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

Olson, Katherine E.; Namminga, Krista L.; Lu, Yaman; Thurston, Mackenzie J.; Schwab, Aaron; Picciotto, Seymour de; Tse, Sze-Wah; Walker, William H.; Iacovelli, Jared; Small, Clayton; Wipke, Brian T.; Mosley, R. Lee; Huang, Eric; Gendelman, Howard Eliot

doi:10.1016/j.biomaterials.2021.120786

Cited by 36 publications

(28 citation statements)

References 81 publications

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“…Studies on lipid nanoparticle-containing GM-CSF mRNA and a long-acting GM-CSF in animal models of PD were conducted to reduce these effects. These formulations enhanced Treg function, reduced microgliosis, and boosted DA neuron survival [ 254 ].…”

Section: Novel Therapeutic Strategies In Pd Managementmentioning

confidence: 99%

Emerging Therapeutic Strategies for Parkinson’s Disease and Future Prospects: A 2021 Update

2022

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Parkinson’s disease (PD) is a neurodegenerative disorder pathologically distinguished by degeneration of dopaminergic neurons in the substantia nigra pars compacta. Muscle rigidity, tremor, and bradykinesia are all clinical motor hallmarks of PD. Several pathways have been implicated in PD etiology, including mitochondrial dysfunction, impaired protein clearance, and neuroinflammation, but how these factors interact remains incompletely understood. Although many breakthroughs in PD therapy have been accomplished, there is currently no cure for PD, only trials to alleviate the related motor symptoms. To reduce or stop the clinical progression and mobility impairment, a disease-modifying approach that can directly target the etiology rather than offering symptomatic alleviation remains a major unmet clinical need in the management of PD. In this review, we briefly introduce current treatments and pathophysiology of PD. In addition, we address the novel innovative therapeutic targets for PD therapy, including α-synuclein, autophagy, neurodegeneration, neuroinflammation, and others. Several immunomodulatory approaches and stem cell research currently in clinical trials with PD patients are also discussed. Moreover, preclinical studies and clinical trials evaluating the efficacy of novel and repurposed therapeutic agents and their pragmatic applications with encouraging outcomes are summarized. Finally, molecular biomarkers under active investigation are presented as potentially valuable tools for early PD diagnosis.

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Section: Novel Therapeutic Strategies In Pd Managementmentioning

confidence: 99%

Emerging Therapeutic Strategies for Parkinson’s Disease and Future Prospects: A 2021 Update

2022

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“…GM-CSF treatment is protective in animal models of neurodegenerative disorders (148)(149)(150). Increasing Treg activity is postulated to improve signs and symptoms of disorders such as Alzheimer and Parkinson diseases, amyotrophic lateral sclerosis and stroke (151).…”

Section: Emerging Uses In Neuro-degenerative Disordersmentioning

confidence: 99%

Sargramostim (rhu GM-CSF) as Cancer Therapy (Systematic Review) and An Immunomodulator. A Drug Before Its Time?

Lazarus

Ragsdale²,

Gale

et al. 2021

Front. Immunol.

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BackgroundSargramostim [recombinant human granulocyte-macrophage colony-stimulating factor (rhu GM-CSF)] was approved by US FDA in 1991 to accelerate bone marrow recovery in diverse settings of bone marrow failure and is designated on the list of FDA Essential Medicines, Medical Countermeasures, and Critical Inputs. Other important biological activities including accelerating tissue repair and modulating host immunity to infection and cancer via the innate and adaptive immune systems are reported in pre-clinical models but incompletely studied in humans.ObjectiveAssess safety and efficacy of sargramostim in cancer and other diverse experimental and clinical settings.Methods and ResultsWe systematically reviewed PubMed, Cochrane and TRIP databases for clinical data on sargramostim in cancer. In a variety of settings, sargramostim after exposure to bone marrow-suppressing agents accelerated hematologic recovery resulting in fewer infections, less therapy-related toxicity and sometimes improved survival. As an immune modulator, sargramostim also enhanced anti-cancer responses in solid cancers when combined with conventional therapies, for example with immune checkpoint inhibitors and monoclonal antibodies.ConclusionsSargramostim accelerates hematologic recovery in diverse clinical settings and enhances anti-cancer responses with a favorable safety profile. Uses other than in hematologic recovery are less-well studied; more data are needed on immune-enhancing benefits. We envision significantly expanded use of sargramostim in varied immune settings. Sargramostim has the potential to reverse the immune suppression associated with sepsis, trauma, acute respiratory distress syndrome (ARDS) and COVID-19. Further, sargramostim therapy has been promising in the adjuvant setting with vaccines and for anti-microbial-resistant infections and treating autoimmune pulmonary alveolar proteinosis and gastrointestinal, peripheral arterial and neuro-inflammatory diseases. It also may be useful as an adjuvant in anti-cancer immunotherapy.

