Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT03867526 |
| Other study ID # |
IPSWilson 06-2018 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
June 19, 2018 |
| Est. completion date |
December 1, 2019 |
Study information
| Verified date |
April 2020 |
| Source |
CENTOGENE GmbH Rostock |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial 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
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.
