Department of Neurology, Fleni, Buenos Aires, Argentina.
Hospital Británico de Buenos Aires, Buenos Aires, Argentina.
Mult Scler Relat Disord. 2021 Nov;56:103264. doi: 10.1016/j.msard.2021.103264. Epub 2021 Sep 14.
With the recent approval of cladribine tablets, siponimod and ozanimod, there has been a renewed interest into the extent to which these current generation disease-modifying therapies (DMTs) are able to cross into the central nervous system (CNS), and how this penetration of the blood-brain barrier (BBB) may influence their ability to treat multiple sclerosis (MS). The integrity of the CNS is maintained by the BBB, blood-cerebrospinal fluid barrier, and the arachnoid barrier, which all play an important role in preserving the immunological environment and homeostasis within the CNS. The integrity of the BBB decreases during the course of MS, with a putative temporal relationship to disease worsening. Furthermore, it is currently considered that progression of the disease is mediated mainly by resident cells of the CNS. The existing literature provides evidence to show that some of the current generation DMTs for MS are able to penetrate the CNS and potentially exert direct effects on CNS-resident cells, in particular the CNS-penetrating prodrugs cladribine and fingolimod, and other sphingosine-1 phosphate receptor modulators; siponimod and ozanimod. Other current generation DMTs appear to be restricted to the periphery due to their high molecular weight or physicochemical properties. As more effective brain penetrant therapies are developed for the treatment of MS, there is a need to understand whether the potential for direct effects within the CNS are of significance, and whether this brings additional benefits over and above treatment effects mediated in the periphery. In turn, this will require an improved understanding of the structure and function of the BBB, the role it plays in MS and subsequent treatments. This narrative review summarizes the data supporting the biological plausibility of a potential benefit from therapeutic molecules entering the CNS, and discusses the potential significance in the current and future treatment of MS.
随着克拉屈滨片、西尼莫德和奥扎尼莫德的最近获批，人们对当前这一代疾病修正治疗（DMT）药物在多大程度上能够穿透中枢神经系统（CNS），以及血脑屏障（BBB）的穿透程度如何影响它们治疗多发性硬化症（MS）的能力产生了新的兴趣。CNS 的完整性由 BBB、血脑脊液屏障和蛛网膜屏障维持，它们在保护 CNS 内的免疫环境和内环境稳定方面都发挥着重要作用。在 MS 病程中，BBB 的完整性下降，与疾病恶化存在时间相关性。此外，目前认为疾病的进展主要是由 CNS 的固有细胞介导的。现有文献提供的证据表明，一些用于 MS 的当前代 DMT 药物能够穿透 CNS，并可能对 CNS 固有细胞产生直接作用，特别是 CNS 穿透前药克拉屈滨和芬戈莫德，以及其他鞘氨醇-1-磷酸受体调节剂；西尼莫德和奥扎尼莫德。其他当前代 DMT 药物由于分子量或理化性质似乎仅限于外周。随着针对 MS 治疗的更有效的穿透脑治疗方法的开发，有必要了解 CNS 内的直接作用是否具有重要意义，以及这是否比外周介导的治疗效果带来额外的益处。反过来，这将需要更好地了解 BBB 的结构和功能，以及它在 MS 及其后续治疗中的作用。本综述总结了支持治疗分子进入 CNS 可能带来益处的生物学合理性的数据，并讨论了其在 MS 当前和未来治疗中的潜在意义。
