Drug Target Linked to Antiphospholipid Syndrome The mammalian target of rapamycin complex (mTORC) pathway is involved in the vascular lesions that occur in patients with antiphospholipid syndrome, according to a new study. Sirolimus, an mTOR inhibitor, may help prevent vasculopathy in patients with the disease, the researchers say. Our study suggests that a specific molecular pathway, the mTORC pathway, leads to intimal hyperplasia, which accompanies the most severe variants of the antiphospholipid syndrome, write Guillaume Canaud, MD, PhD, from the Institut Necker-Enfants Malades in Paris, France, and colleagues in an article published in the July 24 issue of the New England Journal of Medicine. They found that antiphospholipid antibodies stimulate the mTORC pathway. However, the mTORC pathway does not seem to be linked to the coagulation aspects of the disease but, instead, triggers the cell proliferation and growth that lead to vascular lesions, including those that cause kidney damage. Thrombotic events are the most common complication of the disease, and long-term anticoagulation is the only treatment that reduces vascular complications. However, that regimen does not prevent organ deterioration and death in high-risk patients, particularly those in whom catastrophic antiphospholipid syndrome develops, the authors write. In specimens from patients who died of catastrophic antiphospholipid syndrome, the investigators found that the mTORC pathway was activated in both the carotid and left anterior descending arteries. Analysis Points to Sirolimus Benefit In laboratory tests, the researchers compared immunoglobulin G antibodies from 12 patients with antiphospholipid syndrome and a history of vascular injury with antibodies from 14 healthy control patients. The antibodies from patients with antiphospholipid syndrome were able to activate key parts of the mTORC pathway in cultured endothelial cells. When the cells were treated with sirolimus, however, the mTORC pathway was no longer activated by patient-derived antibodies. Sirolimus (previously known as rapamycin) is known to inhibit the mTORC pathway. Together, the data suggest sirolimus may be an effective treatment for the vascular aspects of antiphospholipid syndrome. The investigators tested this hypothesis with data from a previous study of kidney transplant recipients. Vascular lesions from antiphospholipid syndrome can lead to the need for a kidney transplant, but the lesions can recur in the new organ. Yet kidney recipients who were given sirolimus as an immunosuppressive drug were less likely to develop subsequent lesions. Among 10 patients who were give sirolimus, 7 (70%) had a functioning renal allograft 144 months after transplantation compared with 3 (11%) of 27 untreated patients. The patients who did and did not receive sirolimus had the same levels of antiphospholipid antibodies and other markers of immune system function, indicating sirolimus helps by specifically inhibiting the mTOR pathway, not by general immune suppression. The investigators propose that antiphospholipid antibodies trigger 2 separate pathways: one that leads to thrombosis and another that activates the mTORC pathway and causes excessive cell growth. Anticoagulants only affect the thrombosis pathway, whereas sirolimus can block the mTORC pathway. The results, although promising, are still preliminary, write John W. Eikelboom, MB BS, from the Department of Medicine, the Population Health Research Institute, and the Thrombosis and Atherosclerosis Research Institute McMaster University, Hamilton, Ontario, Canada, and Jeffrey I. Weitz, MD, from the Department of Medicine and the Department of Biochemistry and Biomedical Sciences and the Thrombosis and Atherosclerosis Research Institute, McMaster University, in an accompanying editorial. [I]f the authors findings are confirmed, patients with mTORC-pathway–directed antiphospholipid antibodies may benefit from sirolimus, not only to improve renal allograft survival but also to prevent the development of vasculopathy — goals that require exploration in clinical trials. The study was supported by grants from the Institut National de la Santé et de la Recherche Médicale, Université Paris Descartes, Assistance Publique-Hôpitaux de Paris, Fondation du Rein, Fondation pour la Recherche. One of the authors reports receiving personal fees from Alexion and Novartis outside the submitted work. The other authors, Dr. Eikelboom, and Dr. Weitz have disclosed no relevant financial relationships.
Posted on: Thu, 24 Jul 2014 21:52:45 +0000
Trending Topics
Recently Viewed Topics
© 2015