You have been saying that pharma have been doing nothing to target progressive MS, but you are wrong and here is another example. In this study they have made an inhibitor of migroglial cell/macrophage activation and they say it inhibits progression in animals and so imply it may be useful for progressive MS.
However targeting microglia will infuence the processes occuring during relapsing EAE
So it will inhibit so called progressive EAE in the NOD mouse. It stops them getting worse and losing nerves
Hurray we say something for progressive MS. I hope so but must admit I have lost the battle when I say this is a very dubious model of progressive MS.
However, then we read that 15 of the 17 authors WERE working with pharma….it makes you concerned. Are they now ex-employees suggesting this is not so ace. The drug target doesn’t yet appear in the pipeline for the company…is for a reason?. Pexidartinib (PLX3397) is one of the lead oral tyrosine kinase inhibitors of CSF1R being developed by other pharma
Haagan N, Kane JL, Grover D, Woodworth L, Madore C, Saleh J, Sancho J, Liu J, Li Y, Proto J, Zelic M, Mahan A, Kothe M, Scholte AA, Fitzgerald M, Gisevius B, Haghikia A, Butovsky O, Ofengeim D. CSF1R signaling is a regulator of pathogenesis in progressive MS. Cell Death Dis. 2020 Oct 23;11(10):904
Microglia serve as the innate immune cells of the central nervous system (CNS) by providing continuous surveillance of the CNS microenvironment and initiating defense mechanisms to protect CNS tissue. Upon injury, microglia transition into an activated state altering their transcriptional profile, transforming their morphology, and producing pro-inflammatory cytokines. These activated microglia initially serve a beneficial role, but their continued activation drives neuroinflammation and neurodegeneration. Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating disease of the CNS, and activated microglia and macrophages play a significant role in mediating disease pathophysiology and progression. Colony-stimulating factor-1 receptor (CSF1R) and its ligand CSF1 are elevated in CNS tissue derived from MS patients. We performed a large-scale RNA-sequencing experiment and identified CSF1R as a key node of disease progression in a mouse model of progressive MS. We hypothesized that modulating microglia and infiltrating macrophages through the inhibition of CSF1R will attenuate deleterious CNS inflammation and reduce subsequent demyelination and neurodegeneration. To test this hypothesis, we generated a novel potent and selective small-molecule CSF1R inhibitor (sCSF1Rinh) for preclinical testing. sCSF1Rinh blocked receptor phosphorylation and downstream signaling in both microglia and macrophages and altered cellular functions including proliferation, survival, and cytokine production. The sCSF1Rinh attenuated a disease-associated microglial phenotype and blocked both axonal damage and neurological impairments in an experimental autoimmune encephalomyelitis (EAE) model of MS. While previous studies have focused on microglial depletion following CSF1R inhibition, our data clearly show that signaling downstream of this receptor can be beneficially modulated in the context of CNS injury. Together, these data suggest that CSF1R inhibition can reduce deleterious microglial proliferation and modulate microglial phenotypes during neuroinflammatory pathogenesis, particularly in progressive MS.