TGFβ inhibitors and L-type calcium channel blockers are potential drug repurposing candidates for LMNA-MD

Topic:

Pre-Clinical Research

Poster Number: 437 O

Author(s):

Nathaniel Mohar, BS, University of Iowa, Brenna Powers, BS, University of Iowa, Amya Saxena, University of Iowa, Benjamin Hinz, BS, University of Iowa, Zachary Darr, BS, University of Iowa, Steven Moore, MD, PhD, The University of Iowa, Carver College of Medicine, Lori Wallrath, PhD, University of Iowa

Background: Mutations in the LMNA gene cause laminopathies, with striated muscle disease (LMNA-MD) as the most common phenotype. Pathogenic mutations typically result in single amino acid substitutions in all domains of the lamin protein: N-terminal head, central coiled-coil rod, and the C-terminal Ig-like fold. Treatment development has been limited because different lamin mutants exhibit different properties, suggesting a need for personalized medicine.

Objective: Our goal is to identify and test drug repurposing candidates for treatment of LMNA-MD through in vivo unbiased screens and genetic analyses of disease mechanisms using Drosophila models of LMNA-MD.

Results: In a Drosophila model of the LMNA R249Q substitution, we performed an unbiased screen of 1,520 compounds assaying for rescue of lethality caused by loss of muscle function. This screen identified the L-type calcium channel antagonists clevidipine and amlodipine as compounds capable of restoring viability. Validation of these findings in Drosophila models of additional lamin mutants demonstrated that rescue was limited to substitutions in a subdomain of the coiled-coil rod (R249Q, R249W, and H222P), however non-dihydropyridine calcium channel blockers (verapamil and diltiazem) were also efficacious in these mutants. To identify candidate treatments for additional mutations, we focused on the TGFβ/SMAD pathway, which we have shown is activated by mutant lamins in Drosophila and human muscle. Genetic inhibition of this pathway rescued structural and functional muscle defects in a Drosophila model of the R527P mutant lamin. To translate these findings to small molecules, we treated this model with five TGFβ inhibitors and improved functional muscle defects with three of the five, supporting TGFβ/SMAD inhibitor repurposing.

Conclusions: Collectively, our findings support L-type calcium channel antagonists and TGFβ inhibitors as repurposing candidates to treat LMNA-MD caused by at least the R249Q, R249W, and R527P substitutions. Furthermore, these data support that mutation specific disease mechanisms drive LMNA-MD pathogenesis, and personalized treatments will likely be required.