Abstract
BackgroundAmyotrophic lateral sclerosis (ALS) is currently an incurable disease without highly effective pharmacological treatments. The peptide drug GM604 (GM6 or Alirinetide) was developed as a candidate ALS therapy, which has demonstrated safety and good drug-like properties with a favorable pharmacokinetic profile. GM6 is hypothesized to bolster neuron survival through the multi-target regulation of developmental pathways, but mechanisms of action are not fully understood.MethodsThis study used RNA-seq to evaluate transcriptome responses in SH-SY5Y neuroblastoma cells following GM6 treatment (6, 24 and 48 h).ResultsWe identified 2867 protein-coding genes with expression significantly altered by GM6 (FDR < 0.10). Early (6 h) responses included up-regulation of Notch and hedgehog signaling components, with increased expression of developmental genes mediating neurogenesis and axon growth. Prolonged GM6 treatment (24 and 48 h) altered the expression of genes contributing to cell adhesion and the extracellular matrix. GM6 further down-regulated the expression of genes associated with mitochondria, inflammatory responses, mRNA processing and chromatin organization. GM6-increased genes were located near GC-rich motifs interacting with C2H2 zinc finger transcription factors, whereas GM6-decreased genes were located near AT-rich motifs associated with helix-turn-helix homeodomain factors. Such motifs interacted with a diverse network of transcription factors encoded by GM6-regulated genes (STAT3, HOXD11, HES7, GLI1). We identified 77 ALS-associated genes with expression significantly altered by GM6 treatment (FDR < 0.10), which were known to function in neurogenesis, axon guidance and the intrinsic apoptosis pathway.ConclusionsOur findings support the hypothesis that GM6 acts through developmental-stage pathways to influence neuron survival. Gene expression responses were consistent with neurotrophic effects, ECM modulation, and activation of the Notch and hedgehog neurodevelopmental pathways. This multifaceted mechanism of action is unique among existing ALS drug candidates and may be applicable to multiple neurodegenerative diseases.
Highlights
Amyotrophic lateral sclerosis (ALS) is currently an incurable disease without highly effective pharmacological treatments
GM604 hexapeptide (GM6) regulates the expression of 2867 protein-coding human genes in SH-SY5Y neuroblastoma cells RNA-seq was used to evaluate gene expression responses of protein-coding genes to GM6 hexapeptide (Fig. 1a)
When viewed in principal component space, effects of GM6 were partially consistent at each time point with better agreement between the 24 and 48 h responses compared to the 6 h response (Fig. 1c and d)
Summary
Amyotrophic lateral sclerosis (ALS) is currently an incurable disease without highly effective pharmacological treatments. The disease most commonly occurs between the ages of 50 and 70 and is twice as common in men compared to women [1] It is a unique disorder with deficits impacting both lower and upper motor neurons, either lower or upper motor neuron dysfunction may be dominant for any one patient [2]. There is strong urgency among ALS researchers and the patient community to develop effective disease-modifying treatments. To this point, clinical ALS management has emphasized supportive measures (e.g., muscle relaxants) and working closely with patients to preserve physiological function (e.g., speech therapy) [4]. No currently approved treatment is expected to substantially alter disease course and existing therapies appear to provide only marginal symptomatic benefits [7, 8]
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