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Proteasomal Inhibition for Patients With Mis-sense Mutated Dysferlin (Dysferlin)

This study has been terminated.
(insufficient enrollment rate)
Sponsor:
ClinicalTrials.gov Identifier:
NCT01863004
First Posted: May 27, 2013
Last Update Posted: September 21, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Information provided by (Responsible Party):
University Hospital, Basel, Switzerland
  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: Intervention Model: Single Group Assignment
Masking: None (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 ]
    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.


Enrollment: 3
Study Start Date: December 2012
Study Completion Date: September 15, 2017
Primary Completion Date: September 15, 2017 (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

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
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
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01863004


Locations
Switzerland
Neuromuskuläres Zentrum, Universitätsspital Basel
Basel, Switzerland, 4031
Sponsors and Collaborators
University Hospital, Basel, Switzerland
Investigators
Principal Investigator: Michael Sinnreich, Prof. Dr. MD Sponsor-Investigator, Neuromuscular Center, Neurology Clinic, University Hospital Basel, Switzerland
  More Information
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