neurodegenerative disorders

Two of masitinib’s main cellular targets are the mast cell and microglia cell. It is well-established that mast cells play a prominent role in neuroinflammatory processes, in part by releasing large amounts of pro-inflammatory mediators that sustain the inflammatory network and modulate permeability of the blood-brain barrier (BBB). Mast cells are found on both sides of the BBB and also have the ability to rapidly cross the BBB, thereby increasing their numbers in response to physiological stimuli. Microglia, resident immune cells of the central nervous system (CNS), also constitute an important source of neuroinflammatory mediators and may have fundamental roles in numerous neurodegenerative disorders. Together, these cells release large amounts of mediators, modulating the neuronal microenvironment and sustaining the inflammatory network of the nervous system.

Masitinib mechanism of action in amyotrophic lateral sclerosis

The mechanism of action of masitinib in amyotrophic lateral sclerosis (ALS) has been demonstrated with the SOD1 rat model and is based on the targeting of mast cells and aberrant glial cells. This mechanism of action has been established and published in four peer-reviewed publications.1, 2, 3, 4

Masitinib exerts a protective effect on the central nervous system:

  • Reduction of microgliosis and aberrant glial cells through CSF-1R inhibition
  • Masitinib prevents motor neuron degeneration
  • Masitinib treatment significantly prolonged survival in post-paralytic SOD1G93A rats

Masitinib exerts a protective effect on the peripheral nervous system:

  • Mast cell infiltration and degranulation contribute to neuromuscular pathology in post-paralytic SOD1G93A rats
  • Masitinib-induced mast cell inhibition significantly reduced rate of neuromuscular junction (NMJ) and motor deficits
  • Significant infiltration of mast cells and neutrophils found in autopsied muscle from ALS patients
  • Mast cells and neutrophils infiltrate the entire peripheral motor pathway (post-paralytic SOD1 rat)
  • Post-paralysis treatment of SOD1G93A rats with masitinib prevented mast cell and neutrophil infiltration, axonal pathology, secondary demyelination, and the loss of type 2B myofibers
  • Specific Schwann cell phenotypes in ALS have the potential to trigger local inflammation along the peripheral motor pathway through two signaling pathways (CSF-1R and c-Kit), which are both targeted by masitinib.
Masitinib mechanism of action in progressive forms of multiple sclerosis

Data from the scientific literature show that mast cells can actively participate in the pathogenesis of multiple sclerosis (MS):

  • Multiple sclerosis is an inflammatory disease of the central nervous system (CNS)
  • The presence of mast cells and evidence of increased mast cell activity have been reported in MS plaques. Mast cells are clustered close to the wall of venules and capillaries
  • Growing evidence suggests that mast cells play a crucial role in the inflammatory process and the subsequent demyelination observed in patients suffering from MS. Recent results from animal models clearly indicate that mast cells act at multiple levels to influence both the induction and the severity of disease.
  • Mast cells are involved in experimental model of demyelination including experimental allergic encephalomyelitis (EAE).
  • Inhibitors of mast cells (hydroxyzine) have been found to effectively inhibit the progression and severity of clinical signs of EAE, and the extent of mast cell degranulation
  • Nedocromyl sodium, a mast cell stabilizer, has also successfully delayed and prevented the development of EAE
  • The EAE model in mast cell-deficient W/Wv mice exhibited significantly reduced disease incidence, delayed disease onset, and decreased mean clinical scores

Taken together, these data suggest that mast cell degranulation is crucial to the development of the EAE model and that mast cell inhibition could be a therapeutic approach in the treatment of MS.

Masitinib mechanism of action in Alzheimer’s disease

The rationale for evaluating masitinib in Alzheimer’s disease is based on masitinib’s inhibition of the c-Kit, Lyn, Fyn and CSF1R kinases5.

  • Neuroinflammation plays a critical role in Alzheimer’s disease and mast cells present in the brain play a central role in the inflammatory process.
  • Alzheimer’s disease is characterized by the loss of blood brain barrier (BBB) integrity. Mast cells participate in the regulation of the BBB’s permeability.
  • Several lines of evidence implicate Fyn in the pathogenesis of Alzheimer’s disease through its dual role in Aβ signaling and Tau phosphorylation, making it a potential target.
  • Hence, the therapeutic benefit of masitinib in Alzheimer’s disease is expected to be exerted through multiple mechanisms of action: via its inhibition of mast cell activity, which will impact on neuroinflammation and regulation of the BBB permeability; and also, inhibition of the protein kinase Fyn, which is involved in Aβ signaling and Tau phosphorylation.

References

  1. Trias E, et al. Post-paralysis tyrosine kinase inhibition with masitinib abrogates neuroinflammation and slows disease progression in inherited amyotrophic lateral sclerosis. J Neuroinflammation. 2016 Jul 11;13(1):177.
  2. Trias E, et al. Evidence for mast cells contributing to neuromuscular pathology in an inherited model of ALS. JCI Insight, 2017. 2(20).
  3. Trias E, et al. Mast cells and neutrophils mediate peripheral motor pathway degeneration in ALS. JCI Insight. 2018. 3(19).
  4. Trias E, et al. Schwann cells orchestrate peripheral nerve inflammation through the expression of CSF1, IL-34, and SCF in amyotrophic lateral sclerosis. Glia. 2020 Jun;68(6):1165-1181. doi: 10.1002/glia.23768. Epub 2019 Dec 20. PMID: 31859421; PMCID: PMC7269115.
  5. Folch J, et al. Masitinib for the treatment of mild to moderate Alzheimer’s disease. Expert Rev Neurother. 2015 Jun;15(6):587-96. doi: 10.1586/14737175.2015.1045419.