LGMD R2 : new pharmacological approaches
A joint study conducted by I-Stem, Genethon and the Institute of Myology reveals the positive effects of two drugs—saracatinib and bazedoxifene—on muscle cell models of dysferlin-related limb-girdle muscular dystrophy type R2. This opens up a novel research avenue.
Limb-girdle muscular dystrophy type R2 (LGMD R2), caused by mutations in the DYSF gene, results from a complete or partial absence, or a dysfunction, of the dysferlin protein. Normally located at the membrane (or sarcolemma) of muscle cells, this protein plays a crucial role in maintaining sarcolemma stability and enabling muscle fibers to withstand mechanical stress.
Teams from I-Stem and Genethon, led by Xavier Nissan and Isabelle Richard, in collaboration with the Institute of Myology, set out to determine whether known molecules with established benefits in other diseases could help relocalize defective dysferlin to the membrane and thereby enhance the resilience of muscle cell models of LGMD R2.
A stronger cellular membrane
The researchers tested the effects of more than 2,200 compounds; only two—saracatinib (an anticancer agent) and bazedoxifene (a hormone therapy for menopause)—showed a significant reduction in cell death.
Saracatinib proved effective in cells where dysferlin is produced but fails to reach the sarcolemma, whereas bazedoxifene was also beneficial in cells that do not express the protein at all, suggesting two distinct mechanisms of action. The results point to an effect of saracatinib on protein folding, while bazedoxifene appears to enhance autophagy—the process by which cells degrade and recycle unwanted components. In both cases, these changes seem to strengthen the membrane's resistance to mechanical stress, particularly by improving membrane repair, and support better cell survival.
Leads among others
These findings offer a complementary approach to gene therapy and exon skipping, both of which are also under investigation for LGMD R2. Moreover, the strategy of pharmacologically compensating for the dysferlin deficit has already shown promise in LGMD R2, notably with the use of galectin-1. I-Stem and Genethon had also demonstrated the efficacy of small molecules such as givinostat and bortezomib in LGMD R3.
These are promising therapeutic avenues worth pursuing further—especially as compounds like bazedoxifene, by stimulating autophagy, may even enhance the efficacy of gene therapy.