When muscle cell membranes are damaged, the repair protein dysferlin is activated and reseals muscle membrane tears. If this repair protein is altered due to a genetic mutation, the body’s own quality control system (the so called proteasome) identifies the protein as being defective and eliminates it. Without dysferlin, injured muscle cell membranes cannot be repaired, which leads to progressive loss of skeletal muscle cells and thus to muscle wasting. It appears that the body’s own quality control system neutralizes mutated dysferlin even if the mutation does not actually impair its repair function.
A research group from the University Hospital of Basel had previously demonstrated that proteasome inhibitors can reactivate mutated dysferlin proteins in cultured muscle cells from muscular dystrophy patients. The inhibition of the exaggerated cellular quality control enables the altered repair protein to regain its function and to repair damaged muscle membranes.
The team succeeded in restoring a missing repair protein in skeletal muscle of patients with muscular dystrophy, a scientific first. The team has offered a proof-of-principle study and restored the missing protein in skeletal muscle of patients with muscular dystrophy. Three patients carrying a dysferlin mutation received a single systemic dose of a proteasome inhibitor. After only a few days the patients’ musculature produced the missing dysferlin protein at levels that could be therapeutically effective.
The new findings serve as groundwork for future long-term clinical trials, and could be of importance for the treatment of patients with muscular dystrophy as well as other, previously incurable genetic diseases.
Source: Universität Basel