Proteasomal Inhibition for Patients With Mis-sense Mutated Dysferlin
Status:
Terminated
Trial end date:
2017-09-15
Target enrollment:
Participant gender:
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.