- Role of growth arrest‐specific gene 6 (Gas6) and protein S pathways in hemostasis, thrombosis and inflammation
- Targeting protein S to treat hemophilia and nucleic acid products for the inhibition of protein S expression for the treatment of hereditary and acquired bleeding disorders (in collaboration with Silence Therapeutics, London, UK)
- Investigation of the in vivo role of Gas6/Axl pathway in Philadelphia-negative myeloproliferative neoplasms
- Investigation of the performance of Gas6 plasma level as predictor of disease severity, thromboembolism occurrence and mortality in patients with COVID-19
- Antiphospholipid syndrome
- Collaboration with Prof. Heinis (EPFL, Lausanne) in his project dedicated to the development of factor XII/XIIa and prekallikrein
Prof. Anne Angelillo-Scherrer is full professor of medicine at the Medical Faculty of the University of Bern (Switzerland) and Head of the Department of Hematology at the Bern University Hospital since 2013. She started her medical career at the University of Geneva where she qualified in medicine and obtained the title of specialist in internal medicine and hematology (FMH) at the University Hospital of Geneva in 1999.
Early in her carrier, Prof. Angelillo-Scherrer was involved in research projects on the role of fibrinolysis in hematological malignancies and obtained her Medical Doctor degree from the University of Lausanne based on the results of this research. In 2000, after a postdoctoral stay at the University of Leuven in Belgium, she built up her research group at the University Hospital of Geneva (Department of Angiology and Hemostasis). Between 2005 and 2011, Prof. Angelillo-Scherrer benefited from a professorship from the SNSF and worked as Attending Physician at the Hematology Department of the University Hospital of Lausanne where she subsequently served as Associate Professor in Hematology as well as consultant for clinical hemostasis, director of the hemophilia center and of the coagulation laboratory. Since 2017, Prof. Angelillo-Scherrer is member of the National Research Council and since 2018, member of the Senate of the Swiss Academy for Medical Sciences.
Prof. Angelillo-Scherrer has more than 20 years of experience in the field of experimental and translational medicine and have been group leader for 20 years. She has focused her work on the discovery and the characterization of biomarkers important for the fields of hemostasis, thrombosis and inflammation. For example, she characterized the role in hemostasis and thrombosis of growth-arrest-specific gene 6 (Gas6) protein (Nature Medicine 2001 and The Journal of Clinical investigation 2005) and of the gap junction protein Connexin37 (Circulation 2011). She also demonstrated that Gas6 can be used as a prognostic biomarker for life-threatening diseases such as thrombosis and sepsis. In parallel, her research laboratory characterized the in vivo role of protein S, an important natural anticoagulant (Blood 2009), and showed, for example, that platelet protein S specifically regulates venous thrombosis but not arterial thrombosis (Blood 2020). These last findings have been considered as a breakthrough in the field of protein S-specific thrombosis and hemostasis research and support the broader concept of the in vivo functionality of anticoagulant factors located in platelets. In addition, Angelillo-Scherrer laboratory demonstrated that protein S is a therapeutic target to treat hemophilia and other bleeding disorders (Blood 2018) and currently works in collaboration with the company Silence Therapeutics GmbH (Berlin, Germany) developing small interfering RNA conjugated to GalNAc ligand to target protein S gene (Pros1) expression exclusively in hepatocytes for this purpose. Because others and Angelillo-Scherrer group (Nature Medicine 2001, The Journal of Clinical Investigation 2005 & 2008) demonstrated that the Gas6/Axl pathway plays a role in hematopoiesis as well as in hemostasis and thrombosis, Angelillo-Scherrer group is currently studying if the Gas6/Axl pathway constitutes a valuable therapeutic target for myeloproliferative neoplasms, a group of hematopoietic stem cell clonal diseases, that develop frequently bleeding and thrombotic complications. Finally, Angelillo-Scherrer laboratory pursues translational studies investigating the in vivo role of Gas6 and protein S in sepsis and, very recently, extended this research to COVID-19, studying Gas6 agonists/antagonists in these life-threatening medical conditions. Based on solid pre-clinical and clinical data, Angelillo-Scherrer laboratory is evaluating whether Gas6 is a valid biomarker to help clinicians to tailor therapy to individual sepsis or COVID-19 patients.
- Project on «targeting protein S to achieve hemostasis in hemophilia». This work, published last year (Prince R. et al., Blood, 2018, 131:1360-1371) and accompanied by an editorial and the cover of the journal, was preceded by the submission of a patent application for the use of specific silencing RNA against protein S for the treatment of hemophilia (A. Angelillo-Scherrer and R. Prince, inventors, PCT EP2017078107, 02.11.2017). Currently, in collaboration with the company Silence Therapeutics (London, UK) Angelillo-Scherrer’ group is testing silencing RNA candidates in order to modulate the expression of the protein S gene (2nd patent application together with Silence Therapeutics: Dames, S.; Schaeper, U.; Prince, R.; Angelillo-Scherrer, A., inventors, EPO EP19173054.8, 07.05.2019).
