Therapeutics

GC 021109

Overview

Name: GC 021109
Therapy Type: Small Molecule (timeline)
Target Type: Inflammation (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 1)
Company: GliaCure

Background

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., 2009Bernier 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).

Findings

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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References

News Citations

  1. Astrocyte ATP, Transmembrane Chemokine Drive Neuroprotection

Paper Citations

  1. . P2Y(6)-Evoked Microglial Phagocytosis. Int Rev Neurobiol. 2009;85:159-63. PubMed.
  2. . Inhibition of P2X4 function by P2Y6 UDP receptors in microglia. Glia. 2013 Dec;61(12):2038-49. Epub 2013 Oct 7 PubMed.
  3. . Purinergic systems, neuropathic pain and the role of microglia. Exp Neurol. 2012 Apr;234(2):293-301. Epub 2011 Sep 17 PubMed.

External Citations

  1. clinicaltrials.gov
  2. Fidler 2014, Xconomy

Further Reading

Papers

  1. . Glial cells in (patho)physiology. J Neurochem. 2012 Apr;121(1):4-27. PubMed.
  2. . The tripartite synapse: roles for gliotransmission in health and disease. Trends Mol Med. 2007 Feb;13(2):54-63. Epub 2007 Jan 4 PubMed.
  3. . Selective loss of P2Y2 nucleotide receptor immunoreactivity is associated with Alzheimer's disease neuropathology. J Neural Transm. 2008 Aug;115(8):1165-72. PubMed.
  4. . [Neuropharmacological study of ATP receptors and their role in neuropathic pain]. Yakugaku Zasshi. 2013;133(10):1035-9. PubMed.
  5. . Uridine 5'-diphosphate induces chemokine expression in microglia and astrocytes through activation of the P2Y6 receptor. J Immunol. 2011 Mar 15;186(6):3701-9. Epub 2011 Feb 11 PubMed.