OxPC and RAGE in MS Brain
2005 Seed Grant
Glyn Dawson, Ph.D.
The University of Chicago
Recent observations in our laboratory have identified a new potential target for MS therapy. We believe that this potential target is a protein, known as RAGE, that has been previously associated with diabetes and heart disease. We are requesting seed funds to verify that RAGEis the target for oxidized fat addition, and get enough data to convince other scientists that this is a new and exciting finding in the field of Multiple Sclerosis research. Studies on patients with heart have disease revealed that fatty build up in artery walls contains a “bad” lipoprotein that had been chemically modified by the addition of an oxidized fat. This modified protein is hypothesized to playa critical role in artery blockage. Using a novel antibody that specifically recognizes oxidized fats, known as TIS, we compared brain samples from normal and diseased brains and noticed one striking difference. Thus, while all brain samples contained the RAGE protein, only patients with Multiple Sclerosis showed a protein the size of RAGE with an oxidized fat modification. We want to prove that this protein is indeed RAGE. We will then test the idea that the presence of oxidized fat modified RAGE plays a role in the in inflammation and destruction of white matter that has been associated with Multiple Sclerosis. We will determine if RAGE is the major oxidized fat modified protein in autopsy brains and spinal cord from patients with Multiple Sclerosis, as well as from EAE mice (a mouse model for Multiple Sclerosis). We will also determine if any other important proteins are modified. We will determine if the fats themselves are oxidized and if the chemical addition of oxidized fat occurs in other neurodegenerative diseases. It is our hope that from these studies we will be able to develop a treatment for Multiple Sclerosis using a combination of anti oxidants (such as vitamin E) and the Ti5 antibody.
Multiple sclerosis robs people of their sight and strength in their most productive years and at present there is no cure. At best we have drugs which slow the progression of the disease in some patients and reduce the incidence of recurrence in others. Our findings with the monoclonal antibody Ti5 (which is being generated by the Fitch Monoclonal Antibody Core Laboratory at the University of Chicago) in MS brain were somewhat unexpected and have not been reported by any other researchers. We think that the chemical modification we have found interferes with the ability of this protein (RAGE) to take care of the repair of injured nerves. The significance of our finding lies in the fact that if we can use the humanized monoclonal antibody to treat multiple sclerosis. Monoclonal antibody therapy is starting to be used to treat eNS brain tumors and Tysabri (Antegren) (a humanized monoclonal antibody which inhibits adhesion molecules on the surface of immune cells) was approved for the treatment of Multiple Sclerosis. Its clinical suspension after some deaths suggests possible problems, but our monoclonal (TI5) should not have the same problems. We think that TI5 could help MS patients recover and the seed funding will allow us to fund important development work.