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

doi:10.1016/j.biomaterials.2021.120786

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 journal › Article › peer-review

34 Scopus citations

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 language	English (US)
Article number	120786
Journal	Biomaterials
Volume	272
DOIs	https://doi.org/10.1016/j.biomaterials.2021.120786
State	Published - 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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10.1016/j.biomaterials.2021.120786

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Olson, K. E., Namminga, K. L., Lu, Y., Thurston, M. J., Schwab, A. D., de Picciotto, S., Tse, S. W., Walker, W., Iacovelli, J., Small, C., Wipke, B. T., Mosley, R. L., Huang, E., & Gendelman, H. E. (2021). Granulocyte-macrophage colony-stimulating factor mRNA and Neuroprotective Immunity in Parkinson's disease. Biomaterials, 272, Article 120786. https://doi.org/10.1016/j.biomaterials.2021.120786

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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.",

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doi = "10.1016/j.biomaterials.2021.120786",

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AU - Olson, Katherine E.

AU - Namminga, Krista L.

AU - Lu, Yaman

AU - Thurston, Mackenzie J.

AU - Schwab, Aaron D.

AU - de Picciotto, Seymour

AU - Tse, Sze Wah

AU - Walker, William

AU - Iacovelli, Jared

AU - Small, Clayton

AU - Wipke, Brian T.

AU - Mosley, R. Lee

AU - Huang, Eric

AU - Gendelman, Howard E.

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AB - 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.

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

Abstract

Keywords

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