Establishment of Human Cellular Disease Models for Wilson Disease

Learn more about:
Related Clinical Trial
Copper and Molybdenum Balance in Participants With Wilson Disease Treated With ALXN1840 A Phase I/II Study of VTX-801 in Adult Patients With Wilson’s Disease Study of ALXN1840 on the Metabolism of a CYP2B6 Substrate in Healthy Participants Phase 1 Study of ALXN1840 on the Metabolism of a CYP2C9 Substrate in Healthy Participants. Clinical Evaluation and Assessment of Instruments and Biomarkers in Subjects With Wilson Disease Copper Concentration and Histopathologic Changes in Liver Biopsy in Participants With Wilson Disease Treated With ALXN1840 Study of Retinal Vascular Parameters in Patients With Wilson’s Disease Evaluation of Patients With Liver Disease ExAblate Transcranial MRgFUS for the Management of Treatment-Refractory Movement Disorders The Assessment of Copper Parameters in Wilson Disease Subjects on Standard of Care Treatment Establishment of Human Cellular Disease Models for Wilson Disease Efficacy and Safety, Long-term Study of Zinc Acetate to Treat Wilson’s Disease in Japan. Study to Assess Long-Term Outcomes of Trientine in Wilson Disease Patients Withdrawn From Therapy With d-Penicillamine A Controlled Study of Potential Therapeutic Effect of Oral Zinc in Manifesting Carriers of Wilson Disease Plasma Exchange and Continuous Hemodiafiltration in Treatment of Wilson’s Disease-related Liver Failure The Individual Therapy for Patients With Wilson’s Disease Study of Zinc for Wilson Disease Trientine Tetrahydrochloride (TETA 4HCL) for the Treatment of Wilson’s Disease Study of Tetrathiomolybdate in Patients With Wilson Disease Efficacy and Safety of ALXN1840 (Formerly Named WTX101) Administered for 48 Weeks Versus Standard of Care in Patients With Wilson Disease With an Extension Period of up to 60 Months WILSTIM – DBS (WILson STIMulation – Deep Brain Stimulation) Efficacy and Safety Study of Zinc Acetate to Treat Wilson’s Disease in Japan. Efficacy of Invitro Expanded Bone Marrow Derived Allogeneic Mesenchymal Stem Cell Transplantation Via Portal Vein or Hepatic Artery or Peripheral Vein in Patients With Wilson Cirrhosis Inhibitory rTMS in Dystonic Wilson Patients Natural History of Wilson Disease A Registered Cohort Study on Wilson’s Disease sCD163 and sMR in Wilsons Disease – Associations With Disease Severity and Fibrosis Cohort Research on Wilson’s Disease Single Daily Dosage of Trientine for Maintenance Treatment for Wilson Disease A Phase 1 Study to Assess the Effects in the Body of a Single Dose of Trientine Dihydrochloride in Wilson’s Disease Patients Efficacy and Safety Study of WTX101 in Adult Wilson Disease Patients

Brief Title

Establishment of Human Cellular Disease Models for Wilson Disease

Official Title

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

Brief 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.
    


Study Type

Observational


Primary Outcome

Reprogramming patient-derived fibroblasts into induced pluripotent stem cells (iPSCs)

Secondary Outcome

 Differentiation of patient-specific iPSCs into disease-affected cell types

Condition

Wilson Disease



Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information



Estimated Enrollment

40

Start Date

June 19, 2018

Completion Date

December 1, 2019

Primary Completion Date

December 1, 2019

Eligibility Criteria

        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
      

Gender

All

Ages

6 Months - 80 Years

Accepts Healthy Volunteers

No

Contacts

Arndt Rolfs, Prof. Dr., , 

Location Countries

Pakistan

Location Countries

Pakistan

Administrative Informations


NCT ID

NCT03867526

Organization ID

IPSWilson 06-2018


Responsible Party

Sponsor

Study Sponsor

Centogene AG Rostock


Study Sponsor

Arndt Rolfs, Prof. Dr., Principal Investigator, Centogene AG Rostock


Verification Date

April 2020