowel disease, all segments of the gastrointestinal tract can be affected, especially the terminal ileum and colon, accompanied by extraintestinal manifestations and related immune disorders. WD complicated by ulcerative colitis has been reported before, but WD complicated by CD has not been reported so far. We presented the first report of a young patient with WD complicated by CD, who was admitted to the hospital because of repeated low fever, elevated C-reactive protein for 3 years, and anal fistula for 6 months. In this complicated disease, Ustekinumab is safe and effective. We conclude that copper metabolism and oxidative stress play important roles in WD and CD.
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Drug Discovery Landscape
23 orphan drug designations for Wilson disease, including 3 approved therapies.
23 orphan drug designations for Wilson disease, including 3 approved therapies.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Trientine tetrahydrochloride | small molecules | EMA | 2026-05-20 | — | Orphalan |
recombinant adeno-associated virus serotype 5 vector carrying the codon-optimized and truncated human ATP7B gene | gene therapies | FDA | 2025-08-15 | — | Beijing Genecradle Therapeutics Co., Ltd. |
modified human P-type copper transporting ATPase (hATP7B) messenger ribonucleic acid encapsulated in a lipid nanoparticle (hATP7B mRNA-LNP) | RNAs | FDA | 2025-03-13 | — | INNORNA USA INC. |
recombinant adeno-associated viral vector of serotype 8 carrying the coding sequence of human ATP7B gene and a hepatic-specific promoter | gene therapies | FDA | 2024-08-06 | — | Lingyi Biotech Co., Ltd |
methanobactin SB2 | small molecules | FDA | 2024-08-06 | — | ArborMed Co., Ltd |
methyl (R)-4-((3S,5R,7R,8R,9S,10S,13R,14S,17R)-7-hydroxy-10,13-dimethyl-3-((4-((pyridin-2-ylmethyl)amino)butyl)amino)hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanoate | small molecules | FDA | 2022-05-12 | — | DepYmed Inc. |
Adeno-associated viral vector serotype 9 encoding human ATP7B | gene therapies | EMA | 2020-12-09 | — | Ultragenyx Germany GmbH |
Adeno-associated viral vector serotype 9 encoding human ATP7B | gene therapies | FDA | 2020-12-07 | — | Ultragenyx Pharmaceutical Inc. |
Nimatpagene pariparvovec | gene therapies | EMA | 2020-08-21 | — | Vivet Therapeutics |
adeno-associated viral vector serotype 3B encoding shortened human ATP7B | gene therapies | FDA | 2017-09-07 | — | Vivet Therapeutics SAS |
Adeno-associated viral vector serotype Anc80 containing the truncated human ATP7B gene under the control of the human alpha-1 antitrypsin promoter | gene therapies | EMA | 2017-08-23 | — | [INACTIVE] Vivet Therapeutics |
trientine tetrahydrochloride [Cuvrior] | small molecules | FDA | 2016-03-10 | 2022-04-28 | Orphalan |
Adeno-associated viral vector serotype 8 encoding the human ATP7B gene under the control of the human alpha-1 antitrypsin promoter | gene therapies | EMA | 2015-11-11 | — | Aligen Therapeutics S.L. |
Trientine tetrahydrochloride [Cuprior] | small molecules | EMA | 2015-03-19 | — | [INACTIVE] Orphalan |
Choline tetrathiomolybdate | small molecules | EMA | 2013-01-24 | — | Monopar Therapeutics |
choline tetrathiomolybdate | small molecules | FDA | 2011-08-25 | — | Monopar Therapeutics, Inc. |
Ammonium tetrathiomolybdate | small molecules | EMA | 2008-04-01 | — | JJGConsultancy Ltd |
Sodium phenylacetate/sodium benzoate 10%/10% Injection | — | FDA | 2005-06-03 | — | Ucyclyd Pharma, Inc. |
Trientine dihydrochloride [Cufence] | small molecules | EMA | 2003-10-24 | — | Univar Solutions B.V. |
Zinc acetate dihydrate [Wilzin] | small molecules | EMA | 2001-07-31 | — | Recordati Rare Diseases |
Ammonium tetrathiomolybdate | small molecules | FDA | 1994-01-31 | — | Pipex Pharmaceuticals, Inc. |
Zinc acetate [Galzin] | small molecules | FDA | 1985-11-06 | 1997-01-28 | Eton Pharmaceuticals, Inc |
Trientine HCl [Syprine] | small molecules | FDA | 1984-12-24 | 1985-11-08 | Merck Sharp & Dohme Research |
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