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FONDATION LEDUCQ NEWSLETTER CALL FORAPPLICATION CYCLE The fifth The fifth Fondation Leducq Symposiumwillbe Sylvie LORAND-HULOT and improve thetreatment ofcardiovascular LEDUCQ SYMPOSIUM 2015 COMMITTEE DEPARTURES Scientific Advisory Committee in2014 Due date isFriday, September 5, 2014, Four new TNEsin2014andfour TNEs TO BEGIN TO CONNECT LEDUCQ FOUNDATION in 2013willincrease theknowledge NEW TRANSATLANTIC SCIENTIFIC ADVISORY NEWSLETTER David TANCREDI held inParis onApril16th,2015. Three new membersjointhe and neurovascular diseases. AND ARRIVAL 11:59 pmParis time Improving healththrough international NETWORKS NETWORKS 2014-2015 Will setup

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vascular research. neuro and cardiovascular and in many inspired so supported Jean, husband who late her Leducq, with along Sylviane president, and founder its of passing the mourns Leducq Fondation The Sylviane Leducq (1925-2013) cardiovascular research 2014 -

Volume 6 and brain, the proposed experiments and blood brain barrier permeability, genetically engineered mice. If successful will concentrate on genetic targeting network members propose specifically this group could help to launch a entirely 2014 of receptors and related pathways. to identify the cell types responsive new platform for the treatment of Building on a strong body of literature to SIP-mediated BBB regulation in neurovascular disease. implicating S1P in vascular regulation large part by the use of a variety of

FONDATION LEDUCQ ANNOUNCES 2014 TRANSATLANTIC 3 , Pathogenesis and Protein-Replacement Therapy in NETWORKS OF EXCELLENCE AWARDS Arrhythmogenic Cardiomyopathy Four new Transatlantic Networks (TNE) received in September 2013, representing platform, which was introduced in the Ali Marian, The University of Texas, Houston, US and were selected by the Scientific a 30% increase in the number of cycle 2013-2014. William McKenna, University College of London , UK Advisory Committee (SAC) at its April LOIs received over the previous year. The networks awarded funding in 2014 2014 meeting in Napa Valley. These Submission now proceeds through a are : programs were chosen from among user-friendly online application service This network is designed to delineate normal structure and function and as the sharing expertise will have access to a 118 Letters of Intent (LOI) that were through the Altum proposalCENTRAL the molecular genetics, genomics, and disease progresses, there is ventricular well phenotyped AC patient popu- pathogenesis of arrhythmogenic cardio- dilation, dysfunction and aneurysm lation. They will continue searching 1 Deciphering the Genomic Topology of Atrial Fibrillation myopathy (AC). The classic right-dominant formation. Clinical failure is a late for new and new mutations, form of AC, known as arrhythmogenic manifestation. A switch in the fate and but most important of all, they will Patrick Ellinor, MGH, Boston, US and right ventricular cardiomyopathy, is a differentiation of a subset of cardiac investigate protein replacement in Vincent Christoffels, Academic Medical Center, Amsterdam, The Netherlands leading cause of sudden cardiac death resident cells to fibro-adipocyte is transgenic mouse models to attempt in young people. The burden of AC the pathological hallmark of AC. The to reverse the phenotype. The syner- is almost certainly underestimated, present challenge lies in elucidating gistic interactions between clinicians Atrial fibrillation (AF) affects over 3 have only a limited understanding the electrical rhythm of the heart? however, owing to frequent missed the intervening steps - from mutation and scientists in this network will million individuals in the US and 4.5 of mechanisms through which these Filling the gap of our understanding of diagnoses and under-recognition of the to pathologically overt disease - and ultimately improve the quality of life million individuals in Europe. Currently, genetic variants lead to AF. By combi- the molecular pathways underlying the left-dominant and biventricular subtypes. identifying therapeutic targets therein. and survival of AC patients. both medical and interventional ning deep insights into GWAS-signals, should ultimately provide Initially in this disease, the heart has a This network pooling resources and therapies for AF are only partially knowledge of the 3D topology of the new diagnostic tools and therapeutic effective, and are associated with human genome, and expertise in the strategies to reduce the unacceptable substantial morbidity. Although recent translation of genetic changes, the burden of , death, and hospita- genome-wide association studies members of this network will address lizations associated with this common (GWAS) have identified over a dozen the major question in AF genetics: arrhythmia. 4 Programming the failing heart to a regenerative state genetic loci associated with AF, we how do the genetic mutations affect Richard Lee, Brigham & Women Hospital, Cambridge, US and Mauro Giacca, ICGEB, Trieste, Italy

