Exploring a New Mechanism of Action for MS Drugs

An Expert Interview With John Dirk Nieland, PhD

Andrew N. Wilner, MD


December 01, 2015

While onsite at the Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) 2015 in Barcelona, Spain, Medscape correspondent Andrew N. Wilner, MD, spoke to John Dirk Nieland, PhD, associate professor of biomedicine at Aalborg University, in Aalborg, Denmark, about a promising investigational multiple sclerosis (MS) drug with an interesting mechanism of action.

Dr Wilner: John, you will be presenting a poster[1] in a few days about a new drug with a different mechanism of action from all of the other new MS drugs that we've heard about. Can you tell us a bit about the compound?

Dr Nieland: The drug we are testing is involved in lipid metabolism. We have found that in the MS-affected brain, lesioned areas undergo a shift in metabolism from glucose to lipid metabolism. Normally lipids are used to make the myelin sheaths and protect the myelin proteins from being seen by the immune system. If lipid metabolism is upregulated, then lipids that are normally used for building myelin sheaths are used for generating energy; as a result, slowly the myelin protein loses its encasing lipids because there is a half-life of myelin-associated lipids of about 3 days.

The exposed myelin protein then becomes immunogenic. As a result of increased lipid metabolism, increased prostaglandin E2 is produced, which activates the immune system locally and contributes to the inflammatory response seen in MS.

We're testing the effect of blocking lipid metabolism in animal models of MS where the treatment is initiated when the first signs of disease occur. After just 2 weeks of once-daily treatment, we're seeing that more than half of the animals are completely symptom-free.

Of note, we also identified that there are mutations in the particular molecule that we are blocking—it's a mitochondrial protein called carnitine palmitoyl transferase 1 (CPT1)—in specific human populations. A total of 98% of Inuit populations in Northern Canada and Greenland have mutations in at least one chromosome, and there has only been one reported case of MS in Inuit people. There are 50,000 Inuits living in that regions, yet the normal frequency of MS is 1 in 350 in these regions.

There is another mutation in this CPT1 gene present in Hutterites, many of whom live in Western Canada. This mutation is present in 30%-60% of these people and is associated with a very low frequency of MS; threefold lower, in fact. Thus, this supports the potential huge importance of this specific protein in relation to MS.

Dr Wilner: Tell us a bit more about the drug itself?

Dr Nieland: It's called etomoxir, and it blocks specifically the CPT1 molecule. CPT1 is a molecule expressed on the mitochondrial membrane that is involved in the transport of lipids over the mitochondrial membrane where they are metabolized in the Kreb cycle. In another rat study of ours on aggressive MS we started treating the animals very late in their disease and were able to rescue 25% of them. They are still symptom-free at the end of the study, which is pretty dramatic.

Dr Wilner: So in your model, MS may be due to a downstream effect of an underlying lipid metabolism problem that is presumably genetic?

Dr Nieland: Yes, it does look like that. In some populations, including white patients, lipid metabolism is easier to induce, and it's harder to revert back to glucose metabolism. We haven't proved this yet, but we know based on the human data that if we have a mutation in a protein that is a key molecule in lipid metabolism, CPT-1A, then we expect to be able to protect the animals for the animal form of multiple sclerosis (experimental autoimmune encephalomyelitis), and studies with the medicine that specifically blocks this molecule have shown that we can revert the disease.

Dr Wilner: What is your next step?

Dr Nieland: Our next step is to secure funding to go into phase 2 clinical trials.

Dr Wilner: How much do you need?

Dr Nieland: We need 20 million euros. We actually want to test it in secondary progressive MS, for which there are no current therapies. We also want to test it in acute optic neuritis. We are hoping we can make a difference.

Disclosures: Dr Nieland has served as an officer for Meta-IQ.


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