Summary: GM6 MoA for AD

Alzheimer’s Disease (AD) is a common cause of dementia in the elderly and is characterized by prominent degenerative changes within the hippocampus. GM6 is a peptide drug consisting of 6 amino acids (Phe-Ser-Arg-Tyr-Ala-Arg) developed by Genervon Biopharmaceuticals (Pasadena, CA) for pro-survival and neurotrophic effects for GM6 as a candidate AD therapy.  

1.    Receptors GM6 interacts with multiple extracellular receptors and acts to antagonize melanocortin 5 receptor (MC5R), neuropeptide FF receptor 1 (NPFFR1), opioid related nociceptin receptor 1 (OPRL1) and domatostatin receptor 2 (SSTR2). GM6 further acts as an agonist of insulin and Notch receptors, while up-regulating expression of nerve growth factor receptor (NGFR) and fibroblast growth factor receptor like 1 (FGFRL1).

2.    Signal Transduction these receptors modulate signal transduction pathways such as the insulin signaling and mitogen-activated protein kinase (MAPK) cascades, with involvement of key downstream proteins such as Shc, PTB domain, IRS-1, PI3 kinase, SOCS and Notch Intracellular domain (NICD).

3.    Transcription Factors these signals converge to control the activity of C2H2 zinc finger transcription factors interacting with GC-rich DNA motifs, as well as helix-turn-helix homeodomain transcription factors interacting with AT-rich DNA motifs. Such transcription factors include hes family bHLH transcription factor 7 (HES7), GLI family zinc finger 1 (GLI1), homeobox D11 (HOXD11), and signal transducer and activator of transcription 3 (STAT3).

4.    Transcription Response Using large-scale RNA-seq transcriptome analyses, we have identified 2867 protein-coding genes with expression significantly altered by GM6 (FDR < 0.10) in SH-SY5Y cells.GM6 controls the expression of AD-associated genes such as APOE, PLAU, NGFR, CACNA1G, CLU, RYR3, COX4I2, NDUFS2, NDUFB8, NDUFS4, COX10 and DOCK2, along with inflammation-associated genes involved in acute phase responses, lymphocyte proliferation, leukocyte migration, and cytokine production.

5.    Pharmacology GM6 penetrates the blood-brain barrier. Additional pharmacological studies demonstrated good penetrance into cells with an estimated brain: plasma ratio of 1.65.

6. AD Animal Model we studied the AD-like phenotype developing in APP/ΔPS1 double-transgenic mice. Effects of GM6 in this model were consistent with beta-secretase inhibition and alpha-secretase activation, favoring overall amyloid degradation and clearance. GM6 further decreased abundance of pro-inflammatory cytokines (TNF-alpha, IL-1beta, and TGF-beta) and increased abundance of nerve growth factor (NGF). Importantly, GM6 led to dose-dependent improvement in behavioral learning deficits in APP/ΔPS1 mice, as demonstrated by water maze testing performance.