系统性先天性免疫系统恢复作为神经退行性疾病的一种治疗方法:NP001对肌萎缩性脊髓侧索硬化症(ALS)进展的影响

IF 3.9 3区 工程技术 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Biomedicines Pub Date : 2024-10-16 DOI:10.3390/biomedicines12102362
Michael S McGrath, Rongzhen Zhang, Paige M Bracci, Ari Azhir, Bruce D Forrest
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引用次数: 0

摘要

背景/目的:肌萎缩性脊髓侧索硬化症(ALS)是一种将多种神经退行性病变过程整合为单一的渐进性和致命性疾病的诊断方法,因此很难开发出统一适用的疗法。最近的多国 ALS 自然史发病率研究发现,先天性免疫系统的系统性慢性激活是 ALS 发病的主要风险因素。ALS 患者体内持续的免疫激活会导致肌肉萎缩和血清肌酐降低。本研究的目的是测试在二期研究中,与对照组相比,NP001治疗ALS患者的神经和肌肉破坏速度减慢是否会导致生存期延长:NP001是一种先天性免疫系统调节剂NaClO2的静脉给药形式,目前进行的2期临床研究报告显示,与安慰剂对照组相比,接受药物治疗的患者仅在6个月的间歇治疗后就获得了长期生存的益处。作为一种原药,NP001 会被巨噬细胞转化为牛磺酸氯胺,这是一种长效的炎症调节剂。我们对两项为期 6 个月的 NP001 2 期试验中完成研究的所有患者进行了汇总分析。与安慰剂相比,接受治疗的患者生存期最长可延长一年:在炎症相关肌肉损失最大的 ALS 患者中观察到的更长生存期进一步证明了 ALS 是一种持续存在先天性免疫功能障碍的疾病,而 NP001 是一种具有持续临床活性的疾病调节药物。
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Systemic Innate Immune System Restoration as a Therapeutic Approach for Neurodegenerative Disease: Effects of NP001 on Amyotrophic Lateral Sclerosis (ALS) Progression.

Background/objective: Amyotrophic lateral sclerosis (ALS) is a diagnosis that incorporates a heterogeneous set of neurodegenerative processes into a single progressive and uniformly fatal disease making the development of a uniformly applicable therapeutic difficult. Recent multinational ALS natural history incidence studies have identified systemic chronic activation of the innate immune system as a major risk factor for developing ALS. Persistent immune activation in patients with ALS leads to loss of muscle and lowering of serum creatinine. The goal of the current study was to test whether the slowing of nerve and muscle destruction in NP001-treated ALS patients compared with controls in phase 2 studies would lead to extension of survival.

Methods: Phase 2 clinical studies with NP001, an intravenously administered form of the innate immune system regulator NaClO2, are now reporting long-term survival benefits for drug recipients vs. placebo controls after only six months of intermittent treatment. As a prodrug, NP001 is converted by macrophages to taurine chloramine, a long-lived regulator of inflammation. We performed a pooled analysis of all patients who had completed the studies in two six-month NP001 phase 2 trials. Changes in respiratory vital capacity and the muscle mass product, creatinine, defined treated patients who, compared to placebo, had up to a year of extended survival.

Conclusions: The observed longer survival in ALS patients with the greatest inflammation-associated muscle loss provides further evidence that ALS is a disease of ongoing innate immune dysfunction and that NP001 is a disease-modifying drug with sustained clinical activity.

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来源期刊
Biomedicines
Biomedicines Biochemistry, Genetics and Molecular Biology-General Biochemistry,Genetics and Molecular Biology
CiteScore
5.20
自引率
8.50%
发文量
2823
审稿时长
8 weeks
期刊介绍: Biomedicines (ISSN 2227-9059; CODEN: BIOMID) is an international, scientific, open access journal on biomedicines published quarterly online by MDPI.
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