Proteasomal Inhibition for Patients With Mis-sense Mutated Dysferlin

University Hospital Basel

Status and phase: Terminated; Phase 1

Conditions: Dysferlinopathy

Treatments: Drug: Bortezomib

Study type: Interventional

Funder types: Other

Identifiers

NCT01863004

2011DR1148 (Registry Identifier)

DYSF001A1

Details and patient eligibility

About

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.

Enrollment: 3 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: N/A

Interventional model: Single Group Assignment

Masking: None (Open label)

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3 participants in 1 patient group

Bortezomib (Velcade®)

Experimental group

Description:

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.

Treatment:

Drug: Bortezomib