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“…Another immunotherapy proposed for the treatment of Parkinson's disease is based in the anti-inflammatory effects of granulocyte-monocyte colony-stimulating factor (GM-CSF) on DCs, which induces the acquisition of tolerogenic properties in these cells, thereby favouring the generation of Treg cells [66][67][68]. Accordingly, Lipid nanoparticle containing mRNA encoding GM-CSF were administered intramuscular in MPTP-mice or rats overexpressing αSyn [69]. The treatment induced a rise in plasma GM-CSF and increased frequency of peripheral Treg cells.…”

Section: Current Experimental Immunotherapies Targeting T-cell Response In Parkinson's Diseasementioning

confidence: 99%

“…The treatment induced a rise in plasma GM-CSF and increased frequency of peripheral Treg cells. Concomitantly, the treatment reduced neuroinflammation and neurodegeneration of dopaminergic neurons in mouse and rat models of Parkinson's disease [69]. Due to the successful results in preclinical models, the therapeutic potential of recombinant human GM-CSF (sargramostim) for the treatment of Parkinson's disease is currently under study in a clinical trial (NCT03790670).…”

Section: Current Experimental Immunotherapies Targeting T-cell Response In Parkinson's Diseasementioning

confidence: 99%

T-cell based immunotherapies for Parkinson’s disease

Pacheco

2021

Explor Neuroprot Ther

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Current evidence indicates that neurodegeneration of dopaminergic neurons of the substantia nigra associated to Parkinson’s disease is a consequence of a neuroinflammatory process in which microglial cells play a central role. The initial activation of microglial cells is triggered by pathogenic protein inclusions, which are mainly composed by α-synuclein. Importantly, these pathogenic forms of α-synuclein subsequently induce a T-cell-mediated autoimmune response to dopaminergic neurons. Depending on their functional phenotype, these autoreactive T-cells might shape the functional features of activated microglia. T-cells bearing pro-inflammatory phenotypes such as T-helper (Th)1 or Th17 promote a chronic inflammatory behaviour on microglia, whilst anti-inflammatory T-cells, such as regulatory T-cells (Treg) favour the acquisition of neuroprotective features by microglia. Thus, T-cells play a fundamental role in the development of neuroinflammation and neurodegeneration involved in Parkinson’s disease. This review summarizes the evidence indicating that not only CD4+ T-cells, but also CD8+ T-cells play an important role in the physiopathology of Parkinson’s disease. Next, this review analyses the different T-cell epitopes derived from the pathogenic forms of α-synuclein involved in the autoimmune response associated to Parkinson’s disease in animal models and humans. It also summarizes the requirement of specific alleles of major histocompatibility complexes (MHC) class I and class II necessaries for the presentation of CD8+ and CD4+ T-cell epitopes from the pathogenic forms of α-synuclein in both humans and animal models. Finally, this work summarizes and discusses a number of experimental immunotherapies that aim to strengthen the Treg response or to dampen the inflammatory T-cell response as a therapeutic approach in animal models of Parkinson’s disease.

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

Cited by 36 publications

References 81 publications

Emerging Therapeutic Strategies for Parkinson’s Disease and Future Prospects: A 2021 Update

Emerging Therapeutic Strategies for Parkinson’s Disease and Future Prospects: A 2021 Update

Sargramostim (rhu GM-CSF) as Cancer Therapy (Systematic Review) and An Immunomodulator. A Drug Before Its Time?

T-cell based immunotherapies for Parkinson’s disease

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