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Sep 15, 2016
 |  BC Innovations  |  Targets & Mechanisms

KOR-recting MS

Why the MS field might invest in biased opioid agonists

Although the failed Phase II multiple sclerosis trial of Biogen Inc.'s anti-LINGO mAb in June dealt a blow to myelin repair, a slew of compounds acting by different mechanisms lies behind it in clinical and preclinical development. Now, two independent groups have added the kappa opioid receptor (KOR) to the list of targets, showing activation of kappa receptors in mouse models of MS triggers production of oligodendrocytes, the cells that make myelin, boosting myelin repair and recovery of muscle function.

But while the obvious challenge will be avoiding the psychotropic side effects of activating the kappa receptor, the results might be relevant beyond the receptors themselves, shedding a light on the control of myelination to inform other strategies.

With marketed therapies for MS achieving at least some control over the inflammatory immune attacks that demyelinate nerve axons, the field has largely turned its focus to repairing the lost myelin, with the goal of reversing the damage rather than merely halting the decline.

"Promoting natural, endogenous repair mechanisms is a leading strategy for MS," said Bruce Bebo, EVP of research at the National Multiple Sclerosis Society (NMSS), who noted that non-immunological approaches such as this could benefit people with forms of the disease in which inflammation plays a smaller role - in particular the progressive forms of MS.

While Biogen's compound, opicinumab, missed its primary endpoint in the SYNERGY trial of improvement on at least one of four measures - Expanded Disability Status Scale (EDSS), timed 25-foot walk (T25FW), nine-hole peg test (9-HPT) or three-second Paced Auditory Serial Addition Test (PASAT-3) - the company believes the compound still holds promise and is planning additional trials.

In addition, at least ten other companies and two universities have 11 products in development that could boost remyelination (see Table: Pipeline in repair).

Moreover, academic researchers have added at least a dozen targets that have not yet appeared in company pipelines (see Table: Myelin modulators).

Although there's no unifying theme around the compounds' targets, which range from various receptor ligands to a viral envelope protein, many regulate the differentiation of oligodendrocyte precursor cells (OPCs) into myelin-making oligodendrocytes (see Figure: Differential effect).

And kappa receptors, discovered by different approaches, expand the list further.

In a study published in Nature Communicationsin April, a group led by Xin Xie at the Chinese Academy of Sciences (CAS) followed evidence linking opioids to MS and used genetic deletion studies in an experimental model of MS to investigate which opioid receptor subtype - mu (MOR), kappa or delta (DOR) - is involved.

Xie is a professor at the Shanghai Institute of Materia Medica at the CAS and is deputy director of Chinese National Center for Drug Screening.

The second study, led by led by Jonah Chan, a professor of neurology at the University of California San Francisco, used an unbiased approach, implementing a screening strategy to identify G protein-coupled receptors (GPCRs) that could increase the formation in vitro of myelin sheaths around axon mimetics dubbed micropillars.Results were published in July in The Journal of Neuroscience.

Returning to opioids

Researchers have suspected for decades that the opioid system may control the severity of MS because endogenous opioid levels decrease in experimental models of MS, and pregnant women with the disease, who often go into remission until the baby is born, produce higher levels of endogenous opioids than before or after pregnancy. A pilot clinical study conducted in the early 1990s showed treatment with methionine-enkephalin produced...

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