Establishment of Human Cellular Disease Models for Wilson Disease
Condition: Wilson Disease
MeSH terms: Hepatolenticular Degeneration
Study type: Observational

Summary: 
      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: 
      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.
    

Observational model: Case-Only
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Patients has a diagnosis of Wilson disease
      
Biospecimen description: 
      The skin biopsy will be carried out for patients with a diagnosis of Niemann Pick. The biopsy
      is performed by the physician by means of punch biopsy (diameter 2-3 mm) under local
      anesthesia, preferably on the forearm (alternatively: thigh). The biopsy is immediately
      transferred to sterile cell culture medium and sent by center representative for the quickest
      possible processing to CENTOGENE's laboratory located in Germany or to professional
      collaborators being part of the project.