Establishment of Human Cellular Disease Models for Wilson Disease
Establishment of Human Cellular Disease Models for Wilson Disease
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
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.
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