Neuroprotective Activities of Long-Acting Granulocyte–Macrophage Colony-Stimulating Factor (mPDM608) in 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine-Intoxicated Mice

Katherine E. Olson, Krista L. Namminga, Aaron D. Schwab, Mackenzie J. Thurston, Yaman Lu, Ashley Woods, Lei Lei, Weijun Shen, Feng Wang, Sean B. Joseph, Howard E. Gendelman, R. Lee Mosley

Research output: Contribution to journalArticle

Abstract

Loss of dopaminergic neurons along the nigrostriatal axis, neuroinflammation, and peripheral immune dysfunction are the pathobiological hallmarks of Parkinson’s disease (PD). Granulocyte–macrophage colony-stimulating factor (GM-CSF) has been successfully tested for PD treatment. GM-CSF is a known immune modulator that induces regulatory T cells (Tregs) and serves as a neuronal protectant in a broad range of neurodegenerative diseases. Due to its short half-life, limited biodistribution, and potential adverse effects, alternative long-acting treatment schemes are of immediate need. A long-acting mouse GM-CSF (mPDM608) was developed through Calibr, a Division of Scripps Research. Following mPDM608 treatment, complete hematologic and chemistry profiles and T-cell phenotypes and functions were determined. Neuroprotective and anti-inflammatory capacities of mPDM608 were assessed in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-intoxicated mice that included transcriptomic immune profiles. Treatment with a single dose of mPDM608 resulted in dose-dependent spleen and white blood cell increases with parallel enhancements in Treg numbers and immunosuppressive function. A shift in CD4+ T-cell gene expression towards an anti-inflammatory phenotype corresponded with decreased microgliosis and increased dopaminergic neuronal cell survival. mPDM608 elicited a neuroprotective peripheral immune transformation. The observed phenotypic shift and neuroprotective response was greater than observed with recombinant GM-CSF (rGM-CSF) suggesting human PDM608 as a candidate for PD treatment.

Original languageEnglish (US)
JournalNeurotherapeutics
DOIs
StateAccepted/In press - 2020

Keywords

  • GM-CSF
  • MPTP
  • Parkinson’s disease
  • Treg
  • neuroprotection
  • regulatory T cell

ASJC Scopus subject areas

  • Pharmacology
  • Clinical Neurology
  • Pharmacology (medical)

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