[P4–572]: INTERIM REPORT OF A PHASE 2 PILOT SAFETY AND EFFICACY TRIAL OF GM‐CSF/LEUKINE<sup>®</sup> IN MILD‐TO‐MODERATE ALZHEIMER'S DISEASE

Potter, Huntington; Woodcock, Jonathan H.; Boyd, Timothy; Sillau, Stefan; Bettcher, Brianne M.; Daniels, Joseph; Heffernan, Kate S.; Gray, Helen

doi:10.1016/j.jalz.2017.07.735

Cited by 4 publications

(3 citation statements)

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“…Improved behavioral function was also attributed to its Treg effects [17]. Likewise, a recent phase II clinical trial utilizing sargramostim [Leukine®, recombinant human GM-CSF (rhGM-CSF)] demonstrated significant changes in mini-mental state examination (MMSE) scores in mild-to-moderate AD patients [181]. Although the study did not evaluate Treg populations, improved memory outcome in AD patients might be attributed to GM-CSF Treg effects that can be studied in future.…”

Section: Alzheimer's Disease (Ad)mentioning

confidence: 99%

Harnessing regulatory T cell neuroprotective activities for treatment of neurodegenerative disorders

Machhi

Kevadiya

Muhammad

et al. 2020

Mol Neurodegeneration

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Emerging evidence demonstrates that adaptive immunity influences the pathobiology of neurodegenerative disorders. Misfolded aggregated self-proteins can break immune tolerance leading to the induction of autoreactive effector T cells (Teffs) with associated decreases in anti-inflammatory neuroprotective regulatory T cells (Tregs). An imbalance between Teffs and Tregs leads to microglial activation, inflammation and neuronal injury. The cascade of such a disordered immunity includes the drainage of the aggregated protein antigens into cervical lymph nodes serving to amplify effector immune responses. Both preclinical and clinical studies demonstrate transformation of this altered immunity for therapeutic gain. We posit that the signs and symptoms of common neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases, amyotrophic lateral sclerosis, and stroke can be attenuated by boosting Treg activities. Graphical Abstract

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Section: Alzheimer's Disease (Ad)mentioning

confidence: 99%

Harnessing regulatory T cell neuroprotective activities for treatment of neurodegenerative disorders

Machhi

Kevadiya

Muhammad

et al. 2020

Mol Neurodegeneration

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“…This altered immune phenotype decreased motor impairments and improved cortical motor activity. In support, an interim report of the AD study also indicated encouraging results in both activities of daily living and the mini mental state exam (MMSE), suggesting a positive effect on neuronal pathways with GM-CSF treatment [34]. Taken together, these clinical assessments point to the therapeutic benefit of altering the adaptive immune response for the treatment of neurodegenerative disease, and the utilization of GM-CSF to generate that response.…”

Section: Introductionmentioning

confidence: 85%

“…However, if diseased Tregs are isolated and stimulated ex vivo, suppressive function is restored, suggesting a potential therapeutic target. Likewise, direct utilization of human GM-CSF (sargramostim) for the treatment of patients suffering from PD or AD has also displayed promising results [20,34]. GM-CSF treatment led to modulation of peripheral Treg populations resulting in increased suppressive function in PD patients [20].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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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.

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Commentary: Combination Therapy for Alzheimer’s Disease: Perspectives of the Eu/Us Ctad Task Force

Siemers¹

2019

J Prev Alz Dis

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In October 2018, the European Union-North American Clinical Trials in Alzheimer’s Disease Task Force (EU/US CTAD Task Force) met to discuss an increasingly important topic, the scientific, regulatory, and logistical challenges to the development of combination therapies for AD. Challenges related to ever-changing scientific knowledge, challenges related to complex regulatory pathways and challenges related to the necessity for pharmaceutical companies to collaborate must all be addressed. These challenges must be met since task Force members unanimously agreed that successful treatment of AD will likely require combination therapies targeting multiple mechanisms and pathways.

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[P4–572]: INTERIM REPORT OF A PHASE 2 PILOT SAFETY AND EFFICACY TRIAL OF GM‐CSF/LEUKINE^® IN MILD‐TO‐MODERATE ALZHEIMER'S DISEASE

Cited by 4 publications

References 0 publications

Harnessing regulatory T cell neuroprotective activities for treatment of neurodegenerative disorders

Harnessing regulatory T cell neuroprotective activities for treatment of 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

Commentary: Combination Therapy for Alzheimer’s Disease: Perspectives of the Eu/Us Ctad Task Force

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[P4–572]: INTERIM REPORT OF A PHASE 2 PILOT SAFETY AND EFFICACY TRIAL OF GM‐CSF/LEUKINE® IN MILD‐TO‐MODERATE ALZHEIMER'S DISEASE

Cited by 4 publications

References 0 publications

Harnessing regulatory T cell neuroprotective activities for treatment of neurodegenerative disorders

Harnessing regulatory T cell neuroprotective activities for treatment of 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

Commentary: Combination Therapy for Alzheimer’s Disease: Perspectives of the Eu/Us Ctad Task Force

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[P4–572]: INTERIM REPORT OF A PHASE 2 PILOT SAFETY AND EFFICACY TRIAL OF GM‐CSF/LEUKINE^® IN MILD‐TO‐MODERATE ALZHEIMER'S DISEASE