2 SphingoNet - Sphingosine 1-Phosphate in Neurovascular Biology and Disease Given the global burden of heart fate in vitro and in vivo, improving of repair mechanisms, they will define disease and its increasing prevalence cardiac function and reducing adverse and optimize methods for enhancing Timothy Hla, Cornell University, New York, US and in aging populations, one of the most ventricular remodeling, this network function of injured mammalian , Christer Betsholtz, Uppsala University, Sweden important challenges of modern will use a combination of factors, and will extend these studies to a large medecine is the development of including microRNAs, to reprogram animal model to bring this know- strategies to regenerate the human adult human fibroblasts into cardio- ledge toward translation, in mini-pigs, Understanding the control and system function to focus on the central and has been found to be effective in heart. This network is focused on myocyte-like cells. The members of non-human primates and human regulation of the BBB is of significant role of sphingosine 1-phosphate (S1P) multiple sclerosis. The network project promoting the regenerative poten- this network will collaboratively develop engineered myocardium. This line of clinical importance because the BBB in the development and regulation will further characterize the role of tial of endogenous cells of the heart a series of interrelated strategies to research should provide new therapeutic remains one of the major obstacles of the neurovascular unit and blood S1P in ischemia. When dysregulated, a different strategy from that found enhance cardiac regeneration and approaches to enhance the limited in the delivery of drugs to the central brain barrier (BBB) in health and S1P signaling causes neuroinflammation in many stem cell programs where repair by the reprogramming of capacity of the heart to regenerate, nervous system. The transatlantic disease. This is a novel approach to the and neurovascular disease. As very exogenous cells are added to produce non-cardiac cells, like macrophages, having applications in diverse cardiac network led by Christer Betsholtz and investigation of the neurovascular unit little is known about S1P and its receptor a therapeutic effect. Building on the into cardiomyocytes and by promoting disorders, including both genetic and Timothy Hla brings together experts in prompted by the discovery of a drug systems that are expressed on multiple finding that mouse fibroblasts can be the homing of cardiac regenerating acquired forms of heart disease. blood vessels, immunology and nervous that influences sphingosine signaling cell types and tissues in vessels reprogrammed toward a cardiac cell cells. Through activation and stimulation

2 3 disease, which may provide additional vascular diseases. With the finding that clinically relevant, large animal models prognostic information over what can newly-discovered non-coding RNAs as a pathway to first-in-man clinical 2014 be gained from established risk factors are associated with vascularization, trials to treat human disease. and co-morbidities. atherosclerosis and aneurysm formation, The diverse and synergistic talents of Surprisingly, the cellular source and researchers now believe that vascular the investigative team will provide an functional significance of circulating miRNAs are central targets for thera- unprecedented, comprehensive approach miRNAs in vascular disease are still peutic manipulation. The network will towards understanding the biological unknown. Determining the importance focus on new and previously identified role and therapeutic potential of FONDATION LEDUCQ 2013 TRANSATLANTIC NETWORKS of miRNAs as novel cell/cell communi- candidate miRNAs as potential therapies miRNAs. This networking and training cators may allow for the development for these three vascular disease areas strategy on vascular miRNAs will signi- OF EXCELLENCE AWARDS of biomarker profiles based on circulating using genetically modified animal models ficantly contribute to future diagnostic mi-RNAs. The central aim of this and pharmacologic strategies. and therapeutic benefits for patients Four Transatlantic Networks (TNE) were selected by the Scientific Advisory Committee (SAC) at its April 2013 meeting in Nice. project, however, is to target selected Therapeutic approaches to silence with CVD. The networks awarded funding in 2013 are : mi-RNAs as potential therapies for pathologic miRNAs will be tested in 1 Cellular and Molecular Targets to Promote Therapeutic Cardiac Regeneration Toren Finkel, NIH, Bethesda, US and David Sassoon, University Pierre et Marie Curie-Sorbonne University, , France

