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Neuroprotective Activities of Long-Acting Granulocyte-Macrophage Colony-Stimulating Factor (mPDM608) in 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine-Intoxicated Mice.
Neurotherapeutics ( IF 5.6 ) Pub Date : 2020-07-07 , DOI: 10.1007/s13311-020-00877-8
Katherine E Olson 1 , Krista L Namminga 1 , Aaron D Schwab 1 , Mackenzie J Thurston 1 , Yaman Lu 1 , Ashley Woods 2 , Lei Lei 2 , Weijun Shen 2 , Feng Wang 3 , Sean B Joseph 2 , Howard E Gendelman 1, 4 , R Lee Mosley 1, 4
Affiliation  

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.



中文翻译:


长效粒细胞巨噬细胞集落刺激因子 (mPDM608) 对 1-甲基-4-苯基-1,2,3,6-四氢吡啶中毒小鼠的神经保护活性。



黑质纹状体轴多巴胺能神经元的丧失、神经炎症和外周免疫功能障碍是帕金森病 (PD) 的病理生物学标志。粒细胞-巨噬细胞集落刺激因子 (GM-CSF) 已成功通过 PD 治疗测试。 GM-CSF 是一种已知的免疫调节剂,可诱导调节性 T 细胞 (Treg),并在多种神经退行性疾病中充当神经元保护剂。由于其半衰期短、生物分布有限和潜在的副作用,迫切需要替代的长效治疗方案。长效小鼠 GM-CSF (mPDM608) 是通过斯克里普斯研究部门 Calibr 开发的。 mPDM608 治疗后,确定了完整的血液学和化学特征以及 T 细胞表型和功能。在 1-甲基-4-苯基-1,2,3,6-四氢吡啶 (MPTP) 中毒小鼠中评估了 mPDM608 的神经保护和抗炎能力,包括转录组免疫谱。单剂量 mPDM608 治疗导致脾脏和白细胞呈剂量依赖性增加,同时 Treg 数量和免疫抑制功能也相应增强。 CD4 + T细胞基因表达向抗炎表型的转变与小胶质细胞增生减少和多巴胺能神经元细胞存活增加相对应。 mPDM608 引发神经保护性外周免疫转化。观察到的表型转变和神经保护反应大于重组 GM-CSF (rGM-CSF) 观察到的表型转变和神经保护反应,表明人 PDM608 作为 PD 治疗的候选者。

更新日期:2020-07-07
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