Zhang Rongzhen, Azhir Ari, McGrath Michael S
Department of Medicine, University of California San Francisco, San Francisco, CA 94110, USA.
Neuvivo, Inc., Palo Alto, CA 94303, USA.
Int J Mol Sci. 2025 May 3;26(9):4349. doi: 10.3390/ijms26094349.
Amyotrophic lateral sclerosis (ALS) is a heterogeneous disease that involves progressive loss of voluntary muscle and ultimately, respiratory function, which is the primary cause of death in ALS patients. Respiratory vital capacity (VC) measurements are objective, reproducible, and directly related to survival. Respiratory function is known to be negatively affected in individuals with excess abdominal fat contributing to a chronic innate immune inflammatory state. To test whether ALS patients might have a body mass index (BMI) related VC response to the innate immune system regulator NP001, clinical results from two NP001 phase 2 trials were evaluated in an intent-to-treat manner, stratified by BMI measurements. Slowing of progressive VC loss and extension of overall survival (OS) occurred primarily in ALS patients who were overweight with a BMI ≥ 25 (70% of patients in the phase 2 trials). Innate immune dysfunction is a characteristic of ALS patients ≤ 65 years of age, and in this group both VC and OS changes in response to NP001 were most significant. This study represents a novel approach to ALS, wherein VC and OS were both significantly improved through immunologic, not neurologic modulation with NP001, a precursor to the dominant regulator of inflammation, taurine chloramine.
肌萎缩侧索硬化症（ALS）是一种异质性疾病，涉及随意肌的进行性丧失，最终导致呼吸功能丧失，这是ALS患者的主要死因。呼吸肺活量（VC）测量是客观、可重复的，且与生存率直接相关。已知腹部脂肪过多的个体呼吸功能会受到负面影响，这会导致慢性先天性免疫炎症状态。为了测试ALS患者的体重指数（BMI）是否可能与对先天性免疫系统调节剂NP001的VC反应相关，以意向性治疗方式评估了两项NP001 2期试验的临床结果，并按BMI测量进行分层。进行性VC丧失的减缓以及总生存期（OS）的延长主要发生在BMI≥25的超重ALS患者中（2期试验中70%的患者）。先天性免疫功能障碍是65岁及以下ALS患者的一个特征，在该组中，对NP001的VC和OS变化最为显著。这项研究代表了一种针对ALS的新方法，其中通过用炎症主要调节剂牛磺酸氯胺的前体NP001进行免疫调节而非神经调节，VC和OS均得到了显著改善。
