Background: Mutations in LMNA cause a collection of diseases known as laminopathies, which include multiple types of muscular dystrophy (LMNA-MD). Pathogenic mutations cause amino acid substitutions in all three domains (N-terminal head, a coiled-coil central rod, and a C-terminal Ig-like fold) of the lamin protein. Currently, there are no treatments available for LMNA-MD beyond symptom management.
Objective: Our goal is to identify candidate treatments for LMNA-MD through an in vivo drug repurposing screen using a Drosophila model of LMNA-MD.
Results: We have generated a Drosophila model of the LMNA R249Q substitution that recapitulates aspects of the human disease. These flies exhibit premature death due to loss of muscle function prior to adulthood. We screened 1,520 FDA/EMA approved drugs for rescue of lethality. This primary screen resulted in 68 positive hit compounds that partially restored viability. Validation of these hits using independently purchased compound revealed clevidipine, an L-type voltage gated calcium channel blocker, as a top candidate. To broaden our analysis, we next tested whether clevidipine could rescue lethality in additional Drosophila models of human R249W, H506P, W514R, and R527P lamin substitutions. Our results indicate that clevidipine rescues lethality caused by the R249Q and R249W rod domain substitutions but not the H506P, W514R, and R527P substitutions, all of which reside in the C-terminal Ig-like fold.
Conclusions: Collectively, our findings support clevidipine as a candidate treatment for LMNA-MD. The positive effect of clevidipine suggest altered calcium dynamics as a disease mechanism for LMNA-MD. However, mutation-specific rescue suggests that multiple mechanisms of pathogenesis exist. Furthermore, these data suggest a potential need for personalized treatments. Future studies will define the effect of these substitutions on calcium dynamics using in vivo fluorescent biosensors.