Natalizumab is effective against relapsing-remitting multiple sclerosis (MS) but increases the risk of progressive multifocal leukoencephalopathy (PML), which is caused by the activation of the JCV polyomavirus. SF2/ASF (splicing factor2/alternative splicing factor) is a potent cellular inhibitor of JCV replication and large T-antigen (T-Ag) expression. We reported that SF2/ASF levels in blood cells increase during the first year of natalizumab therapy and decrease thereafter, inversely related to T-Ag expression, and suggested a correlation with JCV reactivation. Here, we report SF2/ASF levels of longitudinal blood samples of two patients undergoing natalizumab therapy, who developed PML while monitored, in comparison to natalizumab-treated controls and to one-off PML samples. After 6 months of therapy, SF2/ASF levels of the two cases were reduced, instead of increased, and their overall SF2/ASF levels were lower than those from natalizumab controls. Since SF2/ASF inhibits JCV, its early reduction might have a role in subsequent PML. We are aware of the limitations of the study, but the uniqueness of serial blood samples collected before and after PML onset in natalizumab-treated patients must be stressed. If confirmed in other patients, SF2/ASF evaluation could be a new and early biomarker of natalizumab-associated PML risk, allowing an 18-24-month interval before PML onset (presently ~ 5 months), in which clinicians could evaluate other risk factors and change therapy.

中文翻译：

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剪接因子2 /替代剪接因子的早期降低：在发展进行性多灶性白质脑病之前很久，那他珠单抗治疗的MS患者JC多瘤病毒的细胞抑制剂。

纳他珠单抗对复发缓解型多发性硬化症（MS）有效，但增加了由JCV多瘤病毒的激活引起的进行性多灶性白质脑病（PML）的风险。SF2 / ASF（剪接因子2 /替代剪接因子）是JCV复制和大T抗原（T-Ag）表达的有效细胞抑制剂。我们报道那他珠单抗治疗的第一年血细胞中的SF2 / ASF水平升高，此后降低，与T-Ag表达成反比，并暗示与JCV激活相关。在此，我们报告了接受那他珠单抗治疗的两名患者的纵向血液样本的SF2 / ASF水平，与那他珠单抗治疗的对照组和一次性PML样本相比，他们在监测时出现PML。经过6个月的治疗，这两例患者的SF2 / ASF水平降低而不是升高，并且其总SF2 / ASF水平低于那他珠单抗对照组的水平。由于SF2 / ASF抑制JCV，因此其早期降低可能在随后的PML中起作用。我们知道这项研究的局限性，但是必须强调那他珠单抗治疗的患者在PML发作之前和之后收集的系列血样的独特性。如果在其他患者中得到证实，SF2 / ASF评估可能是那他珠单抗相关PML风险的新的早期生物标志物，允许PML发作前间隔18-24个月（目前约5个月），其中临床医生可以评估其他风险因素并改变疗法。其早期降低可能在随后的PML中起作用。我们知道这项研究的局限性，但是必须强调那他珠单抗治疗的患者在PML发作之前和之后收集的系列血样的独特性。如果在其他患者中得到证实，SF2 / ASF评估可能是那他珠单抗相关PML风险的新的早期生物标志物，允许PML发作前间隔18-24个月（目前约5个月），其中临床医生可以评估其他风险因素并改变疗法。它的早期减少可能在随后的PML中起作用。我们知道这项研究的局限性，但是必须强调那他珠单抗治疗的患者在PML发作之前和之后收集的系列血样的独特性。如果在其他患者中得到证实，SF2 / ASF评估可能是那他珠单抗相关PML风险的一种新的早期生物标志物，允许PML发作前间隔18-24个月（目前约5个月），其中临床医生可以评估其他风险因素并改变疗法。