|Articles|March 10, 2021
Masitinib May Slow Disease Progression in Neurodegenerative Disorders
Author(s)Marco Meglio
Treatment with masitinib was shown to prevent the amyloid-induced hemichannel-dependent mast cell activity in bone marrow-derived mast cells and brain mast cells.
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Masitinib’s ability to block hemichannels (HCs) on mast cells (MCs) pose as a promising novel strategy for slowing the progression of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and Alzheimer disease (AD), according to a recently published peer-reviewed study.1,2
The independent publication was led by Paloma A. Harcha, PhD, post-doctoral researcher, University of Vaparaiso, exposes the fact that these HCs allow cell communication with the extracellular environment and have diverse and pathophysiological roles in the nervous system. The review article focuses on HCs formed by connexins (Cxs) and pannexins (Panxs) proteins and their contribution to MC degranulation in AD, ALS, and harmful stress conditions.
“This research provides further supportive evidence that masitinib, through its dual targeting of mast cells and microglia, has a unique and effective profile for neurodegenerative diseases such as Alzheimer’s disease and amyotrophic lateral sclerosis,” Phillip Scheltens, MD, professor of neurology, Alzheimer Center Amsterdam, said in a statement.
Masitinib, a tyrosine kinase inhibitor, has shown to decrease the number of MCs in the extensor digitorum longus (EDL), and reduces the rate of neuromuscular junction (NMJ) denervation and motor deficits in rats with the mutant SOD1 ALS gene. While it remains unclear how exactly masitinib targets skeletal muscle MCs in ALS, studies have shown that it inhibits migration and degranulation.
The drug also targets colony-stimulating factor 1 receptors (CSF-1Rs) that are expressed by microglial cells, pointing to a double action. The researchers noted that similar neuroprotective effects in ALS were also observed in another study that used a compound that targets MCs as well as microglia.
"Thus, chronic treatment of mutant SOD1 mice (from postnatal day 60 onwards) with diosodium chromoglycate (cromolyn)—an FDA-approved compound that inhibits MC activation and degranulation and induces anti-inflammatory microglia activation—decreases the degranulation of MCs in the anterior tibialis muscle, reduces NMJ denervation, and extends the survival of ALS mice,” Harcha et al wrote.2
Overall, the outstanding plasticity of MCs was displayed upon a variety of stimuli, which can lead to different activation responses such as the release of pre-stored inflammatory mediators, release of de novo synthetized inflammatory mediators, or both processes. These processes impact the microenvironment of the tissues, since they cause vascular permeabilization, leukocyte infiltration, and parenchymal cell interactions, among other outcomes.
The review article also examined HCs and their contribution to MC degranulation in AD. Of particular interest are data from the authors in vitro and in vivo (APP/PS1dE9 mouse models) experiments that show increased MC HC activity after treatment with amyloid peptide, with subsequent degranulation response and enhanced histamine release.
In those models, the decrease of synaptophysin immunoreactivity detected completely recovered to normal values after MC depletion or treatment with masitinib, suggesting an additional synaptic protection.
In December 2020, AB Science announced results from its phase 2b/3 study (NCT01872598) of masitinib in patients with mild and moderate AD. Treatment with masitinib 4.5 mg/kg/day (n = 182) generated a significant treatment effect on the primary endpoint of change from baseline in the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) compared to those in the control arm (n = 176; P = .0003).3
In addition to the effect on cognition and memory, masitinib 4.5 mg/kg/day generated a significant change from baseline in the Alzheimer’s Disease Cooperative Study Activities of Daily Living (ADCS-ADL) score, an instrument that assesses self-care and activities of daily living (P = .0381).
REFERENCES
1. AB Science announces that a new independent publication confirms the role of masitinib as a potential therapy in neurodegenerative disorders including Alzheimer disease. News release. AB Science SA. March 8, 2021. Accessed March 9, 2021. https://www.globenewswire.com/news-release/2021/03/08/2188331/0/en/AB-Science-announces-that-a-new-independent-publication-confirms-the-role-of-masitinib-as-a-potential-therapy-in-neurodegenerative-disorders-including-Alzheimer-s-Disease.html
2. Harcha PA, Garcés P, Arredondo C, Fernández G, Sáez JC, van Zundert B. Mast cell and astrocyte hemichannels and their role in Alzheimer’s disease, ALS, and harmful stress conditions. Int. J. Mol. Published online February 15, 2021. doi: 10.3390/ijims22041924
3. AB Science announces that phase 2b/3 study evaluating oral in Alzheimer’s disease met its primary endpoint. News release. AB Science SA. December 16, 2020. Accessed March 9, 2020. https://www.globenewswire.com/news-release/2020/12/16/2145869/0/en/AB-Science-announces-that-Phase-2B-3-study-evaluating-oral-in-Alzheimer-s-disease-met-its-primary-endpoint.htm l
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