Evaluation of protein arginine methyltransferase 5 (PRMT5) as an actionable target in hemophagocytic lymphohistiocytosis (HLH)
Ohio State University
Columbus, OH USA
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Hemophagocytic lymphohistiocytosis, also known as HLH, is a rare but often fatal disease in adults. Normally, our immune system responds to infections or to cancer by killing the offending infection or destroying cancer cells. In HLH, the immune response to a stimulus such as infection or cancer does not work correctly and becomes overwhelming. This can lead to organ damage and even death. Currently we do not have many effective therapies to treat HLH, and up to one half of adult patients with HLH can die despite treatment with approved therapies. Therefore, the discovery of new therapies is urgently needed.
Protein arginine methyltransferase 5, or PRMT5, is a protein that is active inside immune cells that appears to regulate immune responses. Dr. Shindiapina’s group at the Ohio State University has discovered that high amounts or PRMT5 are produced by immune cells in HLH, and an experimental drug that inhibits PRMT5 works to treat HLH in a mouse model of this potentially deadly disease. However, humans may be different from mice, and the function of PRMT5 has never been tested in humans with HLH. We propose to study the function of PRMT5 in white blood cells (which form a significant part of the immune system) obtained from the blood and bone marrow of patients with HLH. We also propose to perform an in-depth analysis of the function of PRMT5 in mouse models of HLH, and investigate is further, alone and in combination with other immune-modulating drugs, in mouse models of the disease. The data acquired in the experiments described in this proposal will lead us to perform clinical trials of drugs that block PRMT5 and may therefore treat human patients with HLH.