GC 021109 is one of the few compounds in Alzheimer's clinical research that specifically target microglial cells. The mediators of microglial responses in neurodegenerative diseases with an inflammatory component are attracting renewed interest in drug-development research, years after several NSAIDs failed clinical trials.
GC 021109 reportedly binds the microglial P2Y6 receptor. This is a metabotropic G-protein coupled receptor, whose natural ligand is adenosine diphosphate, a metabolite of ATP. Astrocytes release the "gliotransmitter" ATP in response to neuronal injury, the presence of cellular debris, and also the presence of amyloid β plaques. P2Y6 signaling is thought to be involved in shifting the phenotype of microglia, which tend to surround amyloid plaques, from patrolling to phagocytic (Dong et al., 2010). Aβ42 increased ATP release in cultured astrocytes, and ATP was neuroprotective in slice culture (Mar 2012 news story). P2Y6 and its family of purinergic receptors has been most studied in neuropathic pain (Inoue et al., 2009; Bernier et al., 2013; Inoue and Tsuda, 2012).
GC 021109 has been reported in the biotech press to stimulate both microglial phagocytosis and inhibit microglial release of pro-inflammatory cytokines such as IL-12; however, this information is not published in the peer-reviewed literature (Fidler 2014, Xconomy).
In September 2014, GliaCure started a Phase 1 trial at one site in New Jersey to compare five different doses, administered once, to placebo in about 44 healthy volunteers. This is a first-in-human safety study. This study is expected to complete by the end of 2014. See clinicaltrials.gov.
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