Abstract
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.
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Acknowledgments
GI and CP share the first authorship. The Authors thank Dr. C. Scarpazza (MS Centre, Spedali Civili, Brescia) for helping in the collection of clinical data.
Funding
This study was financially supported in part by Fondazione Italia Sclerosi Multipla (AD, FISM2016_R_12; LI, FISM2016_R_16).
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The study was approved by the Brescia Ethical Committee Board (protocols 2713 of 05/24/2017 and NP0 of 07/18/2018).
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Claudia Piu and Gabriele Ibba share the first authorship
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Piu, C., Ibba, G., Bertoli, D. et al. Early reduction of the splicing factor2/alternative splicing factor: a cellular inhibitor of the JC polyomavirus in natalizumab-treated MS patients long before developing progressive multifocal leukoencephalopathy. J. Neurovirol. 26, 133–137 (2020). https://doi.org/10.1007/s13365-019-00793-4
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DOI: https://doi.org/10.1007/s13365-019-00793-4