Researchers headed by a team at Campbell Family Mental Health Research Institute Centre for Addiction and Mental Health (CAMH) reported promising data from preclinical in vivo studies evaluating a small molecule drug that targets the glutamate receptor AMPA, as a potential new treatment for multiple sclerosis (MS).
Expanding on earlier work by study lead and CAMH senior scientist Fang Liu, MD, PhD, which identified the glutamate receptor as a novel potential drug target for MS, the team created a small molecule compound that the newly reported studies indicated is effective in two different animal models of MS. “Our compound had a stunning effect on rescuing myelin and motor function in the lab models, and I hope these effects will translate to the clinic to add to current treatments and bring new hope to patients with MS,” said Liu.
Liu et al., reported their results in Science Advances, in a paper titled, “Small-molecule targeting AMPA-mediated excitotoxicity has therapeutic effects in mouse models for multiple sclerosis,” in which they concluded, “This class of MS therapeutics could be useful as an alternative or complementary treatment to existing therapies.”
MS is a progressive neurological disease that is associated with a wide range of debilitating symptoms, including problems with coordination, cognition, muscle weakness, and depression. There is currently no cure for MS, and for unknown reasons it is more common in northern latitudes and more than twice as common in women as it is in men.
MS damages myelin, the protective sheath that forms around nerves in the brain and spinal cord. It’s generally been reasoned that the myelin damage is triggered by inflammation in the immune system, and until now all drug treatments for MS have targeted the immune system. “MS has traditionally been considered an autoimmune disorder in which CD4+ T cells target myelin, leading to inflammation that causes demyelination and white matter lesions throughout the nervous system,” the authors wrote. “With autoimmunity as the presumed pathophysiology of MS, the development of treatments for MS have focused on modulating the immune system.”
However, the researchers noted, an alternative pathophysiological hypothesis is that MS is primarily or initially a neurodegenerative disorder in which the death of neurons releases myelin, and it’s this that in turn triggers a secondary autoimmune reaction.
“Neuroprotective strategies could thus act upstream of the autoimmune mechanisms leading to demyelination,” they suggested. And regardless of which model is correct, “neuroprotective treatments could be effective against neurodegeneration in progressive MS and reduce autoimmunity by decreasing the myelin released by dying neurons,” they suggested. “With this strategy in mind, targeting the processes that lead to neuronal death becomes a promising prospect for developing treatments.”
There is increasing evidence for the role of glutamate-mediated excitotoxicity in MS, and that glutamate receptors may represent a target for neuroprotection. Interestingly, previous studies had shown that inhibition of the AMPA and NMDA glutamate receptors rescued neurological deficits and reduced inflammatory cytokines in the experimental autoimmune encephalitis (EAE) rodent model for MS. “Our group previously found that protein interactions involving the GluA2 subunit of AMPA receptors were involved in regulating excitotoxic cell death, and disrupting these interactions reduced neurological deficits, demyelination, and axon damage in EAE mice,” the investigators further stated. “Clearly, the evidence points to ionotropic glutamate receptors as a target for neuroprotection in MS.”
Inhibitors of AMPA and NMDA receptors are associated with significant side effects, as these receptors are found throughout the central nervous system and play key roles in brain function. Fortunately, the authors noted, the structure of the AMPA receptor is well characterized, so scientists can carry out detailed molecular simulations of binding sites as potential targets for drugs that might modulate AMPA function, resulting in neuroprotective effects without side effects. The team had previously identified one such ligand binding site with the GluA2 AMPA subunit, and used a machine learning approach to screen for small molecules targeting this binding site.
Reporting on tests with three newly synthesized compounds, the team found that the lead candidate—designated ZCAN262—not only reduces MS-like symptoms, but also may repair the damaged myelin in two different mouse models of MS. “The lead candidate has potent effects in restoring neurological function and myelination while reducing the immune response in experimental autoimmune encephalitis and cuprizone MS mouse models without affecting basal neurotransmission or learning and memory,” they reported in their published paper.
Acknowledging limitations of their reported study, the researchers nevertheless concluded, “These findings facilitate development of a treatment for MS with a different mechanism of action than current immune modulatory drugs and avoids important off-target effects of glutamate receptor antagonists … These data are a proof of principle that a small-molecule allosteric modulator affecting AMPA-mediated excitotoxicity could have potential as a treatment for MS.”
A team led by Iain Greig, PhD, reader in medicinal chemistry at the University of Aberdeen, is working to turn the molecules identified by Liu into advanced “drug-like” molecules suitable for continued development towards clinical use. He added: “In all my years as a medicinal chemist, I have never seen a more promising starting point for a drug development project. It has been a huge pleasure to be involved in this program and I am looking forward to continuing to drive it toward the clinic.”
Liu believes that the evidence of efficacy and tolerability generated in this study for the small molecule drug makes it a good candidate to be developed for human trials. The next steps in drug development will include further preclinical research, including compound safety and stability studies. CAMH and the University of Aberdeen have already filed patent applications to protect this research and are actively seeking industry partners to further advance this work towards clinical trials over the next few years.
“It is possible that one of our compounds could be used in conjunction with current immunological treatments and could have complementary effects,” the researchers pointed out. “As with cancer chemotherapy drug cocktails, simultaneous targeting of a disease pathway at multiple points can have synergistic effects that result in better outcomes and fewer side effects than monotherapy. Another potential application of our small-molecule compounds could be to treat the progressive forms of MS, for which there are no effective treatments available to arrest the neurodegeneration and accumulating neurological deficits.”