Granulocyte-macrophage colony-stimulating factor mRNA and Neuroprotective Immunity in Parkinson's disease

Katherine E. Olson, Krista L. Namminga, Yaman Lu, Mackenzie J. Thurston, Aaron D. Schwab, Seymour de Picciotto, Sze Wah Tse, William Walker, Jared Iacovelli, Clayton Small, Brian T. Wipke, R. Lee Mosley, Eric Huang, Howard E. Gendelman

Research output: Contribution to journalArticlepeer-review

Abstract

Restoring numbers and function of regulatory T cells (Tregs) is a novel therapeutic strategy for neurodegenerative disorders. Whether Treg function is boosted by adoptive cell transfer, pharmaceuticals, or immune modulators, the final result is a robust anti-inflammatory and neuronal sparing response. Herein, a newly developed lipid nanoparticle (LNP) containing mRNA encoding granulocyte-macrophage colony-stimulating factor (Gm-csf mRNA) was developed to peripherally induce Tregs and used for treatment in preclinical Parkinson's disease (PD) models. Administration of Gm-csf mRNA to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice and rats overexpressing alpha-synuclein produced dose-dependent increases in plasma GM-CSF levels and peripheral CD4+CD25+FoxP3+ Treg populations. This upregulation paralleled nigrostriatal neuroprotection, upregulated immunosuppression-associated mRNAs that led to the detection of a treatment-induced CD4+ T cell population, and decreased reactive microgliosis. The current findings strengthen prior works utilizing immune modulation by harnessing Gm-csf mRNA to augment adaptive immune function by employing a new delivery platform to treat PD and potentially other neurodegenerative disorders.

Original languageEnglish (US)
Article number120786
JournalBiomaterials
Volume272
DOIs
StatePublished - May 2021

Keywords

  • GM-CSF
  • Neuroprotection
  • Parkinson's disease
  • Regulatory T cells
  • mRNA

ASJC Scopus subject areas

  • Biophysics
  • Bioengineering
  • Ceramics and Composites
  • Biomaterials
  • Mechanics of Materials

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