Can the other type of Inflammation important for Progressive MS be targeted? It may in another sclerosis

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Today I talk about another sclerosis and this amyothrophic lateral sclerosis = motor neuron disease = Lou Gerics disease. The FDA has given special status for a drug to be targetted at ALS. This is called sotuletinib. Why could this be important to MS?

So we have been chastised for not working on the Real MS, but I just need you to cast your minds back a few years

Gushchina S, Pryce G, Yip PK, Wu D, Pallier P, Giovannoni G, Baker D, Bo X. Increased expression of colony-stimulating factor-1 in mouse spinal cord with experimental autoimmune encephalomyelitis correlates with microglial activation and neuronal loss. Glia. 2018;66(10):2108-2125

Microglia contribute to pathophysiology at all stages of multiple sclerosis. Colony-stimulating factor-1 (CSF1) is crucial for microglial proliferation and activation. In this study we measured the CSF1 levels and studied its cellular expression in the mouse spinal cords with experimental autoimmune encephalomyelitis (EAE) to explore the potential contribution of CSF1 in neuronal death…… CSF1 levels were significantly higher in the spinal cords with acute (e.g. relapsing) and chronic (secondary progressive) EAE than those of normal and adjuvant-injected mice……CSF1 was expressed in astrocytes and neurons in normal mouse spinal cord…..Significant large motoneuron loss was seen in chronic EAE and the remaining motoneurons with high-level CSF1 were enwrapped by microglia.

Viral vector mediated over-expression of CSF1 in spinal neurons induced profound proliferation and activation of microglia at the injection site and microglia enwrapped CSF1-transduced neurons and their neurites. Significant loss of large CSF1-transduced neurons was seen at 2 and 3 weeks post-viral injection. Demyelination in the CSF1-transduced areas was also significant.

These results implicate that CSF1 upregulation in CNS may play an important role in the proliferation and activation of microglia in EAE, contributing to neuroinflammation and neurodegeneration.

So too much CSF-1(Macrophage Colony-stimulating Factor 1) Receptor…is bad…so lets block it with a CSF-1R inhibitor and it should be good….Fastforward…a few years

Hagan N et al. CSF1R signaling is a regulator of pathogenesis in progressive MS. Cell Death Dis. 2020 ;11(10):904.

But MS pharma have been on this case

Edling A et al. Targeting innate immune cells as a novel therapeutic approach for multiple sclerosis ECTRIMS Online Library. Edling A. 10/09/15; 116071; 1652

They used the Secondary Progresive small molecule inhibitor of CSF-1R and what did they see.

So now a different CSF-1R inhibitor that enters the CNS has been approved and made by a manufacturer that has a number of drugs that are used in MS..Will they won’t they?….. If they don’t other companies with an MS interest have other small molecule inhibitors. CSF-1 is also known as the FMS receptor.

FMS, first discovered as the gene responsible for Feline McDonough Sarcoma, is a type III receptor tyrosine kinase (signalling molecule) that binds to the macrophage or monocyte colony-stimulating factor (M-CSF or CSF-1) there are other CSF-1R inhibitors in development such as edicotinib for CNS conditions so we will know that the approach is safe….Cos I imagine you need microglia for brain health.

Is this the next race in MS after brutons tyrsoine kinase another kinase inhibitor that will block microglial function

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Disclaimer These are my views

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3 comments

  • Glad to know pharma paid attention to you on this one. It may or not work but it’s definitely more exciting to me than yet another drug targeting B-cells. I assume this wouldn’t be a great therapy on its own, but would probably be best used as maintenance therapy after an induction therapy of some sort.

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