John Dirk Nieland on Discovering Lipid Metabolism's Role in MS

MAY 27, 2017
Kevin Kunzmann
Danish researchers are unearthing major information in both multiple sclerosis (MS) physical makeup, and a possible treatment. But John Dirk Nieland, PhD, said none of it was intentional.
Nieland, an associate professor of the Department of Health Science and Technology at Aalborg University in Denmark, represented his research team at the annual Consortium of Multiple Sclerosis Centers in New Orleans this week.
Nieland discussed “Blocking the Lipid Metabolism as a New Treatment Strategy for Multiple Sclerosis” at the conference, introducing a novel hypothesis that MS’ original causation may come from a lipid metabolism disorder and inflammation.
Lipid comprises about 80% of myelin in the central nervous system (CNS), and a disorder in its metabolism was noted in animal models with over CNS diseases prior to the team’s more extensive MS research.
Researchers blocked Carnitine Palmitoyl Transferase-1A (CPT- 1A), a key molecule involved in lipid catabolism, with antagonist Etomoxir, in mice and rat models with MS in the phase I trial.
When the molecule is blocked, lipid metabolism is reversed to glucose metabolism, and cause a reparation of myelin sheaths, re-lipidation of myelin sheath proteins for immunity system shielding, and the restoration of signaling capacity of receptors using lipids.
Neuronal function in 50% of mice models was reported by day 24 of the study, and in 25% of rat models by day 7.
As Nieland and researchers work on a clinical phase II trial for Etomoxir — testing particularly for efficacy in progressive MS and acute optic neuritis — the Danish professor shared the particular story of how his team came to look into lipid metabolism blockers.
John Dirk Nieland, MD: It was actually just by complete coincidence, that we found this way of how central nervous system (CNS) diseases and multiple sclerosis could be induced. At that point in time I was also connected to a biotechnical company where they were doing research on a heart medicine, where they found if you block lipid metabolism you could have beneficial effects on the heart, for people who have enlarged hearts.
My job for them at that point was to look if we could maybe use this medicine for other indications. I started to look into where is this molecule we are blocking actually operated at. Based on that, we screened databases. To my surprise — actually, it was the biggest surprise — all these brain diseases came out. You’ve got Alzheimer’s disease, depression, multiple sclerosis. I wasn’t expecting this to happen.
So, we asked, “How can we explain this?” We started building up a hypothesis. By then, I had left the biotech company and went to Aalborg University to research this. I started building my hypothesis, finding out how a lipid metabolism could be such an importance in brain diseases. Based on that, we hypothesized if we have this medicine, we should be able to have an effect on at least 3 diseases — memory loss, depression, and multiple sclerosis.
For memory loss, there is not such good models, so we started most of it looking at depression and multiple sclerosis. We had a researcher doing really good research on depression, where he had models to show effects in depression that are normally difficult. He could mimic the responses you see in humans with the response he would see in animal models. For instance, if you treat these diseases with the best medicine on the market, you get about 30-50% response rates. That’s what he sees in his animal models.
We tested the lipid metabolism blocker against depression, and we got up to 70% response rates after one week, and 90% within 4 weeks of treatment. This is not seen in these kinds of diseases.
We also tested in experimental autoimmune encephalomyelitis (EAE) models for multiple sclerosis and we saw up to more than 50% of the animals were completely healthy again. That was a big surprise, and a big support of the hypothesis that we built.
If you look at literature, you find a lot of data — but no one really supporting — in combining medicine (for MS). We had some contact with Angelique Corthals (PhD) from Stonybrook University. She pointed out there’s more than just the inflammatory response.
So the story is getting along, and now we’re waiting for the clinical data to come out.

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