The National Multiple Sclerosis (MS) Society reports that 1.2 million people worldwide and more than 400,000 people in the U.S. have clinically diagnosed MS. Currently there are 10 FDA approved drugs for MS but none of the current drugs have impacted the course of MS to prevent relapses or progression of disease. An efficient means to control the autoimmune inflammation in MS is crucial to disease management. A major inflammatory interaction that has been identified in MS is the CD40/CD154 axis. In fact controlling this pro-inflammatory dyad has been in previous years, a high priority. The problem for therapeutic development has been the method to control CD40/CD154 interaction, specifically monoclonal antibodies. CD40 antibodies are agonistic, thus promoting inflammation and CD154 antibodies induced thrombosis. We created a novel means to control the interaction using a targeted peptide that binds directly to the CD40 protein at the CD154 interaction site. Using an autoimmune inflammatory diabetes model we showed that this peptide, KGYY15 prevents diabetes onset and reverses diabetes complications by controlling CD40 mediated signals. In the current grant we will test KGYY15 for efficacy in controlling experimental autoimmune encephalomyelitis (EAE) the mouse model for multiple sclerosis. We will examine how KGYY15 impacts a chronic disease model as well as a relapsing/remitting disease model. These Phase I experiments will provide the necessary basis for creating a new drug indication to control auto-inflammation in MS. By controlling the inflammation in the central nervous system it may be possible to stop or even reverse the nerve degeneration that is prevalent with the progression of this disease.
This project is an innovative approach to blocking CD40 - CD154 interactions, which are critically involved in numerous autoimmune diseases including multiple sclerosis. We designed a small peptide that blocks CD40 - CD154 interaction and hypothesize that this peptide will substitute for anti-CD154 in preventing EAE and alleviating symptoms in established disease. This peptide could provide a unique treatment option for MS.
