Pharma are Blocking Microglia

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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

Hagan et al. 2020

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.

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MouseDoctor

10 comments

  • MD,

    “However targeting microglia will infuence the processes occuring during relapsing EAE“

    I thought Prof G’s hypothesis was that a virus (ebv) in the brain caused inflammation (smouldering MS) which was a result of microglia involvement. The external immune system senses the smouldering MS and gets involved (causing focal inflammation / relapses / lesions). Does the EAE progressive model reflect this, or is it based on the hypothesis that the external immune system attacks myelin (causing lesions) and leaves behind smouldering MS / neurodegeneration?

    • The external immunw system senses the Ms and comes in to cause relapses is an idea saying dealing with the immune system will never be enough, another view is that the immune system creates the damage to smoulder. The original idea was based on the wrong premise (outside in inside-out) that there is no connection between the brain and the outside. There is a connection.

      In the animals there is no virus as they are maintained in bubbles but the external immune system creates damage and when there is enough of it smouldering damage can become clinically apparent, at earlier times it seems it is histologically apparent. So even if is smoulders first I am sure the external immune sytem can create an environment to smoulder also.

      • Surely the fact that antivirals used in HIV seem to result in improvement of MS is evidence of virus(es) being involved in and perhaps even the original instigator of MS. (In individuals susceptible for genetic reasons etc.)

        • There is a connection – Yes, original instigator – maybe. But it doesn’t change the FACT immune cells are causing damage and we don’t have sound evidence of virus activities plays a role after disease onset. The very limited evidence of improvement of MSers also infected by HIV could be resulted by an interaction between HIV and the immune system. These few cases only presented improvement over few years, and only showed lower relapsing rate, instead of something relates to the progressive course.

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