Dysferlinopathy
Conditions
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.
Interventions
DRUGBortezomib
Sponsors
University Hospital, Basel, Switzerland
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 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. |
Countries
Switzerland
Outcome results
None listed