The limited regenerative capacity of Cardiomyocyte de-differentiation may vitro and in vivo models will facilitate the mammalian heart was long thought either lead directly to new cardiac characterization of resident cardiac to reflect the lack of a cellular reservoir muscle formation or proceed through stem and progenitor cells, and a thorough MIRVAD-Transatlantic Network of Excellence to generate new cardiac tissue. a transient CSC state. Furthermore, a dissection of the process of direct in Yale University on March 2014 However, numerous lines of evidence resident population of adult mesen- cardiac de-differentiation. Unraveling now suggest that the heart may have a chymal stem cells that originate the complex and poorly understood From left to right: significant capacity for cardiac rege- in the epicardium has emerged as processes mediating the age- Constanza Emanueli, Nathan Lawson, Manuel Mayr, neration and repair. The first major a major potential contributor to dependent decline in cardiovascular Stefanie Dimmeler, Carlos Fernandez-Hernando, discovery was the identification of cardiac repair. Collectively, these data stem cell efficacy and regenerative Anna Zampetaki (Mayr lab), Jan Fiedler (Thum lab), cardiac progenitor cells, which showed suggest that the adult heart is likely to capacity is a core objective of this in the front: Bill Sessa & Thomas Thum. the ability to differentiate into the have significant intrinsic regenerative network. These mechanistic studies specialized cell types that make up capacity, but the regulatory mechanisms will lead to the identification of targets the heart. Resident cardiac stem cells that direct and limit this process remain that can be modulated to boost the (CSCs) that persist throughout life were to be delineated. endogenous regenerative potential of discovered only within the last decade At present, no scientific consensus the adult mammalian heart, including and have been shown to be an important has emerged regarding the processes the use of small molecules that stimulate 3 The function and regulation of PCSK9: a novel modulator of LDLR activity mechanism of cardiac adaptation regulating cardiac regeneration. The the mobilization of endogenous CSCs and repair. In addition, emerging data rationale for this network lies in the or transiently activate de-differentiation. Nabil G. Seidah, Clinical Research Institute of Montreal, Canada and now suggest that cardiomyocyte de- need for defining the mechanisms With a little help the heart may just be differentiation and proliferation may regulating and ultimately limiting capable of repairing itself in the setting Anders Hamsten, Karolinska Institute, Stockholm, Sweden be another major component of the regenerative responses of the adult of injury or disease. cardiac adaptation/repair program. heart. A shared, robust platform of in This team of 17 scientists and clinicians in cardiovascular research in the last and thus the burden of atherosclerosis from 6 distinct research centers in decade is the discovery in 2003 of and the incidence of CVD. Pharmaceutical Canada, France and Sweden is dedicated PCSK9, an enzyme encoded by a companies are racing to develop PCSK9 to the comprehensive understanding whose mutations are associated with inhibitors that may in the future substi- 2 MicroRNA-based Therapeutic Strategies in Vascular Disease (MIRVAD) of the biology of PCSK9 and its hypercholesterolemia. This relationship tute or complement the use of statins, implication in hypercholesterolemia was established in French families by and would be especially beneficial in a William C. Sessa, Yale University School of Medicine, New Haven, US and and (CVD). members of this team, and revealed an setting of statin intolerance. Promising Thomas Thum, Hannover Medical School, Hannover, Germany Elevated cholesterol levels fuel the unsuspected regulatory component of monoclonal PCSK9 antibody-based atherosclerotic disease process that the LDL receptor (LDLR). The role of therapies that block PCSK9-LDLR leads to CVD and premature death. PCSK9 in LDLR protein degradation interaction have now reached Phase-3 MicroRNAs (miRNAs) are small non- of this network have identified several vascular remodeling. Additionally, they Familial hypercholesterolemia, which in cells, animal models and humans clinical trials, but there is still much to coding RNAs that modulate gene intracellular miRNAs regulating have characterized circulating miRNAs affects 1 in 500 subjects worldwide, is signifies that its inhibition or be learned about the biology of PCSK9, expression. In the emerging field of vascular biology that play key roles in the blood, as novel biomarkers and known to be caused by genetic mutation. suppression will be a powerful means its regulation, its interacting proteins vascular miRNA research, the members in vascularization, atherosclerosis and potential signaling mediators of vascular One of the most exciting developments of reducing LDL-cholesterol levels, and genetics.

4 5 SCIENTIFIC ADVISORY COMMITTEE CHANGES 2014 The 2014 Spring meeting of the of three members: Dr. Robert Roberts Germany), and Dr. Stephen O’Rahilly Scientific Advisory Committee (SAC) (University of Ottawa, Canada), Dr. Thomas (University of Cambridge, UK). marked the conclusion of the terms Meinertz (University of Hamburg,

This research program will address Although highly valuable, this line of the study of PCSK9, and its role in SAC Meeting, Ehlers Estate, St-Helena, many of the current knowledge gaps inquiry is not likely to be pursued by lipid metabolism. The knowledge gained Napa Valley, CA, USA- April 2014 surrounding PCSK9 biology. What will be pharmaceutical companies, and can will be put towards the development of From left to right: learned could be critical to develop new only be obtained by an international therapeutics involving PCSK9 for people Martin Landaluce, Hugh Watkins, Friedhelm therapeutic approaches to achieve team of significant size, made up of with high cholesterol levels and cardio- Beyersdorf, Joseph Woo, Shaun Coughlin, vascular disease. optimal serum LDL-cholesterol levels. multidisciplinary experts dedicated to Alain Tedgui, Dan Roden, Helen Hobbs, Robert Bonow, Bo Norrving, Thomas Meinertz, Robert Roberts, Margaret Buckingham, David Tancredi, Steve O’Rahilly, Michael Moskowitz.

