Treatment of thrombosis and prevention of toxicity caused by neutrophil extracellular traps (NETs)
Inventors: Denisa Wagner, Tobias Fuchs, Simon De Meyer, Kimberly Martinod, Alexander Brill, Grace Thomas
Invention Types: Therapeutics
Research Areas: Allergy/Respiratory/Pulmonary Disease, Immunology, Oncology/Hematology
Keywords: Method of UseFor More Information Contact: Ives, Catherine L.
During an infection, the body's innate immune system will be activated, bringing a number of non-specific defensive mechanisms (as opposed to the specific responses of the adaptive immune system such as antibodies) to bear on the threat. Neutrophils are one of the cell types involved in the innate immune response and they will engulf and then destroy pathogenic cells or damaged host cells. When activated neutrophils die, they release fibers of DNA associated with histones and antimicrobial proteins. These neutrophil extracellular traps (NETs) serve to entangle and kill pathogens.
Researchers in the lab of Denisa Wagner and collaborators have shown that NETs contribute to experimental deep vein thrombosis (DVT). NETs stimulate thrombus formation and coagulation and are abundant in thrombi in animal models of DVT. It appears that, in addition to fibrin and von Willebrand factor, NETs represent a third thrombus scaffold that need to be undone during thrombolysis. Prevention of NETs formation or their destruction by the enzyme DNase I drastically reduced the incidence of DVT.
Recently, Dr. Wagner found, in collaboration with Thomas Wakefield's group at the University of Michigan, increased levels of DNA in plasma from patients with DVT compared with healthy controls and symptomatic patients who did not have DVT. Here also, plasma DNA concentrations correlated with D-dimers. Therefore, it is plausible that circulating DNA may reflect presence of DVT in a patient as it reflects the degradation of NETs within a thrombus.
This research shows that subjects treated with DNase or anti-histone antibodies may reduce the level of NETs and reduce the incidence and severity of deep vein thrombosis. NETs represent a good biomarker of thrombosis.
Researchers in Dr. Wagner's lab have shown that NET biomarkers are present in transfusion-related acute lung injury (TRALI) patients' blood and that NETs are produced in vitro by primed human neutrophils when challenged with anti-HNA-3a antibodies previously implicated in TRALI. NETs are found in alveoli of mice experiencing antibody-mediated TRALI. DNase 1 inhalation prevents their alveolar accumulation and improves arterial oxygen saturation even when administered 90 minutes after TRALI onset suggesting that that NETs form in the lungs during TRALI could be targeted to prevent or treat TRALI.
• Treatment with DNase or anti-histone antibodies to reduce the incidence and severity of deep vein thrombosis.
• Novel methods for treating patients to prevent cardiovascular conditions.
• Treatment of stored blood products with DNase reduces the accumulation of NETs in the blood product.
• Methods and devices for treating accumulations of NETs in both stored blood products and a patient's blood to avoid NET-induced cytotoxicity and thrombosis.
• DNase 1 inhalation as a prophylactic agent or treatment for TRALI we observed that NET deposition in mouse lungs.
• The success rate of pharmacological catheter-directed thrombolysis ranges from 59% to 100%.
• Morbidity from venous thromboembolism has not substantially changed within the last 2 decades, and contemporary prophylaxis is not always efficient.
• This technology could lead to a targeted drug therapy for a population of patients with DVT.
• All blood products can cause TRALI, and no specific treatment is available.
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Key Publications: Fuchs TA, Brill A, Wagner DD. Neutrophil extracellular trap (NET) impact on deep vein thrombosis. Arterioscler Thromb Vasc Biol. 2012 Aug;32(8):1777-83.
Martinod K, Witsch T, Farley K, Gallant, M, Remold-O’Donnell E, Wagner DD. Neutrophil elastase-deficient mice form neutrophil extracellular traps in an experimental model of deep vein thrombosis. J Thromb Haemost. 2016 Mar; 14(3): 551-558
IPStatus: Pat. Pend.