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 6

Administration of harmine to SMA mice partially restores the expression of target genes, as predicted by CMap analyses.

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Administration of harmine to SMA mice partially restores the expression ...
All treated animals received a daily dose of harmine (10 mg/kg, diluted in 0.9% saline) by gavage starting at P0. (A) qPCR analysis of Snrnp27, Gls, Aspm, and Mcm2 in triceps of P7 untreated and harmine-treated Smn–/–;SMN2 SMA mice and Smn+/–;SMN2 control littermates. Data are shown as a scatter plot and are represented as mean ± SEM, n = 4 animals per experimental group except for harmine-treated Smn+/–;SMN2 where n = 3, 2-way ANOVA followed by a Sidak’s multiple comparisons test, F = 25.77 (Snrnp27), F = 1.103 (Gls), F = 0.5143 (Aspm), F = 0.3992 (Mcm2), df = 11 for all, *P < 0.05, **P < 0.01. (B) qPCR analysis of Clpx, Ppm1b, Tob2, and Cdkn1a in triceps of P7 untreated and harmine-treated Smn–/–;SMN2 SMA mice and Smn+/–;SMN2 control littermates. Data are shown as a scatter plot and are represented as mean ± SD; n = 4 animals per experimental group except for harmine-treated Smn+/–;SMN2 where n = 3, 2-way ANOVA followed by a Sidak’s multiple comparisons test, F = 0.4275 (Clpx), F = 0.006960 (Ppm1b), F = 8.167 (Tob2), F = 1.195 (Cdkn1a), df = 11 for all, **P < 0.01.