The Prolyl Isomerase PIN1: A Novel Therapeutic Target in SLE
Lu, Kun Ping, MD, PhD
Beth Israel Deaconess Medical Center
Recent studies into the underlying mechanisms of lupus have shown that dysregulation of the immune response pathway TLR/IRAK1/IRF/IFN plays a major role in the disease. Errors in this pathway can lead to overproduction of certain hormones, particularly interferon alpha, a major culprit in lupus development. Thus, studies on how this pathway becomes dysregulated are important in identifying potential targets for new therapies.
Dr. Lu and his team previously discovered a new enzyme called PIN1 that controls protein function and plays a major role the development of numerous diseases, including cancer. Earlier work by Dr. Lu and his team suggest that PIN1 might play a major role in the development of lupus. In these studies, they found higher activity of PIN1 in peripheral blood cells of lupus patients. Importantly, Pin1 controlled the activation of the TLR/IRAK1/IRF/IFN pathway. When the researchers removed the PIN1 gene in mice and immune cells, they prevented overproduction of interferon alpha. These results led them to hypothesize that PIN1 may represent an attractive, more specific and safer novel drug target for lupus than those currently available.
With this grant, the researchers plan to test their hypothesis in three ways:
• Comparing changes related to PIN1 activity and expression in immune cells from healthy individuals and those with lupus to determine the potential role of the enzyme in human lupus
• Using animal and cell models to determine the role of PIN1 during the pathogenesis of lupus
• Delivering a highly potent and specific PIN1 peptide inhibitor specifically to certain immune cells to evaluate whether it prevents the development of lupus or suppresses lupus disease activity in cells and mouse models
What this means for people with lupus: These studies and the further development of targeted PIN1 inhibitors may represent an exciting new treatment strategy for lupus.