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 9

RNA sequencing and pathway analysis reveals full rescue of 20% of dysregulated genes in SMA muscle following harmine administration.

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RNA sequencing and pathway analysis reveals full rescue of 20% of dysreg...
All treated animals received a daily dose of harmine (10 mg/kg, diluted in 0.9% saline) by gavage starting at P0. TAs were harvested at P7 from untreated and harmine-treated Smn–/–;SMN2 mice and WT animals and were processed for RNA sequencing. (A) Venn diagram representation of the differentially expressed (DE) genes based on the negative binomial distribution (DESeq2) in untreated Smn–/–;SMN2 mice versus untreated WT mice (blue), harmine-treated Smn–/–;SMN2 mice versus untreated Smn–/–;SMN2 mice (purple), and untreated WT mice versus harmine-treated WT mice (orange). (B) Venn diagram representation of the DE genes based on the negative binomial distribution (DESeq2) in untreated Smn–/–;SMN2 mice versus untreated WT mice (blue), harmine-treated Smn–/–;SMN2 mice versus untreated Smn–/–;SMN2 mice (purple), and harmine-treated Smn–/–;SMN2 mice versus untreated WT mice (green). (C) Gene ontology (GO) biological processes enriched in genes DE in untreated Smn–/–;SMN2 mice versus untreated WT mice (blue), in harmine-treated Smn–/–;SMN2 mice versus untreated Smn–/–;SMN2 mice (purple), in untreated WT mice versus harmine-treated WT mice (orange), and in harmine-treated Smn–/–;SMN2 mice versus untreated WT (green). –LogP values for the enrichment are reported.