Combining multiomics and drug perturbation profiles to identify muscle-specific treatments for spinal muscular atrophy
Katharina E. Meijboom, Viola Volpato, Jimena Monzón-Sandoval, Joseph M. Hoolachan, Suzan M. Hammond, Frank Abendroth, Olivier G. de Jong, Gareth Hazell, Nina Ahlskog, Matthew J.A. Wood, Caleb Webber, Melissa Bowerman
Katharina E. Meijboom, Viola Volpato, Jimena Monzón-Sandoval, Joseph M. Hoolachan, Suzan M. Hammond, Frank Abendroth, Olivier G. de Jong, Gareth Hazell, Nina Ahlskog, Matthew J.A. Wood, Caleb Webber, Melissa Bowerman
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Research Article Muscle biology Neuroscience

Combining multiomics and drug perturbation profiles to identify muscle-specific treatments for spinal muscular atrophy

Abstract

Spinal muscular atrophy (SMA) is a neuromuscular disorder caused by loss of survival motor neuron (SMN) protein. While SMN restoration therapies are beneficial, they are not a cure. We aimed to identify potentially novel treatments to alleviate muscle pathology combining transcriptomics, proteomics, and perturbational data sets. This revealed potential drug candidates for repurposing in SMA. One of the candidates, harmine, was further investigated in cell and animal models, improving multiple disease phenotypes, including lifespan, weight, and key molecular networks in skeletal muscle. Our work highlights the potential of multiple and parallel data-driven approaches for the development of potentially novel treatments for use in combination with SMN restoration therapies.

Authors

Katharina E. Meijboom, Viola Volpato, Jimena Monzón-Sandoval, Joseph M. Hoolachan, Suzan M. Hammond, Frank Abendroth, Olivier G. de Jong, Gareth Hazell, Nina Ahlskog, Matthew J.A. Wood, Caleb Webber, Melissa Bowerman

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Figure 8

Administration of harmine to SMA mice improves neuromuscular phenotypes.

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Administration of harmine to SMA mice improves neuromuscular phenotypes....
All treated animals received a daily dose of harmine (10 mg/kg, diluted in 0.9% saline) by gavage starting at P0. (A) Relative frequency of myofiber sizes in P7 untreated and harmine-treated Smn–/–;SMN2 and Smn+/–;SMN2 mice. Data are shown as percentages, with n = 3 animals per experimental group and > 400 myofibers per experimental group. (B) Western blot and quantification of GLT-1/vinculin expression in the spinal cord of P7 untreated and harmine-treated Smn–/–;SMN2 and Smn+/–;SMN2 mice. Data are shown as a scatter plot and are represented as mean ± SEM; n = 3 for untreated and harmine-treated Smn+/–;SMN2 mice, n = 4 for untreated and harmine-treated Smn–/–;SMN2 mice, 2-way ANOVA followed by a Sidak’s multiple comparisons test, F = 35.01, df = 10, ****P < 0.0001. (C) Number of motor neuron cell bodies per ventral horn area in the spinal cord of P7 untreated and harmine-treated Smn–/–;SMN2 and Smn+/–;SMN2 mice. Data are represented as mean ± SEM n = 3 for untreated Smn+/–;SMN2 mice, n = 4 for harmine-treated Smn–/–;SMN2 and Smn+/–;SMN2 mice, n = 5 for untreated Smn–/–;SMN2 mice, 2-way ANOVA followed by a Tukey’s multiple comparisons test, F = 4.617, df = 12, *P < 0.05, **P < 0.01. Images are representative spinal cord ventral horn areas of untreated and harmine-treated Smn–/–;SMN2 mice. Total original magnification, ×20.