Why teriflunomide is a dark horse and may pack the killer punch. #ResearchSpeak #CharcotProject
Earlier this year I did a post on Teriflunomide being antiviral and many sceptics didn’t like the idea of it working as an anti-viral in MS. I am pleased to say that someone has now extended the antiviral effects of Teriflunomide to EBV. The study below includes one of the studies we were proposing to do. We simply did not get around to doing it quickly enough due to a current lack of funding and resources. Despite this it shows that Teriflunomide is a potent inhibitor of EBV infection in the laboratory and that it prevented EBV-induced lymphomas in an animal model. The next step is to look at what Teriflunomide does in pwMS in relation to EBV biology. Let’s hope our grant application that has been submitted gets funded so we can extend these observations into pwMS.
What the study below shows is that there are no original ideas only people who act on their ideas. Could Teriflunomide be working as an antiviral in MS? Importantly, there is evidence that Teriflunomide penetrates the central nervous system (CNS) and therefore may be working with the brain and spinal cord of pwMS.
It is a great pity that when you have an idea it takes months to years to get the work done. This is why science takes longer than you would like it to take. The only solution to this is to have a large discretionary pot of money to do blue sky projects of this nature or a science sugar mommy/daddy who is willing to fund such projects.
I have little doubt that EBV is the cause of MS. What we now need to do is convince the wider community and use the information to design trials to to treat and prevent MS based on this hypothesis. The latter is one of the arms of our new initiative called ‘Preventive Neurology‘. Could Teriflunomide provide us with a window to get there sooner?
Bilger et al. Leflunomide/teriflunomide inhibit Epstein-barr virus (EBV)- induced lymphoproliferative disease and lytic viral replication. Oncotarget. 2017 May 15. doi: 10.18632/oncotarget.17863.
Background: EBV infection causes mononucleosis and is associated with specific subsets of B cell lymphomas. Immunosuppressed patients such as organ transplant recipients are particularly susceptible to EBV-induced lymphoproliferative disease (LPD), which can be fatal. Leflunomide (a drug used to treat rheumatoid arthritis) and its active metabolite teriflunomide (used to treat multiple sclerosis) inhibit de novo pyrimidine synthesis by targeting the cellular dihydroorotate dehydrogenase, thereby decreasing T cell proliferation. Leflunomide also inhibits the replication of cytomegalovirus and BK virus via both “on target” and “off target” mechanisms and is increasingly used to treat these viruses in organ transplant recipients.
Research question: However, whether leflunomide/teriflunomide block EBV replication or inhibit EBV-mediated B cell transformation is currently unknown.
Results: We show that teriflunomide inhibits cellular proliferation, and promotes apoptosis, in EBV-transformed B cells in vitro at a clinically relevant dose. In addition, teriflunomide prevents the development of EBV-induced lymphomas in both a humanized mouse model and a xenograft model. Furthermore, teriflunomide inhibits lytic EBV infection in vitro both by preventing the initial steps of lytic viral reactivation, and by blocking lytic viral DNA replication.
Conclusions: Leflunomide/teriflunomide might therefore be clinically useful for preventing EBV-induced LPD in patients who have high EBV loads yet require continued immunosuppression.