Establishment of Human Cellular Disease Models for Wilson Disease

Study Overview
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Brief Summary
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Establishment of human cellular disease models for Wilson disease for an individualized therapy develop-ment having the capacity to address both hepatic and neurologic forms of the disease

Detailed Description
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Wilson disease (WD) is caused by a defective gene for a copper-transporting protein that regulates cellular copper homeostasis in all major organs. Copper is an essential metal ion that is required for physiological cell functions (e.g. numerous enzymes require copper as a co-factor). It often occurs in people without a known family history of the condition. The condition affects females and males likewise. Wilson disease occurs in approximately 1 out of every 30,000 births and belongs to the class of rare diseases. Because this is an inherited disorder, risks include a family history of Wilson disease. Symptoms most often appear during adolescence or early adulthood. Symptoms may include: increased thickness of the interventricular septum and left ventricular posterior wall supraventricular tachycardias tremors in hands, legs, head repetitive muscle contractions (dystonia) renal stones renal failure psychiatric symptoms (e.g. depression) liver disease Therapeutic approaches include the drug Penicillamine, which binds to accumulated copper and eliminate it through urine. However, its use is controversy, since it is associated with an extended range of adverse effects and patients with neurologic manifestations deteriorated throughout the use of Penicillamine. Another strategy is the use of zinc salts that function via a detoxification effect of the stored copper ions. Recent studies suggested that zinc salts are effective in presymptomatic Wilson disease, but are problematic in hepatic Wilson disease and not suitable as a monotherapy. In Wilson disease, the mutations of the hepatic copper transport ATP7B lead to a defective accumulation of copper in the cells. In addition to this primary pathological process, certain allelic variants (mutations in the protein-coding DNA region) are associated with the formation of a protein folding defect, often associated with considerable endoplasmic reticulum (ER) stress, which exposes the cell to a stress that leads to inflammatory reactions and in the worst case can lead to apoptotic cell death with the consequence of functional organ confinement, devastating disorders of whole organ systems and formation of tumors. Thus, ER stress can be involved in a substantial part of the clinical picture of the disease and support the progressive character of the disease. ER stress-associated protein mutants are generally able to re-spond to certain low-molecular-weight substances affecting cellular proteostasis. i.e. that the malignant influence of the misfolded protein on cellular physiology is mitigated or corrected. A newly developed molecular therapeutic approach involves Pharmacological Chaperone therapy suitable to overcome protein misfolding and ER stress. The concept is that active-site binding low molecular competitive inhibitors (Pharmacological Chaperones) are able to stabilize the misfolded protein, bypass early degradation pathways (such as the ubiquitin-proteasome-system) and enhance/re-establish protein function at the site of action within the cell. These drugs are typically orally available, can reach even difficult to target organs (e.g. central nervous system) and are able to correct the pathophysiology. In addition to this class of inhibitory Pharmacological Chaperones, non-inhibitory PCs are being developed, because the multi-functional ATP7B protein provides distinct sites for a putative ligand binding. A second class of low-molecular-weight substances target other components of the proteostasis network, e.g. the heat shock proteins or the proteasome as mediators to handle abnormally accumulated proteins within the ER. Among the amenable protein folding diseases, the investigators investigated a few lysosomal storage dis-eases like Fabry, Gaucher and Pompe disease within recent years. A proof-of-concept study revealed Wilson disease as another pathology that can be addressed via this molecular therapeutic approach. Therefore it is the goal of the study to prepare a cell culture from patients affected with Wil-son´s disease in order to identify novel pathways and proteins involved in disease progression that allow for an earlier diagnosis (i.e. before symptom onset) and that are suitable targets for an individualized therapeutic approach able to address not only the hepatic form, but also the neurologic form of the disease, which is less responsive to the current therapeutic approaches.

Official Title
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Induced Pluripotent Stem Cells for the Development of Novel Drug Therapies for Hepatic and Neurological Wilson Disease

Conditions
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Wilson Disease

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Informed consent will be obtained from the patient or the parents before any study related procedures. Patients of both genders older than 6 months and younger than 80 years The patient has a diagnosis of Wilson dis-ease Exclusion Criteria: No Informed consent from the patient or the parents before any study related procedures Patients of both genders younger than 6 months and older than 80 years No diagnosis of Wilson disease

Ages Eligible for Study
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Minimum Age: 6 Months
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Reprogramming patient-derived fibroblasts into induced pluripotent stem cells (iPSCs) | Generation of patient-specific iPSCs by using sendai-virus reprogramming method | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Differentiation of patient-specific iPSCs into disease-affected cell types | Establishment of iPSC-based disease model to recapitulate/phenocopy the disease in a dish | 24 months |