An Unbiased Drug Screen in a Drosophila Model of LMNA -Muscular Dystrophy Identifies Calcium Channel Blockers as Potential Treatments

Nathaniel P Mohar; Brenna A Powers; Benjamin E Hinz; Alex R Bock; Hailey McCoy-Munger; Zachary Darr; Maxwell W Shumaker; Alexander T Wemmie; Amya Saxena; Lori L Wallrath

doi:10.3390/ijms27188367

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An Unbiased Drug Screen in a Drosophila Model of LMNA -Muscular Dystrophy Identifies Calcium Channel Blockers as Potential Treatments

Journal article

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An Unbiased Drug Screen in a Drosophila Model of LMNA -Muscular Dystrophy Identifies Calcium Channel Blockers as Potential Treatments

Nathaniel P Mohar, Brenna A Powers, Benjamin E Hinz, Alex R Bock, Hailey McCoy-Munger, Zachary Darr, Maxwell W Shumaker, Alexander T Wemmie, Amya Saxena and Lori L Wallrath

International journal of molecular sciences, Vol.27(18), 8367

09/19/2026

DOI: 10.3390/ijms27188367

PMCID: PMC13607455

PMID: 42794794

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Abstract

Mutations in the LMNA gene encoding A-type lamins cause multiple muscular dystrophies (LMNA-MD). Lamins are intermediate filaments with three conserved domains: an N-terminal head, a coiled-coil rod, and a C-terminal domain possessing an Ig-like fold. Missense mutations in all three domains can cause LMNA-MD by mechanisms that are not well understood. Currently, there are limited treatments for LMNA-MD beyond symptom management. In this study, our goal was to identify candidate treatments through an in vivo drug repurposing screen using Drosophila models of LMNA-MD that recapitulate aspects of the disease phenotype. Expression of LamC R264Q (Drosophila orthologue of human LMNA R249Q) in fly muscles causes muscle defects and premature death. We fed 1520, mostly FDA/EMA-approved, drugs to larvae and screened for rescue of lethality. This screen resulted in 68 positive hit drugs that partially restored viability. Molecular fingerprinting clustered a subset of these compounds into six structurally related groups, including L-type voltage-gated calcium channel inhibitors. We tested these inhibitors using multiple fly models expressing different mutant lamins and discovered that only flies expressing amino acid substitutions in the rod domain benefited, supporting a need for personalized treatments. Collectively, our findings support L-type voltage-gated calcium channel blockers as candidate treatments that warrant testing in pre-clinical models.

Animals

Calcium Channel Blockers - pharmacology

Calcium Channel Blockers - therapeutic use

Disease Models, Animal

Drosophila melanogaster - genetics

Drosophila Proteins - genetics

Drosophila Proteins - metabolism

Drug Evaluation, Preclinical

Humans

Lamin Type A - genetics

Lamin Type A - metabolism

Muscular Dystrophies - drug therapy

Muscular Dystrophies - genetics

Muscular Dystrophies - metabolism

Details

Title: Subtitle: An Unbiased Drug Screen in a Drosophila Model of LMNA -Muscular Dystrophy Identifies Calcium Channel Blockers as Potential Treatments
Creators: Nathaniel P Mohar - University of Iowa
Brenna A Powers - University of Iowa
Benjamin E Hinz - University of Iowa
Alex R Bock - University of Iowa
Hailey McCoy-Munger - University of Iowa
Zachary Darr - University of Iowa
Maxwell W Shumaker - University of Iowa
Alexander T Wemmie - University of Iowa
Amya Saxena - University of Iowa
Lori L Wallrath - University of Iowa
Resource Type: Journal article
Publication Details: International journal of molecular sciences, Vol.27(18), 8367
DOI: 10.3390/ijms27188367
PMID: 42794794
PMCID: PMC13607455
NLM abbreviation: Int J Mol Sci
ISSN: 1661-6596
eISSN: 1422-0067
Publisher: MDPI
Grant note: R21AR075193 / NIAMS NIH HHS T32GM144636 / NIGMS NIH HHS 22-1061420 / Muscular Dystrophy Association 25PRE1373209 / American Heart Association
Language: English
Date published: 09/19/2026
Academic Unit: Biochemistry and Molecular Biology; University College Courses
Record Identifier: 9985236321902771

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