Brutons tyrosine kinase inhibitors are being trialed in progressive MS. What will happen? BTK is not only expressed by B cells but it is also expressed my macrophages. Angy microglia have been considered to be the bad guys in progressive MS, yet they can be the good guys too and you have to remove the myelin debris to get repair. So blocking them could be a good or bad thing. It is going to be a balance that determines the outcome.
Another approach to getting rid of microglai is to inhibit CSF-1. In the study in mice they evaluated the effects of a reduction in microglial activation through orally administered brain-penetrant colony-stimulating factor-1 receptor (CSF-1R) inhibitor BLZ945 (BLZ) on neurodegeneration and its correlation with demyelination, astroglial activation and behavior in a chronic CPZ-induced demyelination model. It was reported that BLZ treatment successfully reduced the microglial population and myelin loss, however axonal degeneration was more prominent upon BLZ treatment. So what will happen with the BTK inhibitors?
Wies Mancini VSB, Di Pietro AA, de Olmos S, Silva PR, Vence M, Marder M, Igaz LM, Marcora MS, Pasquini JM, Correale JD, Pasquini LA. Colony-stimulating factor-1 receptor inhibition attenuates microgliosis and myelin loss but exacerbates neurodegeneration in the chronic cuprizone model. J Neurochem. 2021 Dec 22. doi: 10.1111/jnc.15566.