- A novel mechanism that distinguishes venous from arterial thrombosis (Figure 2): In veins, platelet protein S limits thrombin generation within the growing thrombus, insuring that highly activated platelets and fibrin remain localized at the injury site. At the luminal surface of the thrombus, there are minimally highly activated platelets and no fibrin. In absence of platelet protein S, the thrombus is much larger and rapidly occlusive, and highly activated platelets and fibrin are distributed homogeneously in the thrombus. During thrombus formation in arteries, platelets accumulate faster than in veins. For this reason, most of the platelets in the arterial thrombus do not become fully activated and, therefore, do not release the content of their granules, including protein S. Consequently, both in the presence and absence of platelet protein S, highly activated platelets remain confined to the site of injury, where most of the fibrin is found. Thus, in arteries, the size and the architecture of the thrombus do not depend on platelet protein S, because the release of platelet protein S during thrombus growth is very limited.
These findings extend current knowledge by demonstrating that platelet protein S is a key player in the control of thrombin activity in venous, but not in arterial thrombosis. They offer insights into the organization of the thrombus and highlight critical differences between arterial and venous thrombosis pathogenesis. It will be interesting to explore whether these results help to understand the effect of vitamin K antagonists as compared to other anticoagulants, especially direct oral anticoagulants. In addition, platelet protein S might constitute a valuable therapeutic target in patients with bleeding disorders. This work has been recently published in Blood (Calzavarini S. et al., Blood 2020, 135: 1969-1982).
- Additional work focused on the role of protein S during pregnancy, liver disease, chronic hemarthrosis, and on the mechanism of purpura fulminans and endotoxemia and infection.
- Gas6 plasma level has been evaluated in two patients cohort, the first one, is the sepsis cohort of Lausanne (Stalder G. et al., PLoS One, 2016, 11:e0163542) and the second one, the Swiss Cohort of elderly patients with venous thromboembolism (Schnegg-Kaufmann A. et al. JTH 2019, 17:306-318). In both studies, Gas6 appeared to be a useful prognostic marker.
- Prof. Angelillo-Scherrer’ laboratory started in April 2020 a project entitled “Investigation of the in vivo role of Gas6/Axl pathway in Philadelphia-negative myeloproliferative neoplasms” that is supported by the SNF.
Besides the work completely accomplished describe above, Angelillo-Scherrer’ research group participated to several studies (only the most important are listed below):
- The paper of Cosemans et al. describing further the role of Gas6 and its receptors on mouse and human platelets (JTH, 2010, 8:1797-1808) and nicely completes Prof. Angelillo-Scherrer’ publications from 2001 in Nature Medicine and from 2005 in JCI.
- A paper published in collaboration with Prof. B. Kwak and P. Fontana (Geneva, Switzerland) described for the first time the role of Connexin37 in platelets (Angelillo-Scherrer A. et al., Circulation, 2011, 124:930-939).
- A collaboration with Dr B. Rochat from the CHUV, Lausanne, allowed the development of a method to measure accurately hepcidin level in mice and human (Bioanalysis, 2013, 5:2509-2520).
- Publications in collaboration with Prof. C. Heinis from EPFL, Lausanne describing the effect of bicyclic peptides in the inhibition of factor XII (J Med Chem, 2013, 56:3742-3746; ACS Chem Biol, 2015, 10:1861-1870 and J Med Chem, 2017,60:1151-1158). Last publication in collaboration has been recently published in Nat Commun (Wilbs J et al. Nat Commun, 2020, 11:3890).
- Prof. Angelillo-Scherrer’ laboratory also performed all the animal experiments for the work of K. Happonen et al. (J Biol Chem, 2016, 291:10586-10601). This work showed that Gas6-Axl protein interaction mediates the endothelial uptake of platelet microparticles.
- Prof. Angelillo-Scherrer have participated to publications on the Swiss cohort of elderly patients with venous thromboembolism and her group is currently writing two additional papers on the Swiss cohort of elderly patients with venous thromboembolism (thrombin generation and D-Dimer analyses).
- Prof. Angelillo-Scherrer’ research group have set up a retrospective study on more than 3000 patients with thrombophilia and another one on the antiphospholipid syndrom.
Role of growth arrest‐specific gene 6 (Gas6) and protein S pathways in hemostasis, thrombosis and inflammation
(1) To further study the regulation of the hemostatic balance by PS; (2) to further investigate the role of Gas6 in hemostasis and thrombosis, and to evaluate its possible use as a therapeutic target for thrombosis, alone or in combination with FXII inhibition; (3) to further investigate the role of PS/Gas6 in two topics linking hemostasis and thrombosis with inflammation: purpura fulminans and sepsis/infection.
