Proteasomal Inhibition for Patients With Mis-sense Mutated Dysferlin

NCT ID: NCT01863004

Last Updated: 2017-09-21

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE1
• Total Enrollment: 3 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2012-12-31
• Study Completion Date: 2017-09-15

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

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

Bortezomib

Intervention Type: DRUG

Interventions

Bortezomib

Intervention Type: DRUG

Other Intervention Names

Velcade®

Eligibility 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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University Hospital, Basel, Switzerland

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Michael Sinnreich, Prof. Dr. MD

Role: PRINCIPAL_INVESTIGATOR

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

Locations

Neuromuskuläres Zentrum, Universitätsspital Basel

Basel, , Switzerland

Countries

Switzerland

References

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.

Reference Type: RESULT

PMID: 22318734 (View on PubMed)

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.

Reference Type: RESULT

PMID: 22174839 (View on PubMed)

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.

Reference Type: RESULT

PMID: 22736764 (View on PubMed)

Other Identifiers

2011DR1148

Identifier Type: REGISTRY

Identifier Source: secondary_id

DYSF001A1

Identifier Type: -

Identifier Source: org_study_id