Proteasomal Inhibition for Patients With Mis-sense Mutated Dysferlin

Study Overview
=================
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.

Official Title
-----------------
Proteasomal Inhibition for Patients With Mis-sense Mutated Dysferlin

Conditions
-----------------
Dysferlinopathy

Intervention / Treatment
-----------------
* Drug: Bortezomib


Participation Criteria
=================
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Bortezomib (Velcade®)<br>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<br> <br> * Other names: Velcade®;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 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. | repeated needle muscle biopsies over a five day period |