DX61
CPT1 inhibitor significantly induce remyelination and neuroprotection in Multiple Sclerosis by a dual mode of action

Friday, May 29, 2015
Griffin Hall
John D Nieland, PhD, Associate Prof. , Health Science and Technology, Aalborg University, Aalborg, Denmark
Jette GK Nieland, MSc , Meta-IQ ApS, Aarhus, Denmark
Soeren Nielsen, MD. Prof. , Health Science and Technology, Aalborg University, Aalborg, Denmark



Background:

Multiple sclerosis (MS) is a complex disease which has been regarded as an inflammatory disease. However, all treatments based solely on the inflammatory response have not been effective in treating MS. In RR-MS blockers of the inflammatory response can at best extend the time between relapses but they do not treat the disease. In SP-MS and PP-MS blockers of the inflammatory response have no effects. Recently new therapies targeted to block the downregulation of myelin protein production, have not shown clinical efficacy.

It is well established that the lipid levels and composition in MS patients are changed compared to healthy individuals. In addition lipid metabolism has been shown to be upregulated. Lipids have quite a number of functions in the brain:

1) Lipids are essential in functionally active myelin sheets (composed of myelin protein with lipids like palmitate coupled to it).

2) to shield the very immunogenic myelin protein from the immune system.

3) lipids have pronounced effect in receptor signaling (e.g. arachidonate is used by the glutamate receptor to transfer signals inside the cell).

4) lipids play fundamental roles in the inflammatory response (e.g.  the lipid PGE2 is generated under stress and hypoxia).

Objectives: not applicable

Methods: not applicable

Results:

We have shown that the CPT1 agonist etomoxir has a dual mode of action. First it blocks lipid metabolism and secondly downregulates the immune response. Treatment with etomoxir of EAE in a  therapeutic relevant setting, with treatment starting 10 days after disease induction, reveals reversement of the disease outcome and repair of the myelin sheet pathology. In total over 50% of the animals were disease free after 2 weeks of treatment.

In major support of the in vitro and in vivo experiments in rodents it has recently it has been shown that individuals that have mutations in CPT1a (the target of etomoxir) are protected from developing Multiple Sclerosis among other CNS diseases. The mutation In CPT1a turns the efficacy of the CPT1a protein only 25% of the wildtype CPT1a. Where people in the same communities have a MS frequency of 1 in 350, no MS case was seen in the people carrying the mutation.

Current studies are focused to elucidate in more detail the mode of action of etomoxir, and based on this new dual mode of action try to identify biomarkers for the different types of MS. Phase 2 clinical trials are underway using Etomoxir in clinical studies in acute optic neuritis (as a pre-stage of Multiple Sclerosis) as well as in SP-MS.

Conclusions: This new dual mode of action approach is highly effective following a new way of thinking for MS development, progression and treatment.