Safety, tolerability, and immune-biomarker profiling for year-long sargramostim treatment of Parkinson's disease
Katherine E. Olson,
Krista L. Namminga,
Yaman Lu,
Aaron D. Schwab,
Mackenzie J. Thurston,
Mai M. Abdelmoaty,
Vikas Kumar,
Melinda Wojtkiewicz,
Helen Obaro,
Pamela Santamaria,
R. Lee Mosley,
Howard E. Gendelman
Affiliations
Katherine E. Olson
Department of Pharmacology and Experimental Neuroscience, Center for Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha , NE 68198, USA
Krista L. Namminga
Department of Pharmacology and Experimental Neuroscience, Center for Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha , NE 68198, USA
Yaman Lu
Department of Pharmacology and Experimental Neuroscience, Center for Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha , NE 68198, USA
Aaron D. Schwab
Department of Pharmacology and Experimental Neuroscience, Center for Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha , NE 68198, USA
Mackenzie J. Thurston
Department of Pharmacology and Experimental Neuroscience, Center for Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha , NE 68198, USA
Mai M. Abdelmoaty
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
Vikas Kumar
Department of Genetics, Cell Biology, and Anatomy, University of Nebraska Medical Center, NE 68198, USA
Melinda Wojtkiewicz
Department of Pharmacology and Experimental Neuroscience, Center for Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha , NE 68198, USA
Helen Obaro
Great Plains Center for Clinical and Translational Research, University of Nebraska, USA
Pamela Santamaria
Neurology Consultants of Nebraska, PC and Nebraska Medicine, Medical Center, Omaha, NE, USA
R. Lee Mosley
Department of Pharmacology and Experimental Neuroscience, Center for Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha , NE 68198, USA
Howard E. Gendelman
Department of Pharmacology and Experimental Neuroscience, Center for Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha , NE 68198, USA; Corresponding author.
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.
