Inhibiting the CXCL7-CXCR1/2 inflammatory pathway to prevent cerebral aneurysm formation and rupture.
Cerebral aneurysms are focal dilations of cerebral arteries that are present in approximately 3-5% of the general population. These lesions can rupture, resulting in subarachnoid hemorrhage, which has a near 50% mortality and morbidity rate. There are currently no medical therapies available, and cerebral aneurysms are managed via open surgical or endovascular approaches. It is thought that cerebral aneurysms are sporadic lesions caused by a combination of inflammation and hemodynamic stress, but standard anti-inflammatory agents increase the risk of hemorrhage and are not routinely used.
Technology Description
New research shows that small molecule inhibitors targeting the platelet-driven CXCL7-CXCR1/2 inflammatory pathway can be used to prevent cerebral aneurysm formation and rupture. This approach may be able to be used to develop a pharmacological treatment of unruptured and coiled aneurysms, enabling a superior healing response and avoiding the risks inherent in open surgery.Advantages
There are currently no medical therapies for treatment of cerebral aneurysms
Avoids use of anti-inflammatory agents that increase the risk of hemorrhage
Attenuates the pan-inflammatory profile by targeting a key modulatorApplications
Preventing the formation, growth, and rupture of cerebral aneurysms
Augmentation of surgical therapy to improve outcomesStage of Development
In vivo data, including cytokine arrays and ELISA data from a hypertensive mouse model of intracranial aneurysm formation; electron microscopy of aneurysm samples, cytokine arrays of aneurysm samples, and blood samples from human patients with aneurysms, and in silico computational data for pathway discovery from the above cytokine arrays.IP Status
Provisional patent application filed
InnovatorsKamil W. Nowicki, MD, PhD
PGY-5 Resident, University of Pittsburgh Department of Neurological Surgery
Junior Endovascular Fellow
Dr. Nowicki's research interests include the interplay between inflammation and hemodynamics in cerebral aneurysm formation. During his graduate research, he focused on chemokines, hemodynamics, biomedical engineering, inflammation, and shear stress. He showed that blockade of shear stress-induced CXCL1 chemokines prevents cerebral aneurysm formation for which he was awarded two research grants from the Brain Aneurysm Foundation. Dr. Nowicki’s most recent efforts have focused on using small molecule inhibitors in preventing aneurysm formation, resulting in two patent applications. His future endeavors will concentrate on a blood test for cerebral aneurysms. He has been awarded the Best Basic Science Abstract award at the Cerebrovascular Section of CNS in 2019 and several other research awards. He has had several funding sources including the Walter. L Copeland Grant from the Pittsburgh Foundation and four grants from the Brain Aneurysm Foundation.Education
MD, University of Florida College of Medicine
PhD, Molecular Cell Biology, University of Florida College of Medicine
BS, Chemistry, University of FloridaRecent Publications
Nowicki KW, D’Angelo MP, Fellows-Mayle W, McDowell MM, Friedlander RM. Blockade of the Platelet-Driven CXCL7-CXCR1/2 Pathway Prevents Cerebral Aneurysm Formation. Neurosurgery 66, Supp_1, nyz310_108, 2019.
Nowicki KW, Hosaka K, Walch FJ, Scott EW, Hoh BL. M1 macrophages are required for murine cerebral aneurysm formation. J Neurointerv Surg 10(1):93-97, 2018.
Nowicki KW, Hosaka K, He Y, McFetridge PS, Scott EW, Hoh BL. Novel High-Throughput In Vitro Model for Identifying Hemodynamic-Induced Inflammatory Mediators of Cerebral Aneurysm Formation. Hypertension 64(6):1306-13, 2014.Robert M. Friedlander, MD
Walter E. Dandy Professor and Chairman, University of Pittsburgh Department of Neurological Surgery
Head of Cerebrovascular Neurosurgery
Director, Complex Brain Surgery Program
Co-Director, UPMC Neurological Institute
Dr. Friedlander is a renowned neurosurgeon. Presently, he is the fourth chairman of the Department of Neurological Surgeons at the University of Pittsburgh School of Medicine and the University of Pittsburgh Medical Center. Prior, Dr. Friedlander was professor of neurosurgery at Harvard Medical School and vice-chairman of neurosurgery and associate director of cerebrovascular surgery at Brigham and Women’s Hospital in Boston. Presently, Dr. Friedlander is the Walter E. Dandy Professor of Neurosurgery, Neurology and Neurobiology, and co-director of the UPMC Neurological Institute. His work has been published in journals including Nature, Science, Nature Medicine, Nature Neuroscience, PNAS, JAMA and the New England Journal of Medicine. He was first to demonstrate a functional role of caspases in a neurological disease and first to delay mortality in both ALS and Huntington’s disease mice. He has been recognized through many academic awards. In 2006, he was elected as a member of the prestigious American Society for Clinical Investigation. Dr. Friedlander is one of only three neurosurgeons elected as a member of the American Association of Physicians, and in 2018, he was elected to the National Academy of Medicine.Education
MD, Harvard Medical School
MA, Biochemistry, Brandeis University
BA, Biochemistry, Brandeis UniversityRecent Publications
Jauhari A, Baranov SV, Suofu Y, Kim J, Singh T, Yablonska S, Li F, Wang X, Oberly P, Minnigh MB, Poloyac SM, Carlisle DL, Friedlander RM. Melatonin inhibits cytosolic mitochondrial-DNA induced neuroinflammatory signaling in accelerated aging and neurodegeneration. J Clin Invest. 2020 Jun 1;130(6):3124-3136.
Gross BA, Jankowitz BT, Friedlander RM. Cerebral Intraparenchymal Hemorrhage: A Review. JAMA. 2019 Apr 2;321(13):1295-1303.