Zhang Rongzhen, Bracci Paige M, Azhir Ari, Forrest Bruce D, McGrath Michael S
Department of Medicine, University of California San Francisco, San Francisco, CA 94110, USA.
Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA 94158, USA.
Biomedicines. 2022 Nov 12;10(11):2907. doi: 10.3390/biomedicines10112907.
Amyotrophic lateral sclerosis (ALS) is a heterogeneous, progressive, and universally fatal neurodegenerative disease. A subset of ALS patients has measurable plasma levels of lipopolysaccharide (LPS) and C-reactive protein (CRP) consistent with low-grade microbial translocation (MT). Unless interrupted, MT sets up a self-perpetuating loop of inflammation associated with systemic macrophage activation. To test whether MT contributed to ALS progression, blood specimens from a phase 2 study of NP001 in ALS patients were evaluated for changes in activity in treated patients as compared to controls over the 6-month study. In this post hoc analysis, plasma specimens from baseline and six-month timepoints were analyzed. Compared with baseline values, biomarkers related to MT were significantly decreased (LPS, LPS binding protein (LBP), IL-18, Hepatocyte growth factor (HGF), soluble CD163 (sCD163)) in NP001-treated patients as compared to controls, whereas wound healing and immunoregulatory factors were increased (IL-10, Epidermal growth factor (EGF), neopterin) by the end of study. These biomarker results linked to the positive clinical trial outcome confirm that regulation of macrophage activation may be an effective approach for the treatment of ALS and, potentially, other neuroinflammatory diseases related to MT.
肌萎缩侧索硬化症（ALS）是一种异质性、进行性且普遍致命的神经退行性疾病。一部分ALS患者的血浆脂多糖（LPS）和C反应蛋白（CRP）水平可测，这与低度微生物易位（MT）相符。除非被阻断，MT会建立一个与全身巨噬细胞激活相关的炎症自我持续循环。为了测试MT是否促进ALS进展，在一项针对ALS患者的NP001的2期研究中，对治疗患者与对照组在6个月研究期间血液标本的活性变化进行了评估。在这项事后分析中，对基线和6个月时间点的血浆标本进行了分析。与基线值相比，与MT相关的生物标志物在NP001治疗的患者中与对照组相比显著降低（LPS、LPS结合蛋白（LBP）、IL-18、肝细胞生长因子（HGF）、可溶性CD163（sCD163）），而在研究结束时伤口愈合和免疫调节因子增加（IL-10、表皮生长因子（EGF）、蝶呤）。这些与阳性临床试验结果相关的生物标志物结果证实，调节巨噬细胞激活可能是治疗ALS以及潜在地治疗与MT相关的其他神经炎症性疾病的有效方法。
