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 the rate of neuromuscular junction (NMJ) denervation 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 myofibres
- Specific Schwann cell phenotypes in ALS have the potential to trigger local inflammation along the peripheral motor pathway through two signalling pathways (CSF-1R and c-Kit), which are both targeted by masitinib.
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 models 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
- Nedocromil sodium, a mast cell stabiliser, 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.
The rationale for evaluating masitinib in Alzheimer’s disease is based on masitinib’s inhibition of the c-Kit, Lyn, Fyn and CSF-1R 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 BBB permeability.
- Several lines of evidence implicate Fyn in the pathogenesis of Alzheimer’s disease through its dual role in Aβ signalling 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 BBB permeability; and also, inhibition of the protein kinase Fyn, which is involved in Aβ signalling and Tau phosphorylation.
