Genervon presented its GM604 Mechanisms of Action at the 29th International Symposium on ALS/MND in Glasgow, UK

March 1, 2019

Genervon Biopharmaceuticals presented its GM604 Mechanisms of Action at the 29th International Symposium on ALS/MND held on Dec. 8-9, 2018 in Glasgow, UK. The paper was published in Translational Neurodegeneration at the same time. The full published paper text can be found at

GM604 (GM6) regulates developmental neurogenesis pathways and the expression of genes associated with amyotrophic lateral sclerosis (ALS). It was developed as a candidate ALS therapy and has demonstrated safety and produced encouraging outcomes in a phase IIA clinical trial. GM6 is a 6 amino acid active site fragment of an endogenous 33 amino acid developmental-stage neurotrophic factor identified from rat muscle and originally designated as motoneuronotrophic factor 1 (MNTF1).  The drug has a favorable pharmacokinetic profile and is able to cross the blood-brain barrier. GM6 is hypothesized to bolster neuron survival through the multi-target regulation of developmental pathways, but mechanisms of action are not yet fully understood.

The objective of this study was to develop hypotheses regarding the mechanisms of action of GM6 using RNA-seq transcriptome profiling combined with bioinformatic analysis. This study used RNA-seq to evaluate transcriptome responses in SH-SY5Y neuroblastoma cells following GM6 treatment (6, 24 and 48 hours).

We identified 2,867 protein-coding genes with expression significantly altered by GM6 (FDR < 0.10). Early (6 hour) 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 hours) 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 (STAT3HOXD11HES7GLI1). 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.

Genervon’s 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.  A phase 3 ALS clinical trial is planned.