Expected value of the proposed project
We aim at a better understanding of protein S/Gas6 pathways in mechanisms of hemostasis, thrombosis and inflammation. Perspectives include clinical trials implying protein S/Gas6 agonists/antagonists to treat human diseases such as bleeding disorders, thrombosis, purpura fulminans or sepsis/infection. More specifically, collaborative work with industry will continue in order to propose protein S/Gas6 targeting for therapy.
Targeting protein S to treat hemophilia and nucleic acid products for the inhibition of protein S expression for the treatment of hereditary and acquired bleeding disorders (in collaboration with Silence Therapeutics, London, UK)
The current state of the project demonstrates that targeting protein S protects mice with hemophilia A from acute and chronic hemarthrosis without provoking inflammation or susceptibility to infection. We plan to carry out some additional experiments to consolidate the part dedicated to the mechanisms before submitting a manuscript. In particular, we would like to investigate the impact of protein S targeting in synovium at the cellular level with the aim to uncover the cell signaling mechanisms in reaction to the hemarthrosis process.
We also completed the preclinical studies in mice using a specific silencing RNA against protein S to treat hemophilia A. This last work has been conducted in collaboration with the company Silence Therapeutics (based in UK and Germany). These data provide the first evidence that using a GalNAc-siRNA conjugate to modulate Pros1 gene expression is well tolerated and has the ability to reduce plasma protein S level and protect hemophilia A mice from acute hemarthrosis pointing to protein S targeting using GalNAc-siRNA-protein S as a new valuable therapeutic approach for hemophilia.
Investigation of the in vivo role of Gas6/Axl pathway in Philadelphia-negative myeloproliferative neoplasms
Hypothesis and aims
We hypothesize that Gas6/Axl pathway plays a role (1) in the development and the pathology of MPNs and in the response to therapy as well as (2) in the development of bleeding and thrombotic complications in the context of MPNs. Consequently, we hypothesize that Gas6/Axl pathway is a valuable therapeutic target for MPNs. Our general aim is to characterize the in vivo role of Gas6/Axl pathway in MPNs Philadelphia-negative myeloproliferative neoplasms.
Expected value of the project
We expect to characterize the role of Gas6/Axl pathway in MPNs. Perspectives include clinical trials implying Gas6/Axl pathway targeting.
Investigation of the performance of Gas6 plasma level as predictor of disease severity, thromboembolism occurrence and mortality in patients with COVID-19
To assess Gas6 performance to predict (1) venous/arterial thromboembolism, (2) clinical deterioration, (3) ARDS development, (4) mortality; and (5) to determine the association between Gas6 and other biomarkers.
Gas6 might constitute a valid biomarker to help clinician to tailor therapy to individual COVID-19 patients according to their risk of venous/arterial thromboembolism, clinical deterioration, ARDS development and mortality.
- Prof. D. Aujesky, Division of General Internal Medicine, Bern University Hospital, Inselspital, University of Bern, Bern
- Prof. C. Heinis, EPFL, Lausanne
- Prof. P. Fontana and PD Dr. A. Casini, Division of Angiology and Haemostasis, University Hospitals of Geneva, Geneva
- Prof. A. Berzigotti, Hepatology, University Clinic of Visceral Surgery and Medicine, Inselspital, DBMR, University of Bern, Bern
- Prof. A. De Gottardi, Gastroenterology and Hepatology, Ente Ospedaliero Cantonale and Università della Svizzera Italiana, Lugano
- Working Party on Haemostasis of the Swiss Society of Haematology
- Dr. François Saller, INSERM & UMR-S 1176, Université Paris-Sud, University Paris-Saclay, Le Kremlin-Bicêtre, France
- Prof. J.H. Griffin and Dr. Fernández JA, Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA
- Prof. Y. Matsumura, Division of Developmental Therapeutics, Research Centre for Innovative Oncology, National Cancer Center Hospital Est, Chiba, Japan
- Prof. T. M. Hackeng, Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands
Role of growth arrest‐specific gene 6 (Gas6) and protein S pathways in hemostasis, thrombosis and inflammation: SNF#314730_173127, SNF R’EQUIP#316030_177126, SNF R’EQUIP#316030_183501
Targeting protein S to treat hemophilia (SNF#314730_173127) and nucleic acid products for the inhibition of protein S expression for the treatment of hereditary and acquired bleeding disorders (in collaboration with Silence Therapeutics, London, UK)
Investigation of the in vivo role of Gas6/Axl pathway in Philadelphia-negative myeloproliferative neoplasms SNF#310030_192635
Investigation of the performance of Gas6 plasma level as predictor of disease severity, thromboembolism occurrence and mortality in patients with COVID-19 Bern Center for Precision Medicine, Call on Covid-19 and SARS-CoV-2