Brutons tyrosine kinase is a molecule involved in B cell development and it is being targeted to treat MS. The race is on to be the first to Market, there are at least four different agents in the running. Will the hare of the tortoise win?
However whilst Brutons tyrosine kinase inhibitors (BTKi) were developed for their B cell inhibiting properties, they also target macrophages. These can block microglial function. Will this mean progressive MS can benefit? Trials are ongoing. But now we get another outcome and it seems that is the bad macrophages that get inhibited. Evobrutanib, one the BTKi in development for MS stimulates repairing macrophages. In this study it seems that remyelination is increased by BTK inhibition
However what is BTKi-1? The drug used in this study. It is not evobrutanib, so they say, but we dont know. It could be any thing, it could be this chemical today or something else tomorrow (companies change the codes all the time), it is a code meaning nothing. Rubbish refereeing as the work can’t be repeated, you need a chemical name.
Often companies don’t give academics compounds in clinical development in case they do something that they were not supposed to do and find something that the company doesn’t want to hear. But we know nothing. Does the compound get into the brain or not? In the test tube cultures it wouldn’t matter but it would if it is being used as a drug.
So it all bodes well for use in MS, but the question. I have is. Are the results reported with the BTK inhibitors that great? and Do they do something that current DMT can’t? I have yet to see a compelling case and based on published results with BTKi people are not making miraculous recoveries.
I remember fingolimod and the other mods being tauted at remyelination agents, as oligodendrocytes express S1P5, which is a target for the imods. Was it that great in slowing diability progression?
Bruton’s Tyrosine Kinase Inhibition Promotes Myelin Repair.Martin E, Aigrot MS, Grenningloh R, Stankoff B, Lubetzki C, Boschert U, Zalc B.Brain Plast. 2020 Oct 1;5(2):123-133. doi: 10.3233/BPL-200100.
Background: Microglia are the resident macrophages of the central nervous system (CNS). In multiple sclerosis (MS) and related experimental models, microglia have either a pro-inflammatory or a pro-regenerative/pro-remyelinating function. Inhibition of Bruton’s tyrosine kinase (BTK), a member of the Tec family of kinases, has been shown to block differentiation of pro-inflammatory macrophages in response to granulocyte-macrophage colony-stimulating factor in vitro. However, the role of BTK in the CNS is unknown.
Methods: Our aim was to investigate the effect of BTK inhibition on myelin repair in ex vivo and in vivo experimental models of demyelination and remyelination. The remyelination effect of a BTK inhibitor (BTKi; BTKi-1) was then investigated in LPC-induced demyelinated cerebellar organotypic slice cultures and metronidazole-induced demyelinated Xenopus MBP-GFP-NTR transgenic tadpoles.
Results: Cellular detection of BTK and its activated form BTK-phospho-Y223 (p-BTK) was determined by immunohistochemistry in organotypic cerebellar slice cultures, before and after lysophosphatidylcholine (LPC)-induced demyelination. A low BTK signal detected by immunolabeling under normal conditions in cerebellar slices was in sharp contrast to an 8.5-fold increase in the number of BTK-positive cells observed in LPC-demyelinated slice cultures. Under both conditions, approximately 75% of cells expressing BTK and p-BTK were microglia and 25% were astrocytes. Compared with spontaneous recovery, treatment of demyelinated slice cultures and MTZ-demyelinated transgenic tadpoles with BTKi resulted in at least a 1.7-fold improvement of remyelination.
Conclusion: Our data demonstrate that BTK inhibition is a promising therapeutic strategy for myelin repair.