Combining multiomics and drug perturbation profiles to identify muscle-specific treatments for spinal muscular atrophy
Katharina E. Meijboom, … , Caleb Webber, Melissa Bowerman
Katharina E. Meijboom, … , Caleb Webber, Melissa Bowerman
Published July 8, 2021
Citation Information: JCI Insight. 2021;6(13):e149446. https://doi.org/10.1172/jci.insight.149446.
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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 1

Restoration of protein and transcript expression in skeletal muscle of SMA mice following early SMN restoration treatment.

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Restoration of protein and transcript expression in skeletal muscle of S...
Smn–/–;SMN2 mice received a facial i.v. injection at P0 and P2 of Pip6a-scrambled or Pip6a-PMO (10 μg/g). The tibialis anterior was harvested from P2 untreated Smn–/–;SMN2 and WT mice; from P7 untreated, Pip6a-scrambled-treated, and Pip6a-PMO-treated Smn–/–;SMN2 mice; and from P7 untreated WT mice. (A) Comparison of the ratio of full-length (FL) SMN2 over total SMN2 quantified by qPCR between P7 untreated, Pip6a-scrambled-treated, and Pip6a-PMO–treated Smn–/–;SMN2 mice. Data are shown as a scatter plot and are represented as mean ± SEM; n = 4 animals per experimental group, 1-way ANOVA followed by a Dunnett’s multiple comparisons test, F ratio (F) = 34.88, degrees of freedom (df) = 11, ***P < 0.001. (B) Heatmap of the transcriptomic and proteomic expression profiles measured by the Pearson correlation between each pair of samples (after the removal of the first principal component). (C) First 2 principal components based on transcriptomic profiles of P7 untreated WT mice, untreated Smn–/–;SMN2 mice, Pip6a-PMO–treated Smn–/–;SMN2 mice, and Pip6a-scrambled Smn–/–;SMN2 mice. (D) First 2 principal components based on proteomic profiles of P7 untreated WT mice, untreated Smn–/–;SMN2 mice, Pip6a-PMO–treated Smn–/–;SMN2 mice, and Pip6a-scrambled Smn–/–;SMN2 mice.