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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article number103380
JournalEBioMedicine
Volume67
DOIs
StatePublished - May 2021

Keywords

  • Granulocyte macrophage-colony stimulating factor
  • Neuroprotection
  • Parkinson's disease
  • Regulatory T cells
  • Sargramostim
  • Unified Parkinson's Disease Rating Scale

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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