High-throughput screening identification of two molecules as potential approaches for treating a form of limb-girdle muscular dystrophy (LGMD-R2)
I-Stem, Genethon and the Institute of Myology, laboratories of the Institute of Biotherapies created by the AFM-Telethon have collaborated on work recently published in the British Journal of Pharmacology of March 19th. Their objective: to identify a pharmacotherapy to treat LGMD-R2, a form of limb-girdle myopathy.
LGMD-R2 is caused by a loss of function of dysferlin, a transmembrane protein essential for muscle cell membrane repair mechanisms.
Led by Celine Bruge from Xavier Nissan’s team at I-Stem, this study began with the development of a high-throughput in vitro screening test using immortalized myoblasts, disease models produced by the MyoLine platform of the Institute of Myology. This test made it possible to select molecules from a library of 2,239 drugs and bioactive compounds that have already been clinically approved. Among these, saracatinib and bazedoxifene emerged as potential candidates to be repositioned for patients with LGMD R2 who carry the L1341P missense mutation of the DYSF gene.
Once these two candidates had been identified, Emilie Pellier from the I-Stem team carried out a functional characterization of these molecules. This analysis showed the protective effect of these two drugs on the plasma membrane of muscle cells expressing this misfolded form of dysferlin. Only bazedoxifene was able to protect those cells expressing other mutations of the same gene. Finally, Anthony Brureau and Nathalie Bourg from Isabelle Richard’s team at Genethon showed that bazedoxifene had an additional protective effect ex vivo on the muscle fibers of mice in which the gene encoding dysferlin had been inactivated.
These results suggest the therapeutic potential of these two approaches, which remains to be confirmed: one with saracatinib for LGMD R2 with an L1341P mutation, the other with bazedoxifene for patients with LGMD R2, regardless of the dysferlin gene mutation. It is important to emphasize that these results are still preliminary. Long and costly in vivo studies will still be necessary to validate these approaches and determine whether they could, in the long term, lead to confirmed therapeutic solutions for patients with LGMD R2.
