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

September 20, 2017 updated by: University Hospital, Basel, Switzerland
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.

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Actual)

3

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Switzerland
      • Basel, Switzerland, 4031
        • Neuromuskuläres Zentrum, Universitätsspital Basel

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
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 Names:
  • Velcade®

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
repeated needle muscle biopsies over a five day period

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University Hospital, Basel, Switzerland

Investigators

  • Principal Investigator: Michael Sinnreich, Prof. Dr. MD, Sponsor-Investigator, Neuromuscular Center, Neurology Clinic, University Hospital Basel, Switzerland

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

December 1, 2012

Primary Completion (Actual)

September 15, 2017

Study Completion (Actual)

September 15, 2017

Study Registration Dates

First Submitted

April 29, 2013

First Submitted That Met QC Criteria

May 22, 2013

First Posted (Estimate)

May 27, 2013

Study Record Updates

Last Update Posted (Actual)

September 21, 2017

Last Update Submitted That Met QC Criteria

September 20, 2017

Last Verified

September 1, 2017

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • DYSF001A1
  • 2011DR1148 (Registry Identifier: Swissmedic Referenznummer 2011DR1148)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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