Blocking the Lipid Metabolism As a New Treatment Strategy for Multiple Sclerosis
Multiple Sclerosis is a complex disease, which has been regarded as both a neurodegenerative and inflammatory disease characterized by damage to myelin sheaths of nerve cells. Normally, lipids of the CNS are important for a lot of functions e.g. hiding the myelin sheath proteins for the immune system and structure of myelin sheaths. Disturbances in the metabolism, as seen in Multiple Sclerosis, result in an upregulated lipid metabolism, thus changing the composition and level of lipids compared to healthy individuals. By blocking CPT-1A, a key molecule involved in lipid catabolism, the metabolism is reversed to a glucose metabolism. This block of lipid metabolism causes lipidation of myelin sheath proteins and reparation of the myelin sheaths, shielding of myelin sheath proteins for the immune system and restoration of signaling capacity of receptors using lipids.
Objectives: Not applicable
Methods: EAE mouse and rat studies.
People carrying CPT-1A mutations are protected from developing Multiple Sclerosis and other CNS diseases. These mutations reduce or delete the activity of CPT-1A. Populations such as Hutterites and Inuits are carrying CPT-1A mutations and have a prevalence of Multiple Scleroses of 1/1100 and 1/50000, respectively. Normally, the prevalence in these regions is 1/350.
On the basis of these facts, both rat and mice models of EAE were established in order to test the effect of Etomoxir, a CPT-1A agonist. In a mice model of EAE, treatment with Etomoxir started at day 10 with daily injections show > 50 % of the mice were cured after two weeks of treatment. In addition, the inflammatory response is downregulated and the myelin sheaths are repaired. A rat model of EAE show 25 % disease free animals after treatment with Etomoxir injected at day 7.
Current studies are underway to elucidate the mode of action of Etomoxir and to identify biomarkers for the different stages of Multiple Sclerosis. Moreover, a phase two clinical trial using Etomoxir for treatment of acute optic neuritis and secondary progressive Multiple Sclerosis is being organized.
Blocking the lipid catabolism through blocking of CPT-1A by Etomoxir opens new avenues for treatment of Multiple Sclerosis and stands for a paradigm shift in the understanding of the development and treatment of Multiple Sclerosis and other CNS diseases.