PMID- 34000620 OWN - NLM STAT- MEDLINE DCOM- 20211122 LR - 20230713 IS - 2352-3964 (Electronic) IS - 2352-3964 (Linking) VI - 67 DP - 2021 May TI - Safety, tolerability, and immune-biomarker profiling for year-long sargramostim treatment of Parkinson's disease. PG - 103380 LID - S2352-3964(21)00173-0 [pii] LID - 10.1016/j.ebiom.2021.103380 [doi] LID - 103380 AB - 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 mug/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 mug/kg/day significantly reduced numbers and severity of AEs/subject/month compared to 6 mug/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 mug/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. CI - Published by Elsevier B.V. FAU - Olson, Katherine E AU - Olson KE AD - Department of Pharmacology and Experimental Neuroscience, Center for Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha , NE 68198, USA. FAU - Namminga, Krista L AU - Namminga KL AD - Department of Pharmacology and Experimental Neuroscience, Center for Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha , NE 68198, USA. FAU - Lu, Yaman AU - Lu Y AD - Department of Pharmacology and Experimental Neuroscience, Center for Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha , NE 68198, USA. FAU - Schwab, Aaron D AU - Schwab AD AD - Department of Pharmacology and Experimental Neuroscience, Center for Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha , NE 68198, USA. FAU - Thurston, Mackenzie J AU - Thurston MJ AD - Department of Pharmacology and Experimental Neuroscience, Center for Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha , NE 68198, USA. FAU - Abdelmoaty, Mai M AU - Abdelmoaty MM AD - Department of Pharmacology and Experimental Neuroscience, Center for Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha , NE 68198, USA; Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, NE 68198, USA. FAU - Kumar, Vikas AU - Kumar V AD - Department of Genetics, Cell Biology, and Anatomy, University of Nebraska Medical Center, NE 68198, USA. FAU - Wojtkiewicz, Melinda AU - Wojtkiewicz M AD - Department of Pharmacology and Experimental Neuroscience, Center for Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha , NE 68198, USA. FAU - Obaro, Helen AU - Obaro H AD - Great Plains Center for Clinical and Translational Research, University of Nebraska, USA. FAU - Santamaria, Pamela AU - Santamaria P AD - Neurology Consultants of Nebraska, PC and Nebraska Medicine, Medical Center, Omaha, NE, USA. FAU - Mosley, R Lee AU - Mosley RL AD - Department of Pharmacology and Experimental Neuroscience, Center for Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha , NE 68198, USA. FAU - Gendelman, Howard E AU - Gendelman HE AD - Department of Pharmacology and Experimental Neuroscience, Center for Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha , NE 68198, USA. Electronic address: hegendel@unmc.edu. LA - eng SI - ClinicalTrials.gov/NCT03790670 GR - P20 GM103427/GM/NIGMS NIH HHS/United States GR - R01 MH115860/MH/NIMH NIH HHS/United States GR - R01 NS034239/NS/NINDS NIH HHS/United States PT - Clinical Trial, Phase I PT - Journal Article DEP - 20210514 PL - Netherlands TA - EBioMedicine JT - EBioMedicine JID - 101647039 RN - 0 (Antiparkinson Agents) RN - 0 (Biomarkers) RN - 0 (Recombinant Proteins) RN - 5TAA004E22 (sargramostim) RN - 83869-56-1 (Granulocyte-Macrophage Colony-Stimulating Factor) SB - IM MH - Aged MH - Antiparkinson Agents/administration & dosage/*adverse effects/therapeutic use MH - Biomarkers/analysis MH - Granulocyte-Macrophage Colony-Stimulating Factor/administration & dosage/*adverse effects/therapeutic use MH - Humans MH - Male MH - Middle Aged MH - Parkinson Disease/*drug therapy/immunology MH - Recombinant Proteins/administration & dosage/adverse effects/therapeutic use MH - T-Lymphocytes/immunology PMC - PMC8138485 OTO - NOTNLM OT - Granulocyte macrophage-colony stimulating factor OT - Neuroprotection OT - Parkinson's disease OT - Regulatory T cells OT - Sargramostim OT - Unified Parkinson's Disease Rating Scale COIS- Declaration of Competing Interest The authors declare no conflicts of interest. EDAT- 2021/05/18 06:00 MHDA- 2021/11/23 06:00 PMCR- 2021/05/14 CRDT- 2021/05/17 20:27 PHST- 2021/01/21 00:00 [received] PHST- 2021/04/04 00:00 [revised] PHST- 2021/04/20 00:00 [accepted] PHST- 2021/05/18 06:00 [pubmed] PHST- 2021/11/23 06:00 [medline] PHST- 2021/05/17 20:27 [entrez] PHST- 2021/05/14 00:00 [pmc-release] AID - S2352-3964(21)00173-0 [pii] AID - 103380 [pii] AID - 10.1016/j.ebiom.2021.103380 [doi] PST - ppublish SO - EBioMedicine. 2021 May;67:103380. doi: 10.1016/j.ebiom.2021.103380. Epub 2021 May 14.