Repeated transplantation of hepatocytes prevents fulminant hepatitis in a rat model of Wilson's disease

Sauer, Vanessa; Siaj, R; Stöppeler, Sandra; Bahde, Ralf; Spiegel, Hans‐Ullrich; Köhler, Gabriele; Zibert, Andree; Schmidt, Hartmut

doi:10.1002/lt.22466

Cited by 23 publications

(14 citation statements)

References 54 publications

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“…LEC rats have been repeatedly used in the development of protocols for hepatocyte transplantation as a treatment of WD and other metabolic liver diseases. Different methods of preconditioning and transplantation have been attempted in this rodent model of WD with varying degrees of success (Yoshida et al 1996;Irani et al 2001;Malhi et al 2002Malhi et al , 2008Joseph et al 2009;Sauer et al 2012). Similarly, Katsuda et al (2010) developed a hyaluronic acid sponge as a scaffold for healthy hepatocytes which they embedded into the mesentery of LEC rats with reduction in liver pathology, lowered plasma copper and prevention of jaundice, while Chen et al (2014) transplanted ATP7B-transduced mesenchymal stem cells with improvement in hepatic copper levels and liver function.…”

Section: Treatment Studiesmentioning

confidence: 99%

Animal models of Wilson disease

Reed

Lutsenko²,

Bandmann

2018

Journal of Neurochemistry

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Wilson disease (WD) is an autosomal recessive disorder of copper metabolism manifesting with hepatic, neurological and psychiatric symptoms. The limitations of the currently available therapy for WD (particularly in the management of neuropsychiatric disease), together with our limited understanding of key aspects of this illness (e.g. neurological vs. hepatic presentation) justify the ongoing need to study WD in suitable animal models. Four animal models of WD have been established: the Long-Evans Cinnamon rat, the toxic-milk mouse, the Atp7b knockout mouse and the Labrador retriever. The existing models of WD all show good similarity to human hepatic WD and have been helpful in developing an improved understanding of the human disease. As mammals, the mouse, rat and canine models also benefit from high homology to the human genome. However, important differences exist between these mammalian models and human disease, particularly the absence of a convincing neurological phenotype. This review will first provide an overview of our current knowledge of the orthologous genes encoding ATP7B and the closely related ATP7A protein in C. elegans, Drosophila and zebrafish (Danio rerio) and then summarise key characteristics of rodent and larger mammalian models of ATP7B-deficiency.

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Section: Treatment Studiesmentioning

confidence: 99%

Animal models of Wilson disease

Reed

Lutsenko²,

Bandmann

2018

Journal of Neurochemistry

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“…These animals were transplanted with Long-Evans agouti rat wild-type hepatocytes. Even in the presence of continued oral intake of copper in the diet, multiple rounds of infusions of adult hepatocytes into the spleen were required to delay onset of hepatitis (40 % rats), normalize hepatitis-associated serum markers and prolong survival until the end of the study, while rats with one or no infusion of hepatocytes failed to survive past 22 days [78]. …”

Section: Hepatocyte Transplantation Into Animal Models Of Liver Diseasementioning

confidence: 99%

New Tools in Experimental Cellular Therapy for the Treatment of Liver Diseases

2015

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The current standard of care for end stage liver disease is orthotopic liver transplantation (OLT). Through improvement in surgical techniques, immunosuppression, and general medical care, liver transplantation has become an effective treatment over the course of the last half-century. Unfortunately, due to the limited availability of donor organs, there is a finite limit to the number of patients who will benefit from this therapy. This review will discuss current research in experimental cellular therapies for acute, chronic, and metabolic liver failure that may be appropriate when liver transplantation is not an immediate option.

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“…Wilson's disease is a genetic disease caused by mutations in the ATP7B gene, which is responsible for the expression of a liver transporter protein that coordinates copper export into bile and blood [65]. Current medical treatments including chelating agents and zinc salts are not effective in all Wilson disease patients.…”

Section: Wilson's Diseasementioning

confidence: 99%

“…Current medical treatments including chelating agents and zinc salts are not effective in all Wilson disease patients. Liver transplantation is the alternative option [65][66][67] [69]. In conclusion, there is still a long way to go until gene therapy can be used for safe treatment of Wilson disease in humans.…”

Section: Wilson's Diseasementioning

confidence: 99%

Gene Therapy in Liver Diseases: State-of-the-Art and Future Perspectives

Domvri¹,

Porpodis²,

Koffa³

et al. 2012

CGT

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Gene therapy is a fundamentally novel therapeutic approach that involves introducing genetic material into target cells in order to fight or prevent disease. A number of different strategies of gene therapy are tested at experimental and clinical levels, including: a) replacing a mutated gene that causes disease with a healthy copy of the gene, b) inactivating a mutated gene that its improper function causes pathogenesis, c) introducing a new gene coding a therapeutic compound to fight a disease, d) introducing to the target organ an enzyme converting an inactive pro-drug to its cytotoxic metabolite. In gene therapy, the transcriptional machinery of the patient is used to produce the active factor that exerts the intended therapeutic effect, ideally in a permanent, tissue-specific and manageable way. The liver is a major target for gene therapy, presenting inherited metabolic defects of single-gene etiology, but also severe multifactorial pathologies with limited therapeutic options such as hepatocellular carcinoma. The initial promising results from gene therapy strategies in liver diseases were followed by skepticism on the actual clinical value due to specificity, efficacy, toxicity and immune limitations, but are recently re-evaluated due to progress in vector technology and monitoring techniques. The significant amount of experimental data along with the available information from clinical trials are systematically reviewed here and presented per pathological entity. Finally, future perspectives of gene therapy protocols in hepatology are summarized.

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Repeated transplantation of hepatocytes prevents fulminant hepatitis in a rat model of Wilson's disease

Cited by 23 publications

References 54 publications

Animal models of Wilson disease

Animal models of Wilson disease

New Tools in Experimental Cellular Therapy for the Treatment of Liver Diseases

Gene Therapy in Liver Diseases: State-of-the-Art and Future Perspectives

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