A Role for RDEA-119 Within the Treatment of Marfan Syndrome
The chemistry technology section at NCGC has aided the Dietz Group (Johns Hopkins University School of Medicine) in its efforts to better understand the role of Mek/Erk signaling in Loeys-Dietz syndrome and Marfan Syndrome (MFS). Transforming growth factor β (TGFβ) signaling is a primary driver in multiple disorders, including MFS, and therapies that inhibit it are now in clinical trials for MFS. TGFβ can stimulate multiple intracellular signaling pathways, but it is unclear which of these pathways drives aortic disease, and/or which result in disease amelioration when inhibited by anti-TGFβ therapies. Recently, the Dietz lab has demonstrated that ERK1/2 and Smad2 are activated in MFS mice and inhibited by anti-TGFβ therapies. By providing appropriate quantities of the potent and selective MEK inhibitor, RDEA-119, the Dietz group has demonstrated ERK1/2 deactivation ameliorated aortic growth.
In addition, Smad4-deficiency exacerbated aortic disease and caused premature lethality in MFS mice. Interestingly, Smad4-deficient MFS mice showed unique activation of JNK1, while a JNK antagonist ameliorated aortic growth in MFS mice that either lacked or retained Smad4. This work indicates that ERK and JNK are prominent drivers of aortic disease in MFS mice, and that selective inhibitors of these molecules offer two novel therapeutic strategies for the disease.
Johns Hopkins University School of Medicine
Harry C. Dietz, M.D.
Public Health Impact
This study offers insight into new therapeutic options for Marfan Syndrome.
Holm TM, Habashi JP, Doyle JJ, et al. Noncanonical TGFβ signaling contributes to aortic aneurysm progression in Marfan syndrome mice. Science, 2011;332(6027):358-361.
The MEK inhibitor RDEA-119 shows preclinical promise as a therapy for Marfan Syndrome.