Table_1_Anti-inflammatory and Neuroprotective Agents in Clinical Trials for CNS Disease and Injury: Where Do We Go From Here?.xlsx

Neurological disorders are major contributors to death and disability worldwide. The pathology of injuries and disease processes includes a cascade of events that often involve molecular and cellular components of the immune system and their interaction with cells and structures within the central nervous system. Because of this, there has been great interest in developing neuroprotective therapeutic approaches that target neuroinflammatory pathways. Several neuroprotective anti-inflammatory agents have been investigated in clinical trials for a variety of neurological diseases and injuries, but to date the results from the great majority of these trials has been disappointing. There nevertheless remains great interest in the development of neuroprotective strategies in this arena. With this in mind, the complement system is being increasingly discussed as an attractive therapeutic target for treating brain injury and neurodegenerative conditions, due to emerging data supporting a pivotal role for complement in promoting multiple downstream activities that promote neuroinflammation and degeneration. As we move forward in testing additional neuroprotective and immune-modulating agents, we believe it will be useful to review past trials and discuss potential factors that may have contributed to failure, which will assist with future agent selection and trial design, including for complement inhibitors. In this context, we also discuss inhibition of the complement system as a potential neuroprotective strategy for neuropathologies of the central nervous system.

神经系统疾病是全球范围内致死与致残的主要诱因之一。损伤与疾病进程的病理过程包含一系列级联事件，通常涉及免疫系统的分子与细胞组分，以及它们与中枢神经系统内细胞和结构的相互作用。正因如此，开发靶向神经炎症通路的神经保护治疗策略受到了广泛关注。已有多种神经保护性抗炎药物针对各类神经系统疾病与损伤开展了临床试验，但迄今为止绝大多数试验结果均不尽如人意。尽管如此，该领域对神经保护策略的研发仍保有极高热情。鉴于越来越多的新兴数据表明补体在介导多种下游活动中发挥关键作用，而这些活动会促进神经炎症与神经退行性病变，补体系统（complement system）正日益被视作治疗脑损伤与神经退行性疾病的极具潜力的治疗靶点。在我们进一步测试更多神经保护与免疫调节药物的过程中，我们认为回顾过往临床试验、探讨可能导致试验失败的潜在因素将极具价值——这将有助于未来的药物筛选与试验设计，包括针对补体抑制剂的相关研究。在此背景下，本文还将探讨将补体系统抑制作为中枢神经系统神经病理病变的潜在神经保护策略。