Trial record 3 of 3 for:    "Dysferlinopathy"

Proteasomal Inhibition for Patients With Mis-sense Mutated Dysferlin

This study is currently recruiting participants.
Verified May 2013 by University Hospital, Basel, Switzerland
Sponsor:
Information provided by (Responsible Party):
Michael Sinnreich, University Hospital, Basel, Switzerland
ClinicalTrials.gov Identifier:
NCT01863004
First received: April 29, 2013
Last updated: May 22, 2013
Last verified: May 2013
  Purpose

Dysferlin is a protein with an important role in the repair of muscle surface membranes. Mutations in dysferlin cause different forms of muscular dystrophies. Dysferlinopathies are inherited in an autosomal recessive manner, and many patients with this disease harbor mis-sense mutations in at least one of their two pathogenic DYSF alleles. These patients have significantly reduced or absent dysferlin levels in skeletal muscle, suggesting that dysferlin encoded by mis-sense alleles is rapidly degraded by the cell's quality-control system. In a series of in-vitro experiments we showed that mis-sense mutated dysferlin can be salvaged from degradation by proteasomal inhibition. This resulted in an increase of functional dysferlin protein and a subsequent repair of plasma membranes of cultured patient-derived muscle cells. In this proof-of-concept study we would like to test wether proteasomal inhibition can salvage mis-sense mutated dysferlin in patients harboring certain dysferlin mis-sense mutations.


Condition Intervention Phase
Dysferlinopathy
Drug: Bortezomib
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Pharmacokinetics/Dynamics Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Proteasomal Inhibition for Patients With Mis-sense Mutated Dysferlin

Resource links provided by NLM:


Further study details as provided by University Hospital, Basel, Switzerland:

Primary Outcome Measures:
  • Dysferlin protein expression levels change from baseline over 5 days assessed by repeated biopsies and blood draws in skeletal muscle and in blood monocytes following administration of a single dose of Bortezomib. [ Time Frame: repeated needle muscle biopsies over a five day period ] [ Designated as safety issue: No ]
    Repeated needle muscle biopsies and blood draws will be performed after administration of a single dose of Bortezomib (Velcade) to assess dysferlin protein expression in skeletal muscle and in blood monocytes over a five day period.


Estimated Enrollment: 5
Study Start Date: December 2012
Estimated Study Completion Date: December 2014
Estimated Primary Completion Date: December 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Bortezomib (Velcade®)

This study tests whether salvage of mis-sense mutated dysferlin through proteasomal inhibition seen in cultured muscle cells can be translated into patients harboring dysferlin mis-sense mutations. The proteasomal inhibitor Bortezomib (Velcade®) is already approved as a medication for the treatment of multiple myeloma in Switzerland and in other countries.

Following an administration of a single dose of Bortezomib repeated needle muscle biopsies and blood draws will be performed to assess dysferlin levels in skeletal muscle and blood monocytes over a five day period.

Drug: Bortezomib
Other Name: Velcade®

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • must carry at least one allele of a salvageable mis-sense mutation of dysferlin
  • Age ≥ 18 years
  • Written informed consent

Exclusion Criteria:

  • Bleeding disorder
  • Acute or chronic kidney failure (CCL <50 ml/min)
  • Advanced liver disease or active hepatitis
  • Congestive heart failure NYHA III and IV
  • Pregnancy or nursing
  • Immunosuppression (prednisolone doses below 20 mg/d are allowed)
  • Therapy with strong inhibitors of cytochrome P450 3A4
  • HCV or HIV infection
  • Regular alcohol consumption (>14 drinks a week)
  • Drug addiction
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01863004

Contacts
Contact: Michael Sinnreich, Prof. Dr. med. Dr. phil. 0041-61-55 ext 86792 michael.sinnreich@usb.ch

Locations
Switzerland
Neuromuskuläres Zentrum, Universitätsspital Basel Recruiting
Basel, Switzerland, 4031
Contact: Michael Sinnreich, Prof. Dr. med. Dr. phil.    0041-61-265 41 30    michael.sinnreich@ubs.ch   
Principal Investigator: Michael Sinnreich, Prof. Dr. med. Dr. phil.         
Sub-Investigator: Bilal A. Azakir, PhD         
Sponsors and Collaborators
Michael Sinnreich
Investigators
Principal Investigator: Michael Sinnreich, Prof. Dr. med. Dr. phil. Sponsor-Investigator, Neuromuscular Center, Neurology Clinic, University Hospital Basel, Switzerland
  More Information

Publications:
Responsible Party: Michael Sinnreich, Prof. Dr. med. Dr. phil., Head Neuromuscular Center, Department of Neurology, University Hospital, Basel, Switzerland
ClinicalTrials.gov Identifier: NCT01863004     History of Changes
Other Study ID Numbers: DYSF001A1, 2011DR1148
Study First Received: April 29, 2013
Last Updated: May 22, 2013
Health Authority: Switzerland: Swissmedic

Additional relevant MeSH terms:
Muscular Dystrophies, Limb-Girdle
Muscular Dystrophies
Muscular Disorders, Atrophic
Muscular Diseases
Musculoskeletal Diseases
Neuromuscular Diseases
Nervous System Diseases
Genetic Diseases, Inborn
Bortezomib
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on April 23, 2014