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

• ClinicalTrials.gov Identifier: NCT01863004
• Recruitment Status: Terminated
• First Posted: May 27, 2013
• Last Update Posted: September 21, 2017
• Sponsor: University Hospital, Basel, Switzerland
• Information provided by (Responsible Party): University Hospital, Basel, Switzerland

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Dysferlinopathy	Drug: Bortezomib	Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 3 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Proteasomal Inhibition for Patients With Mis-sense Mutated Dysferlin
• Study Start Date: December 2012
• Actual Primary Completion Date: September 15, 2017
• Actual Study Completion Date: September 15, 2017

Arms and Interventions

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 Name: Velcade®

Outcome Measures

Primary Outcome Measures :

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. [ 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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• 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

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

Publications of Results:

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):10344-54. doi: 10.1074/jbc.M111.329078. Epub 2012 Feb 8. Retraction in: J Biol Chem. 2017 Jul 28;292(30):12542.

Retraction in: J Biol Chem. 2017 Jul 28;292(30):12542

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. Retraction in: PLoS One. 2018 Jan 29;13(1):e0192239.

Retraction in: PLoS One. 2018 Jan 29;13(1):e0192239

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. Retraction in: J Biol Chem. 2017 Jul 28;292(30):12543.

Retraction in: J Biol Chem. 2017 Jul 28;292(30):12543

• Responsible Party: University Hospital, Basel, Switzerland
• ClinicalTrials.gov Identifier: NCT01863004
• Other Study ID Numbers: DYSF001A1; 2011DR1148 ( Registry Identifier: Swissmedic Referenznummer 2011DR1148 )
• First Posted: May 27, 2013
• Last Update Posted: September 21, 2017
• Last Verified: September 2017

Additional relevant MeSH terms:

Bortezomib; Antineoplastic Agents