Department of Medicine, University of California San Francisco, San Francisco, CA 94110, USA.
Neuvivo, Inc., Palo Alto, CA 94301, USA.
Cells. 2023 Mar 28;12(7):1031. doi: 10.3390/cells12071031.
Amyotrophic lateral sclerosis (ALS) is a clinical diagnosis used to define a neurodegenerative process that involves progressive loss of voluntary muscle function and leads to death within 2-5 years after diagnosis, in most cases because of respiratory function failure. Respiratory vital capacity (VC) measurements are reproducible and strong predictors of survival. To understand the role of the innate immune response in progressive VC loss we evaluated ALS clinical trial and biomarker results from a 6-month phase 2 study of NP001, a regulator of innate immune function. All ALS baseline values were similar between treated and controls except for those > 65 years old who were excluded from analysis. Treated patients with plasma CRP ≥ 1.13 mg/L (high CRP) showed a 64% slower rate of VC decline compared with placebo and those with plasma CRP < 1.13 mg/L (low CRP) who showed no response. High CRP patients showed no age associated loss of VC whereas low CRP patients showed an age dependent loss of VC function. Plasma levels of serum amyloid A (SAA) were similarly elevated in high CRP patients consistent with ongoing innate immune activation. Plasma TGFB1 in high CRP treated patients was 95% higher than placebo at 6-months, confirming the activation and release of this anti-inflammatory factor by the innate immune alpha 2 macroglobulin (A2M) system. This report is the first to link a biomarker confirmed regulation of the innate immune system with a therapeutic approach for controlling VC loss in ALS patients.
肌萎缩侧索硬化症（ALS）是一种临床诊断，用于定义一种神经退行性过程，涉及进行性丧失自主肌肉功能，并导致大多数情况下因呼吸功能衰竭在诊断后 2-5 年内死亡。呼吸肺活量（VC）测量具有可重复性，是预测生存的有力指标。为了了解固有免疫反应在进行性 VC 丧失中的作用，我们评估了 NP001 的 6 个月 2 期临床试验和生物标志物结果，NP001 是固有免疫功能的调节剂。除了排除在分析之外的年龄大于 65 岁的患者，治疗组和对照组的所有 ALS 基线值相似。血浆 CRP≥1.13mg/L（高 CRP）的治疗患者与安慰剂相比，VC 下降速度慢 64%，而 CRP<1.13mg/L（低 CRP）的患者没有反应。高 CRP 患者没有年龄相关的 VC 丧失，而低 CRP 患者则表现出年龄相关的 VC 功能丧失。高 CRP 患者的血清淀粉样蛋白 A（SAA）血浆水平也类似升高，表明固有免疫持续激活。高 CRP 治疗患者的血浆 TGFB1 在 6 个月时比安慰剂高 95%，证实了固有免疫α2巨球蛋白（A2M）系统对这种抗炎因子的激活和释放。本报告首次将生物标志物证实的固有免疫系统调节与治疗 ALS 患者 VC 丧失的方法联系起来。
Zotero 插件
