Potential Multiple Sclerosis Therapy Seen in Addex’s mGluR4 Modulator

Margarida Azevedo, MSc avatar

by Margarida Azevedo, MSc |

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MS research

Addex Therapeutics, a biopharmaceutical company developing novel small molecule allosteric modulators for neurological disorders, recently announced the publication of positive results from studies evaluating the therapeutic effect of ADX88178, a metabotropic glutamate receptor 4 (mGluR4) modulator, in an animal model of multiple sclerosis. The research article, titled “Allosteric modulation of metabotropic glutamate receptor 4 activates IDO1-dependent, immunoregulatory signaling in dendritic cells,” appeared in the journal Neuropharmacology.

mGluR4, primarily expressed on presynaptic terminals in nerve cells, is known to possess immune modulatory properties in vivo. Its activation, through a positive allosteric modulator (PAM), has been shown to decrease neurotransmitter release from presynaptic terminals and to confer protection in mice with relapsing-remitting experimental autoimmune encephalomyelitis (RR-EAE), a model mimicking human MS. mGluR4 function has been implicated in several diseases besides multiple sclerosis (MS), such as Parkinson’s disease, anxiety, schizophrenia, autism, and diabetes.

Addex’s ADX88178, a recently developed and highly selective PAM with considerable potency and optimized pharmacokinetic properties, was tested in the RR-EAE model system. Treatment of RR-EAE mice with ADX88178 converted the disease into a mild form of neuroinflammation, a state that remained stable for more than two months after the treatment was stopped. In vitro assays also showed that ADX88178 modified the cytokine secretion profile of dendritic cells; in particular, it increased the production of IL-10 and TGF-β, molecules that induce immune tolerance. Furthermore, researchers uncovered molecular signaling pathways induced by the response to the drug, involving specific kinases (PI3K, Src) and indoleamine 2,3-dioxygenase 1 (IDO1), known to play a vital role in several autoimmune diseases.

Professor Ursula Grohmann, from the University of Perugia in Italy and the study’s senior author, said of the results in an Addex press release, “Our findings demonstrate the central role played by mGlu4 receptors in the regulation of immune response mediated through dendritic cells. The effects observed with Addex’s highly selective and potent mGluR4 PAM, which activates long-lived regulatory pathways, suggest that such a compound could be therapeutically exploited in chronic autoimmune diseases.”

Tim Dyer, CEO at Addex Therapeutics, added, “We are very pleased with our ongoing collaboration with Professor Grohmann’s group and the data generated in their specialized models. This collaboration is a great example of how we are able to advance the understanding of the role of mGluRs and generate significant value in our portfolio of allosteric modulator drug candidates.”

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