Grant: Project Grant

There are limited treatments options for progressive MS, with only one approved drug. Unlike relapsing-remitting MS, progressive MS is not responsive to anti-inflammatory drugs. This suggests that progressive MS is not mainly an inflammatory disease but could be a neurodegenerative disease caused by 'oxidative stress'. 'Ferroptosis' is a newly discovered form of oxidative stress, triggered by excess iron which causes damage to lipids (or fats) found in cells. Ferroptosis can cause damage to myelin which is rich in lipids. It can also cause damage to cells in the brain that produce myelin as well as to nerve cells (neurodegeneration). We have preliminary evidence from a mouse model of MS called experimental autoimmune encephalomyelitis (EAE) that ferroptosis occurs in a chronic form of EAE (CH-EAE), which models aspects of progressive MS. Once ferroptosis starts, it can take off like "wildfire in the hot, dry summer". The good news is, that there are drugs that can "quench this fire" and stop damage to lipids. We already have evidence that certain biomarkers of ferroptosis are produced more highly in CH-EAE. We propose to treat CH-EAE mice with a drug that blocks ferroptosis. We have preliminary evidence that such treatment works. We will confirm this by assessing if this treatment improves weakness and paralysis in these mice and also analyze improvement in pathology. We also plan to study a combination-treatment with a ferroptosis inhibitor and an iron chelator to block ferroptosis-mediated damage to lipids, and other iron-mediated damage to proteins and DNA. We hope this will act like a "one-two punch" to stop progression. In addition, we will also assess various ferroptosis biomarkers in human MS brain autopsy samples of secondary progressive and primary progressive MS. This work could open the way for the development of novel therapies for progressive forms of MS for which there is currently no effective treatment.