insufficient enrollment rate

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.

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