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Richard Bucala
Advancing Personalized Medicine by Targeting the MIF Protein
The immune system can be a fickle defender. Though it protects us during microbial invasion, it can also overreact so vigorously that organs fail in the crossfire. It can even turn against the body, causing autoimmune diseases like rheumatoid arthritis or lupus.
Which response will prevail is determined in part by a signaling protein called MIF, or macrophage migration inhibitory factor. MIF counteracts “calm down” signals sent by steroids, and it prevents activated immune cells from self-destructing to further incite the immune response. Since first cloning this crucial cytokine in 1993, Richard Bucala, M.D., Ph.D., has studied MIF intensively; what he’s learned is helping to demystify immune regulation.
MIF helps to explain why some people are more genetically susceptible to malaria, bacterial sepsis, autoimmune disorders, and even some cancers. The MIF gene tells the body how much MIF to make: extra MIF leads to more severe malaria, and to complications from autoimmune diseases such as lupus. Yet, extra MIF also provides for the body’s greater capacity to fight off some common infections, including bacterial pneumonia and tuberculosis. To sort out susceptibilities, Bucala has licensed genetic testing for high- or low-expression MIF alleles. That innovation may allow for personalized medicine, in which people with a certain MIF genotype can be treated with the most appropriate drug for their condition.
Figuring out which drugs is a major focus of Bucala’s research. Bucala has developed small molecules that block MIF’s ability to activate its receptor, and the lab has shown that a prototypic inhibitor is remarkably protective in mice infected with West Nile virus infection or that are genetically susceptible to developing lupus. Based on these results, an anti-MIF antibody developed by Bucala and licensed to Baxter International is in human clinical testing for lupus and cancer. Administering MIF itself also protected the heart in a preclinical study of ischemic heart disease.
Currently, Bucala is working with Yale chemist William Jorgensen, Ph.D., to develop first-in-class MIF “modulators” that could be used in a personalized medicine approach to selectively inhibit or augment MIF action. Such small molecule MIF agonists and antagonists were promising in mouse models of neonatal lung disease. Not only would small-molecule MIF modulators be available in oral form and be much less expensive than antibody-based biologic drugs, they could also be used to selectively increase or decrease MIF action based on a person’s genetic profile and as needed to treat their disease. Licensed to Debiopharm SA, one class of MIF antagonists is advancing into clinical development for use in autoimmune diseases.
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