Proteasomal Inhibition for Patients With Mis-sense Mutated Dysferlin

NCT01863004 | Terminated Phase 1 DMC

• 2 other identifiers: DYSF001A12011DR1148
• Study Type: interventional
• Target: 3
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Dysferlinopathy

Outcome Measures

Primary Outcomes (1)

• 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.

  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

Study Arms (1)

Bortezomib (Velcade®)

EXPERIMENTAL

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

Interventions

Bortezomib DRUG

Also known as: Velcade®

Bortezomib (Velcade®)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

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

You may not qualify if:

• 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

Sponsors & Collaborators

• University Hospital, Basel, Switzerland: lead

Study Sites (1)

Neuromuskuläres Zentrum, Universitätsspital Basel

Basel, 4031, Switzerland

Location

Related Publications (3)

• Azakir BA, Di Fulvio S, Kinter J, Sinnreich M. Proteasomal inhibition restores biological function of mis-sense mutated dysferlin in patient-derived muscle cells. J Biol Chem. 2012 Mar 23;287(13):10344-10354. doi: 10.1074/jbc.M111.329078. Epub 2012 Feb 8.

  PMID: 22318734 RESULT

• Di Fulvio S, Azakir BA, Therrien C, Sinnreich M. Dysferlin interacts with histone deacetylase 6 and increases alpha-tubulin acetylation. PLoS One. 2011;6(12):e28563. doi: 10.1371/journal.pone.0028563. Epub 2011 Dec 8.

  PMID: 22174839 RESULT

• Azakir BA, Di Fulvio S, Salomon S, Brockhoff M, Therrien C, Sinnreich M. Modular dispensability of dysferlin C2 domains reveals rational design for mini-dysferlin molecules. J Biol Chem. 2012 Aug 10;287(33):27629-36. doi: 10.1074/jbc.M112.391722. Epub 2012 Jun 26.

  PMID: 22736764 RESULT

MeSH Terms

Conditions

Dysferlinopathy

Interventions

Bortezomib

Intervention Hierarchy (Ancestors)

Boronic Acids; Acids, Noncarboxylic; Acids; Inorganic Chemicals; Boron Compounds; Organic Chemicals; Pyrazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Michael Sinnreich, Prof. Dr. MD

  Sponsor-Investigator, Neuromuscular Center, Neurology Clinic, University Hospital Basel, Switzerland

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 29, 2013
• First Posted: May 27, 2013
• Study Start: December 1, 2012
• Primary Completion: September 15, 2017
• Study Completion: September 15, 2017
• Last Updated: September 21, 2017

Record last verified: 2017-09

Locations

CH (1)