Zahid Maryam, Busmail Alberto, Penumetcha Sai Sri, Ahluwalia Saher, Irfan Rejja, Khan Sawleha Arshi, Rohit Reddy Sai, Vasquez Lopez Maria Elisa, Mohammed Lubna
Research & Development, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA.
Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA.
Cureus. 2021 Oct 17;13(10):e18847. doi: 10.7759/cureus.18847. eCollection 2021 Oct.
Multiple sclerosis (MS) is the most common disabling disease of the central nervous system (CNS) with a progressive neurodegenerative pattern. It is characterized by demyelination of white matter in CNS and apoptosis of oligodendrocytes. Tumor necrosis factor (TNF) alpha is a major cytokine in the pathogenesis of MS. However, the failure of TNF alpha inhibitors in preclinical and clinical trials disapproved of their use in MS patients. Nevertheless, failures and misses sometimes open avenues for new hits. In the later years, it was discovered that TNF signaling is mediated via two different receptors, TNFR1 and TNFR2, both of which have paradoxical effects. TNFR1 mediates demyelination and apoptosis, while TNFR2 promotes remyelination and neuroprotection. This explained the cause of the failure of non-selective TNF alpha-blockers in MS. It also enlightened researchers that repurposing the previously formulated non-selective TNF alpha-blockers using a receptor-selective approach could lead to discovering novel biologic agents with a broader spectrum of indications and better safety profiles. This review focuses on a novel premier TNFR1 blocker, atrosab, which has been tested in animal models of MS, experimental autoimmune encephalomyelitis (EAE), where it demonstrated a reduction in symptom severity. The early promise shown by atrosab in preclinical studies has given us hope to find another revolutionary drug for MS in the future. Clinical trials, which will finally decide whether this drug can be used as a better therapeutic agent for MS or not, are still going on, but currently, there is no approved evidence regarding efficacy of these agents in treating MS.
多发性硬化症（MS）是中枢神经系统（CNS）最常见的致残性疾病，具有进行性神经退行性病变模式。其特征是中枢神经系统白质脱髓鞘和少突胶质细胞凋亡。肿瘤坏死因子（TNF）α是MS发病机制中的主要细胞因子。然而，TNFα抑制剂在临床前和临床试验中的失败不支持其在MS患者中的使用。尽管如此，失败和未成功有时会为新的突破开辟道路。在后来的几年里，人们发现TNF信号是通过两种不同的受体TNFR1和TNFR2介导的，这两种受体都具有矛盾的作用。TNFR1介导脱髓鞘和凋亡，而TNFR2促进髓鞘再生和神经保护。这解释了非选择性TNFα阻滞剂在MS中失败的原因。它也启发研究人员，使用受体选择性方法重新利用先前配制的非选择性TNFα阻滞剂可能会发现具有更广泛适应症和更好安全性的新型生物制剂。本综述重点关注一种新型的主要TNFR1阻滞剂阿曲单抗，它已在MS动物模型实验性自身免疫性脑脊髓炎（EAE）中进行了测试，在该模型中它显示出症状严重程度有所降低。阿曲单抗在临床前研究中显示出的早期前景让我们有希望在未来找到另一种治疗MS的革命性药物。最终将决定这种药物是否可作为MS更好治疗剂的临床试验仍在进行中，但目前，尚无关于这些药物治疗MS疗效的批准证据。
