A Hypothesis-Generating Pharmacologic Profile for Sargramostim Treatment of Parkinson's Disease.

The connection between immunity and Parkinson’s disease (PD) is well-established. Myeloid immune responses influence the microenvironment of the central nervous system (CNS), which can be modulated by sargramostim, a recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF). Previous studies have demonstrated sargramostim’s neuroprotective effects, which are linked to its safety and tolerability, as well as its ability to regulate innate immunity. Changes in myeloid biomarkers correlate with clinical responses. PD symptoms were assessed using the Unified PD Rating Scale (UPDRS). Ten subjects received sargramostim through subcutaneous injections of 3 µg/kg, administered five days every week. Myeloid biomarkers were measured before treatment and at six and twelve months of treatment. Protein expression by Western blotting and gene expression by transcriptomic analysis was correlated with UPDRS III scores. Recognizing the exploratory nature of this study, patient responses were classified into potent, moderate, or no change groups based on UPDRS III score reductions of 9–13, 5–7, or none, respectively. Biomarkers from all 10 patients identified FOXP3 as a “potential” signature biomarker. The potent responders showed biomarkers linked to autophagy, inflammatory, and antioxidant proteins, including ATG7, HMOX1, RELA, and TLR8. Moderate responders displayed biomarkers associated with RELA and LRRK2. Transcriptomic analysis revealed over 2000 differentially expressed anti-inflammatory, calcium-binding, and epigenetic genes. Among these, genes such as ANXA9, CALM3, CY7B1, HDAC4, HMGB2, NR2F6, PDIA3, REST, SACS and SOX4 were identified as potential predictors of changes in UPDRS III scores. Baseline levels of ATG7, CARD9, and SACS may serve as initial biomarkers to identify subjects likely to respond to sargramostim. Female patients exhibited unique UPDRS III scores in response to sargramostim treatment. Novel cell-based biomarker signatures were identified that may predict responses to sargramostim treatment in this hypothesis-generating study. We acknowledge the inherent study limitations by limited patient numbers. This was reflected in the comparisons offered for the patient sub-groups in the year-long trial.Trial Registration The trial is registered on ClinicalTrials.gov under identifier NCT03790670, dated 01.30.2019.