A Gene Therapy Approach to Improve Copper Metabolism and Prevent Liver Damage in a Mouse Model of Wilson Disease

Greig, Jenny A.; Nordin, Jayme M.L.; Smith, Melanie K.; Ashley, Scott N.; Draper, Christine; Zhu, Yanqing; Bell, Peter; Buza, Elizabeth L.; Wilson, James M.

doi:10.1089/humc.2018.219

Cited by 16 publications

(8 citation statements)

References 28 publications

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“…These studies stimulated search for new therapeutic modalities, including small molecule drugs, cell replacement therapies, and gene therapies 10,29,32,33 . Hepatocyte-directed ATP7B gene transfer has recently shown significant promise in improving liver morphology and function in Atp7b −/− mouse models of WD [33][34][35] . In future studies, it would be important to show whether the Atp7b deficit is corrected in hepatocytes alone or also in other non-parenchymal cells when the liver function is restored.…”

Section: Discussionmentioning

confidence: 99%

Systemic deletion of Atp7b modifies the hepatocytes’ response to copper overload in the mouse models of Wilson disease

Muchenditsi

Talbot²,

Gottlieb

et al. 2021

Sci Rep

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Wilson disease (WD) is caused by inactivation of the copper transporter Atp7b and copper overload in tissues. Mice with Atp7b deleted either globally (systemic inactivation) or only in hepatocyte recapitulate various aspects of human disease. However, their phenotypes vary, and neither the common response to copper overload nor factors contributing to variability are well defined. Using metabolic, histologic, and proteome analyses in three Atp7b-deficient mouse strains, we show that global inactivation of Atp7b enhances and specifically modifies the hepatocyte response to Cu overload. The loss of Atp7b only in hepatocytes dysregulates lipid and nucleic acid metabolisms and increases the abundance of respiratory chain components and redox balancing enzymes. In global knockouts, independently of their background, the metabolism of lipid, nucleic acid, and amino acids is inhibited, respiratory chain components are down-regulated, inflammatory response and regulation of chromosomal replication are enhanced. Decrease in glucokinase and lathosterol oxidase and elevation of mucin-13 and S100A10 are observed in all Atp7b mutant strains and reflect the extent of liver injury. The magnitude of proteomic changes in Atp7b−/− animals inversely correlates with the metallothioneins levels rather than liver Cu content. These findings facilitate identification of WD-specific metabolic and proteomic changes for diagnostic and treatment.

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Section: Discussionmentioning

confidence: 99%

Systemic deletion of Atp7b modifies the hepatocytes’ response to copper overload in the mouse models of Wilson disease

Muchenditsi

Talbot²,

Gottlieb

et al. 2021

Sci Rep

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“…This product has been shown in vitro to have ATP7B activity [35,36]. The effectiveness of adeno-associated vector encoding human ATP7B cDNA variants in a mouse model of WD [34,[36][37][38] in restoring copper metabolism has led to the evaluation of the two gene therapies, UX701 and VTX-801, for the treatment of WD in human studies (NCT04537377; NCT04884815).…”

Section: Gene Therapymentioning

confidence: 99%

Neurological-Type Wilson Disease: Epidemiology, Clinical Manifestations, Diagnosis, and Management

Kipker¹,

Alessi²,

Bojkovic³

et al. 2023

Cureus

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Wilson disease (WD) is a complex metabolic disorder caused by disruptions to copper regulation within the body, leading to an unregulated accumulation of copper within various tissues. A less understood organ affected by the collection of copper is the brain, which further leads to the generation of oxygen-free radicals and resultant demyelination. Healthcare providers must keep the neurological form of WD in their list of differentials when patients present with diverse neurological manifestations. The initial step to diagnosis will be to distinguish the characteristic disease presentation with a thorough history and physical and neurological examination. A high clinical disease suspicion of WD should warrant further investigation by laboratory workup and imaging modalities to support the clinical findings and confirm the diagnosis of WD. Once a WD diagnosis is established, the healthcare provider should treat the underlying biological process of WD symptomatically. This review article discusses the epidemiology and pathogenesis of the neurological form of WD, its clinical and behavioral implications, diagnostic features, and treatment modalities (current and emerging therapies), further aiding healthcare professionals in early diagnosis and management strategies.

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“…Currently, its practical application still requires further investigation, although good outcomes have been reported in experimental animal models by using an infusion of recombinant adeno-associated virus bearing ATP7B cDNA. [ 72 73 74 75 ] A recent study reported the use of CRISPR/Cas9 technology to correct ATP7B point mutation frequently detected in WD patients. [ 67 ] However, clinical studies for WD gene modification are required so that these could become alternative curative strategies in the future.…”

Section: Treatmentmentioning

confidence: 99%

Wilson disease in children and young adults - State of the art

Dhawan

Chanpong

2022

Saudi J Gastroenterol

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Wilson disease (WD) is an autosomal recessive disorder caused by mutations of the ATP7B gene, with a reported prevalence of 1:30,000–50,000. ATP7B encodes an enzyme called transmembrane copper-transporting ATPase, which is essential for copper incorporation into ceruloplasmin and for copper excretion into the bile. A lack or dysfunction of this enzyme results in a progressive accumulation of copper in several organs, especially in the liver, the nervous system, corneas, kidneys, and heart. Children with WD can present with asymptomatic liver disease, cirrhosis, or acute liver failure, with or without neurological and psychiatric symptoms. Approximately 20%–30% of WD patients present with ALF, while most of the other patients have chronic progressive hepatitis or cirrhosis if untreated. Although genetic testing has become a more important diagnostic tool for WD, the diagnosis remains based on both clinical features and laboratory investigations. The aims of treatment are to reduce copper levels and prevent its accumulation in the liver and other organs, especially in the central nervous system. Liver transplantation in WD is a life-saving option for patients presenting with liver failure and encephalopathy. For WD patients treated with chelating agents, adherence to the therapy is essential for long-term success. In this review, we also address specific issues in young adults as compared to children.

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A Gene Therapy Approach to Improve Copper Metabolism and Prevent Liver Damage in a Mouse Model of Wilson Disease

Cited by 16 publications

References 28 publications

Systemic deletion of Atp7b modifies the hepatocytes’ response to copper overload in the mouse models of Wilson disease

Systemic deletion of Atp7b modifies the hepatocytes’ response to copper overload in the mouse models of Wilson disease

Neurological-Type Wilson Disease: Epidemiology, Clinical Manifestations, Diagnosis, and Management

Wilson disease in children and young adults - State of the art

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