Safety, tolerability, and immune-biomarker profiling for year-long sargramostim treatment of Parkinson's disease.

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.

Granulocyte-macrophage colony-stimulating factor mRNA and Neuroprotective Immunity in Parkinson's disease.

Restoring numbers and function of regulatory T cells (Tregs) is a novel therapeutic strategy for neurodegenerative disorders. Whether Treg function is boosted by adoptive cell transfer, pharmaceuticals, or immune modulators, the final result is a robust anti-inflammatory and neuronal sparing response. Herein, a newly developed lipid nanoparticle (LNP) containing mRNA encoding granulocyte-macrophage colony-stimulating factor (Gm-csf mRNA) was developed to peripherally induce Tregs and used for treatment in preclinical Parkinson's disease (PD) models. Administration of Gm-csf mRNA to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice and rats overexpressing alpha-synuclein produced dose-dependent increases in plasma GM-CSF levels and peripheral CD4+CD25+FoxP3+ Treg populations. This upregulation paralleled nigrostriatal neuroprotection, upregulated immunosuppression-associated mRNAs that led to the detection of a treatment-induced CD4+ T cell population, and decreased reactive microgliosis. The current findings strengthen prior works utilizing immune modulation by harnessing Gm-csf mRNA to augment adaptive immune function by employing a new delivery platform to treat PD and potentially other neurodegenerative disorders.

Neuroprotective Activities of Long-Acting Granulocyte-Macrophage Colony-Stimulating Factor (mPDM608) in 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine-Intoxicated Mice.

Loss of dopaminergic neurons along the nigrostriatal axis, neuroinflammation, and peripheral immune dysfunction are the pathobiological hallmarks of Parkinson's disease (PD). Granulocyte-macrophage colony-stimulating factor (GM-CSF) has been successfully tested for PD treatment. GM-CSF is a known immune modulator that induces regulatory T cells (Tregs) and serves as a neuronal protectant in a broad range of neurodegenerative diseases. Due to its short half-life, limited biodistribution, and potential adverse effects, alternative long-acting treatment schemes are of immediate need. A long-acting mouse GM-CSF (mPDM608) was developed through Calibr, a Division of Scripps Research. Following mPDM608 treatment, complete hematologic and chemistry profiles and T-cell phenotypes and functions were determined. Neuroprotective and anti-inflammatory capacities of mPDM608 were assessed in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-intoxicated mice that included transcriptomic immune profiles. Treatment with a single dose of mPDM608 resulted in dose-dependent spleen and white blood cell increases with parallel enhancements in Treg numbers and immunosuppressive function. A shift in CD4+ T-cell gene expression towards an anti-inflammatory phenotype corresponded with decreased microgliosis and increased dopaminergic neuronal cell survival. mPDM608 elicited a neuroprotective peripheral immune transformation. The observed phenotypic shift and neuroprotective response was greater than observed with recombinant GM-CSF (rGM-CSF) suggesting human PDM608 as a candidate for PD treatment.

Immunotherapy for Parkinson's disease.

With the increasing prevalence of Parkinson's disease (PD), there is an immediate need to interdict disease signs and symptoms. In recent years this need was met through therapeutic approaches focused on regenerative stem cell replacement and alpha-synuclein clearance. However, neither have shown long-term clinical benefit. A novel therapeutic approach designed to affect disease is focused on transforming the brain's immune microenvironment. As disordered innate and adaptive immune functions are primary components of neurodegenerative disease pathogenesis, this has emerged as a clear opportunity for therapeutic development. Interventions that immunologically restore the brain's homeostatic environment can lead to neuroprotective outcomes. These have recently been demonstrated in both laboratory and early clinical investigations. To these ends, efforts to increase the numbers and function of regulatory T cells over dominant effector cells that exacerbate systemic inflammation and neurodegeneration have emerged as a primary research focus. These therapeutics show broad promise in affecting disease outcomes beyond PD, such as for Alzheimer's disease, stroke and traumatic brain injuries, which share common neurodegenerative disease processes.

Axonal damage in spinal cord is associated with gray matter atrophy in sensorimotor cortex in experimental autoimmune encephalomyelitis.

BACKGROUND: Gray matter (GM) atrophy in brain is one of the best predictors of long-term disability in multiple sclerosis (MS), and recent findings have revealed that localized GM atrophy is associated with clinical disabilities. GM atrophy associated with each disability mapped to a distinct brain region, revealing a disability-specific atlas (DSA) of GM loss. OBJECTIVE: To uncover the mechanisms underlying the development of localized GM atrophy. METHODS: We used voxel-based morphometry (VBM) to evaluate localized GM atrophy and Clear Lipid-exchanged Acrylamide-hybridized Rigid Imaging-compatible Tissue-hYdrogel (CLARITY) to evaluate specific pathologies in mice with experimental autoimmune encephalomyelitis (EAE). RESULTS: We observed extensive GM atrophy throughout the cerebral cortex, with additional foci in the thalamus and caudoputamen, in mice with EAE compared to normal controls. Next, we generated pathology-specific atlases (PSAs), voxelwise mappings of the correlation between specific pathologies and localized GM atrophy. Interestingly, axonal damage (end-bulbs and ovoids) in the spinal cord strongly correlated with GM atrophy in the sensorimotor cortex of the brain. CONCLUSION: The combination of VBM with CLARITY in EAE can localize GM atrophy in brain that is associated with a specific pathology in spinal cord, revealing a PSA of GM loss.