Therapeutic Inhibition of MIF to Improve Glucocorticoid Response

Abstract Despite the advent of biological therapiesglucocorticoidsGCsremain the most widely prescribed medicines for the management of inflammatory diseases such as lupusasthmamultiple sclerosisand rheumatoid arthritisHoweverlong term and high dose GC use is inevitably accompanied by systemic toxicityThere are no adjunctive therapies that could enhance the disease modifying effects of GCs at low doses thus minimizing their dose dependent toxicityThe long term product goal of this Phase I SBIR project is a small molecule GC adjunct that will enable an efficacious GC regimen at non toxic dosesTo accomplish this goalwe propose an innovative strategy to improve GC responsiveness by blocking macrophage migration inhibitory factorMIFa proinflammatory cytokine known for its ability to antagonize GC actionWe will block MIF function using a novel family of small molecule MIF inhibitors and a MIF specific monoclonal antibody and evaluate the therapeutic effect of this blockade in restoring GC response in a GC resistant autoimmune disease modelFor the purpose of this studywe have already developed a unique mouse model of autoimmune disease that is refractory to GC treatmentIn this model of experimental autoimmune encephalomyelitisEAEthe rodent equivalent of multiple sclerosiswe discovered that female mice develop fulminant and lethal disease despite GC treatmentand that disease progression can be effectively halted by neutralizing MIF activityBuilding from this observationwe have developed a rigorous experimental plan to interrogate the therapeutic effect of MIF inhibition in restoring GC responsiveness in the EAE miceThe achievable milestone for this Phase I SBIR project is efficacy evaluation of two novel small molecule MIF inhibitors and one MIF specific monoclonal antibody in restoring GC response in the GC resistant EAE miceThe scientific premise of this study is based on a vast body of literature on the interactions between MIF and GCsand the relevance of this regulatory dyad in contributing to clinical resistance to GC therapyA successful outcome of this study will lay the foundation for further pre clinical development of a novel and `first in classandaposadjunctive therapy that would enable prolonged use of lower and non toxic doses of GCs in autoimmune patients Public Health Significance GlucocorticoidsGCsare widely used to treat symptoms in many inflammatory disorders such as lupusasthmamultiple sclerosisand rheumatoid arthritisHoweverthe use of high GC doses over an extended period is often accompanied by toxicityThe current project proposes an innovative strategy for efficacious GCtherapy with less toxicity by blocking macrophage migration inhibitory factorMIFa proinflammatory cytokine that counteracts GCandapos s disease modifying activity