Clinical Neurosciences, Clinical & Experimental Sciences, Faculty of Medicine, University of Southampton, Mailpoint 806, Level D, Southampton General Hospital, Southampton SO16 6YD, United Kingdom.
MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom.
Mult Scler Relat Disord. 2019 May;30:257-261. doi: 10.1016/j.msard.2019.02.027. Epub 2019 Feb 26.
Nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2) is a master transcriptional regulator of the protective cellular response to oxidative stress. Sulforaphane is a Nrf2 activator but is unstable at ambient temperature. SFX-01 is a novel composition comprised of synthetic sulforaphane stabilised within the pocket of an α-cyclodextrin complex. Here we tested the efficacy of SFX-01 in murine relapsing experimental autoimmune encephalomyelitis (EAE), a model of relapsing-remitting MS (RRMS).
Relapsing EAE was induced in female SJL mice using immunization against PLP. In the therapeutic experiment, the aim was to model initiation of treatment after diagnosis in RRMS, so treatment was started at day 19, one day prior to the expected relapse onset. In the prophylactic experiment, mice were treated from the time of immunization and followed for three weeks.
SFX-01 reduced residual disability in both experiments. Most of this effect was mediated by a decrease in maximum severity of relapses and improved recovery during follow-up. Histological examination of the spinal cord was consistent with the clinical findings, with improvement in demyelination and the number of apoptotic cells, but not inflammatory cell infiltration, compared to the vehicle group.
SFX-01 is efficacious in EAE. In first-in-man and phase II clinical trials for other indications, SFX-01 was found to be well-tolerated. A trial comparing BG-12 and SFX-01 would address whether SFX-01 can offer RRMS patients a better option with respect to efficacy and tolerability.
核因子红细胞 2（NF-E2）相关因子 2（Nrf2）是细胞对氧化应激产生保护反应的主要转录调节因子。萝卜硫素是一种 Nrf2 激活剂，但在环境温度下不稳定。SFX-01 是一种由合成萝卜硫素稳定在α-环糊精复合物口袋内的新型组合物。在这里，我们测试了 SFX-01 在实验性自身免疫性脑脊髓炎（EAE）中的疗效，EAE 是复发缓解型多发性硬化症（RRMS）的模型。
通过用 PLP 免疫诱导雌性 SJL 小鼠发生复发 EAE。在治疗实验中，目的是模拟 RRMS 中治疗开始时的诊断后，因此在预计复发发作前一天，即第 19 天开始治疗。在预防实验中，从免疫开始治疗并随访 3 周。
SFX-01 在两项实验中均减少了残留残疾。这种作用主要是通过降低复发的最大严重程度和改善随访期间的恢复来介导的。脊髓的组织学检查与临床发现一致，与载体组相比，脱髓鞘和凋亡细胞的数量得到改善，但炎症细胞浸润没有改善。
SFX-01 在 EAE 中有效。在其他适应症的首次人体和 II 期临床试验中，SFX-01 被发现具有良好的耐受性。一项比较 BG-12 和 SFX-01 的试验将解决 SFX-01 是否能为 RRMS 患者提供一种在疗效和耐受性方面更好的选择。
