帕金森病患者接受长达一年的沙格司亭治疗的安全性、耐受性和免疫生物标志物分析。
Safety, tolerability, and immune-biomarker profiling for year-long sargramostim treatment of Parkinson's disease.
机构信息
Department of Pharmacology and Experimental Neuroscience, Center for Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha , NE 68198, USA.
Department of Pharmacology and Experimental Neuroscience, Center for Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha , NE 68198, USA; Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, NE 68198, USA.
出版信息
EBioMedicine. 2021 May;67:103380. doi: 10.1016/j.ebiom.2021.103380. Epub 2021 May 14.
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.
背景
神经炎症在帕金森病（PD）中起着致病作用。通过改变 T 细胞表型，恢复大脑内环境稳定的免疫疗法可以减轻神经退行性变。沙格司亭作为一种免疫调节剂，已经从实验室研究到床边临床研究都得到了广泛关注。然而，其治疗用途因剂量依赖性不良反应而受到限制。因此，我们进行了减少药物剂量方案，以评估安全性，并在每周 5 天接受沙格司亭治疗 1 年期间发现新的与疾病相关的生物标志物。
方法
5 名 PD 患者参加了一项 1b 期、非盲、开放标签研究，以评估 3 μg/kg/天沙格司亭的安全性和耐受性。评估了全血细胞计数和化学特征、体检、不良事件（AE）、免疫分析、运动障碍协会赞助的帕金森病修订统一评分量表（MDS-UPDRS）评分、T 细胞表型/功能、DNA 甲基化以及基因和蛋白质图谱。
结果
与 6 μg/kg/天的治疗相比，每天 3 μg/kg 的沙格司亭给药可显著减少 AE/患者/月的数量和严重程度。尽管记录了 MDS-UPDRS 第 III 部分评分的降低，但外周血免疫调节表型和功能升高。FOXP3 基因上游 DNA 元件的去甲基化也增加。
解释
长期每天 3 μg/kg 的沙格司亭治疗耐受良好，并且有效恢复了免疫内稳态。AE 的数量和严重程度减少，外周免疫功能恢复，Treg 的数量和功能增加。MDS-UPDRS 第 III 部分评分没有恶化。需要评估更多的患者数量以评估药物的疗效（ClinicalTrials.gov NCT03790670）。
资金
这项研究得到了内布拉斯加大学基金会社区资金和 5 个 R01NS034239-25 联邦研究支持的支持。
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