Identification of Novel CSF-Derived miRNAs in Treated Paediatric Onset Spinal Muscular Atrophy: An Exploratory Study

Abstract

The availability of disease modifying therapies for spinal muscular atrophy (SMA) have created an urgent need to identify clinically meaningful biomarkers that provide insight into disease progression and therapeutic response. microRNAs (miRNA) have been shown to be involved in the pathogenesis of SMA and have the potential to provide insight within the field of SMA. miRNA-sequencing was utilized to identify differential miRNA expression in the cerebrospinal fluid (CSF) in six children with SMA treated with nusinersen in this exploratory study. Fourteen differentially expressed miRNAs were significantly altered in CSF from baseline to follow-up during treatment with nusinersen. The greatest magnitude of change was noted in miR-7-5p, miR-15a-5p, miR-15b-3p/5p, miR-126-5p, miR-128-2-5p and miR-130a-3p which encompassed a spectrum of functions predominantly in neurogenesis, neuronal differentiation and growth. The dominant signaling pathways identified in this study were the mammalian target of rapamycin and the mitogen-activated protein kinase signaling pathways. This study identified multiple miRNAs that were involved in the complex interplay between neurodevelopment and neurodegeneration.

Keywords: biomarker; microRNA; nusinersen; pharmacodynamic; spinal muscular atrophy.

Figure 1

Flowchart of the experimental approach for identification of miRNA in cerebrospinal fluid of children affected with spinal muscular atrophy.

Figure 2

Flowchart depicting experimental approach for filtration of significant miRNAs in cerebrospinal fluid of children affected with spinal muscular atrophy for further exploration comparing follow-up and baseline phase of therapy.

Figure 3

Gene ontology (GO) analysis of the target genes from the 14 candidate miRNAs to elucidate their key roles in (A) Biological Processes, (B) Cellular Components (C) Molecular Function and (D) KEGG pathway enrichment analysis of target genes from the 14 candidate miRNAs.

Figure 4

Gene ontology (GO) analysis using the DAVID software. Role of the affected genes (indicated as red stars) within the mTOR signaling pathway associated with miR-378.

Figure 5

Gene ontology (GO) analysis using the DAVID software. Role of the affected genes (indicated as red stars) within the MAPK signaling pathway associated with miR-338.