@article{ad6d35b6d021494f87516a17a4969b04,
title = "Safety, tolerability, and immune-biomarker profiling for year-long sargramostim treatment of Parkinson's disease",
abstract = "Background: Neuroinflammation plays a pathogenic role in Parkinson's disease (PD). Immunotherapies that restore brain homeostasis can mitigate neurodegeneration by transforming T cell phenotypes. Sargramostim has gained considerable attention as an immune transformer through laboratory bench to bedside clinical studies. However, its therapeutic use has been offset by dose-dependent adverse events. Therefore, we performed a reduced drug dose regimen to evaluate safety and to uncover novel disease-linked biomarkers during 5 days/week sargramostim treatments for one year. Methods: Five PD subjects were enrolled in a Phase 1b, unblinded, open-label study to assess safety and tolerability of 3 μg/kg/day sargramostim. Complete blood counts and chemistry profiles, physical examinations, adverse events (AEs), immune profiling, Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) scores, T cell phenotypes/function, DNA methylation, and gene and protein patterns were evaluated. Findings: Sargramostim administered at 3 μg/kg/day significantly reduced numbers and severity of AEs/subject/month compared to 6 μg/kg/day treatment. While MDS-UPDRS Part III score reductions were recorded, peripheral blood immunoregulatory phenotypes and function were elevated. Hypomethylation of upstream FOXP3 DNA elements was also increased. Interpretation: Long-term sargramostim treatment at 3 μg/kg/day is well-tolerated and effective in restoring immune homeostasis. There were decreased numbers and severity of AEs and restored peripheral immune function coordinate with increased numbers and function of Treg. MDS-UPDRS Part III scores did not worsen. Larger patient numbers need be evaluated to assess conclusive drug efficacy (ClinicalTrials.gov NCT03790670). Funding: The research was supported by community funds to the University of Nebraska Foundation and federal research support from 5 R01NS034239-25.",
keywords = "Granulocyte macrophage-colony stimulating factor, Neuroprotection, Parkinson's disease, Regulatory T cells, Sargramostim, Unified Parkinson's Disease Rating Scale",
author = "Olson, {Katherine E.} and Namminga, {Krista L.} and Yaman Lu and Schwab, {Aaron D.} and Thurston, {Mackenzie J.} and Abdelmoaty, {Mai M.} and Vikas Kumar and Melinda Wojtkiewicz and Helen Obaro and Pamela Santamaria and Mosley, {R. Lee} and Gendelman, {Howard E.}",
note = "Funding Information: The authors would like to thank the participants and family members for their willingness to participate and dedication to the study as well as those who supported our research efforts. We greatly appreciate the time and effort put in by staff within our investigational pharmacy services, the Great Plains Center for Clinical and Translational Research, and Red Cross Apheresis Center for assistance with drug dispensation, subject scheduling, and sample collection. We also thank the members of our data safety monitoring board including R. Gregory Bociek, MD, Kenneth Follett, MD, Daniel Murman, MD, Gleb Haynatzki, PhD, and Christopher Kratochvil, MD for review and discussion of the work, as well as Farah Shahjin and Jatin Machhi for assistance with proteomic sample preparation. The authors would also like to thank the UNMC Flow Cytometry Research Facility for exceptional flow cytometric analysis and support, the INBRE grant from NIH (2P20GM103427) for supporting a site license to EndNote software, the UNMC elutriation core for isolation of subject monocyte and lymphocyte populations, and the UNMC Epigenomics Core Facility for assessing methylation status of isolated DNA samples. The authors would also like to acknowledge the professional services of UNMC Mass Spectrometry & Proteomics Core and Bioinformatics and Systems Biology Core for assistance with proteomic analysis. Lastly, we express our gratitude to the funding sources that made this work possible, Partner Therapeutics and the University of Nebraska Foundation, which includes community donations from the Carol Swarts, M.D. Emerging Neuroscience Research Laboratory, the Margaret R. Larson Professorship, the Eisenberg Parkinson's Research Fund, and the Frances and Louie Blumkin and Harriet Singer Research Foundations. We also thank the Vice Chancellor's Office of the University of Nebraska Medical Center for Core Facility support. Funding Information: The authors would like to thank the participants and family members for their willingness to participate and dedication to the study as well as those who supported our research efforts. We greatly appreciate the time and effort put in by staff within our investigational pharmacy services, the Great Plains Center for Clinical and Translational Research, and Red Cross Apheresis Center for assistance with drug dispensation, subject scheduling, and sample collection. We also thank the members of our data safety monitoring board including R. Gregory Bociek, MD, Kenneth Follett, MD, Daniel Murman, MD, Gleb Haynatzki, PhD, and Christopher Kratochvil, MD for review and discussion of the work, as well as Farah Shahjin and Jatin Machhi for assistance with proteomic sample preparation. The authors would also like to thank the UNMC Flow Cytometry Research Facility for exceptional flow cytometric analysis and support, the INBRE grant from NIH ( 2P20GM103427 ) for supporting a site license to EndNote software, the UNMC elutriation core for isolation of subject monocyte and lymphocyte populations, and the UNMC Epigenomics Core Facility for assessing methylation status of isolated DNA samples. The authors would also like to acknowledge the professional services of UNMC Mass Spectrometry & Proteomics Core and Bioinformatics and Systems Biology Core for assistance with proteomic analysis. Lastly, we express our gratitude to the funding sources that made this work possible, Partner Therapeutics and the University of Nebraska Foundation, which includes community donations from the Carol Swarts, M.D. Emerging Neuroscience Research Laboratory, the Margaret R. Larson Professorship, the Eisenberg Parkinson's Research Fund, and the Frances and Louie Blumkin and Harriet Singer Research Foundations. We also thank the Vice Chancellor's Office of the University of Nebraska Medical Center for Core Facility support. Publisher Copyright: {\textcopyright} 2021",
year = "2021",
month = may,
doi = "10.1016/j.ebiom.2021.103380",
language = "English (US)",
volume = "67",
journal = "EBioMedicine",
issn = "2352-3964",
publisher = "Elsevier BV",
}