@article{1d5c4f55b9994500841c013024536c4d,
title = "Neuroprotective Activities of Long-Acting Granulocyte–Macrophage Colony-Stimulating Factor (mPDM608) in 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine-Intoxicated Mice",
abstract = "Loss of dopaminergic neurons along the nigrostriatal axis, neuroinflammation, and peripheral immune dysfunction are the pathobiological hallmarks of Parkinson{\textquoteright}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.",
keywords = "GM-CSF, MPTP, Parkinson{\textquoteright}s disease, Treg, neuroprotection, regulatory T cell",
author = "Olson, {Katherine E.} and Namminga, {Krista L.} and Schwab, {Aaron D.} and Thurston, {Mackenzie J.} and Yaman Lu and Ashley Woods and Lei Lei and Weijun Shen and Feng Wang and Joseph, {Sean B.} and Gendelman, {Howard E.} and Mosley, {R. Lee}",
note = "Funding Information: We would like to thank the UNMC Flow Cytometry Research Facility for the exceptional flow cytometric analysis and support. We also thank the INBRE grant from NIH (2P20GM103427) for supporting a site license to EndNote software. Disclosure forms provided by the authors are available with the online version of this article. The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request. Disclosure forms provided by the authors are available with the online version of this article. Funding Information: The work was supported, in part, by the University of Nebraska Foundation, which includes donations from the Carol Swarts, M.D. Emerging Neuroscience Research Laboratory, the Margaret R. Larson Professorship, and the Frances and Louie Blumkin and Harriet Singer Research Foundations. We thank the Vice Chancellor{\textquoteright}s Office, of the University of Nebraska Medical Center, for Core Facility support. The research was supported by the California Institute of Biomedical Research (Calibr), Scripps, and National Institutes of Health grants P01 DA028555, R01 NS36126, P01 NS31492, P01 MH64570, P01 NS43985, P30 MH062261, and R01 AG043540 (HEG), and 2R01 NS034239 (HEG and RLM). Funding Information: We would like to thank the UNMC Flow Cytometry Research Facility for the exceptional flow cytometric analysis and support. We also thank the INBRE grant from NIH (2P20GM103427) for supporting a site license to EndNote software. ",
year = "2020",
month = oct,
doi = "10.1007/s13311-020-00877-8",
language = "English (US)",
volume = "17",
pages = "1861--1877",
journal = "Neurotherapeutics",
issn = "1933-7213",
publisher = "Springer New York",
number = "4",
}