At the April 2014 meeting in Napa Valley, the newly named to the SAC were • Dr. Christian Hamm, Kerckhoff Heart Center, Bad Nauheim, Germany • Dr. Göran Hansson, Karolinska Institute, Stockholm, Sweden • Dr. Daniel Drucker, Lunenfeld Tanenbaum Research Institute, Toronto, Canada.

CALL FOR APPLICATION CYCLE 2014-2015 PCSK9-TNE in Montreal on March 2014 Fondation Leducq announces a call disease. As of 2014, the foundation has the application process and details for applications for the 2014-2015 supported 43 networks, representing about important dates in the 2014-2015 Transatlantic Networks of Excellence more than 390 investigators at 128 application cycle can be found on our Program. Under this program the institutions in 18 countries. website at flcq.org under Transatlantic 4 Mechanical Triggers to Programmed Cell Death in Fondation Leducq awards grants of up For the 2014-2015 application cycle, Networks of Excellence. Cardiomyocytes – and how to prevent their Action in Failing Hearts to U.S. $6,000,000 over five years for Fondation Leducq will use a web-based Due date for letters of intent is Friday, internationally collaborative research application system hosted by Altum September 5, 2014, 11:59 pm Paris time. Siegfried Labeit, University of Heidelberg, Mannheim, Germany and in cardiovascular and neuro-vascular proposalCENTRAL. Information about Hendrikus Granzier, University of Arizona, Tucson, US NEXT TRANSATLANTIC NETWORK SYMPOSIUM A progressive loss of cardiac myo- trigger of apoptosis. Recent findings role of titin mediated stretch as a cytes-heart muscle cells-by cell death strongly indicate that cell loss is a leading mechanical trigger of cardiomyocyte Fondation Leducq announces the fifth networks that were launched in 2009 its support and helps researchers to (apoptosis) is a feature of all types of primary pathological mechanism in HF apoptosis. The program brings together Leducq Symposium, to be held in Paris and 2010. This symposium provides make contact among other Fondation . It appears that the heart, driven by changes in the titin filament, an interdisciplinary team of world- on April 16th, 2015. It will call the fondation with an opportunity to Leducq network coordinators. exposed to lifelong cycles of stretch a giant protein that contributes to the leading experts who will work to identify together researchers from six different take stock of the work performed with and release, loses its capacity to elasticity of the heart. Elasticity, in the cellular mechanisms underlying regenerate over time. This proposal turn, helps to determine the conditions progressive cytoskeletal pathologies focuses on mechanisms linking under which the heart fills with blood in HF. Transgenic mouse models with FONDATION LEDUCQ TO BEGIN TO CONNECT NETWORKS mechanical stress to apoptosis in during diastole, the period in the genetically altered titin compliances Later this year the Fondation Leducq service through which all members this email group is the universe of cardiomyocytes, a phenomenon known cardiac cycle when the heart is not will be examined, and the network has will begin to put in place a mechanism and coordinators from any Transat- investigators participating in any as mechanoptosis. The members of actively pumping blood. A loss of the ability to transition from mouse to to allow different Leducq networks lantic Network of Excellence can TNE. It is hoped that by facilitating this network argue that mechanoptosis elasticity is associated with diastolic large mammal studies in the case of to collaborate with each other. This pose questions to any member of communication among networks, is an important determinant of heart heart failure. A recently published promising gene candidates. Furthermore, initiative comes at the request of another TNE on issues in cardiovascular investigators can benefit from additional failure, and that by preventing this genetic study identified a mutation the network will support the deve- network investigators, who perceive and neurovascular research. Appropriate collaborative advantages through the process, cardiomyocytes can be in titin as the cause of arrythmogenic lopment of innovative therapies for the advantage of making connections topics include grant administration, Leducq program. The foundation will preserved and cardiac function cardiomyopathy, a primary disease of heart failure by identifying plausible with members of other networks program evaluation, and issues be examining other ways to leverage maintained. They plan to address this the heart muscle caused by a breakdown targets for regenerative/protective who are working in related fields. The related to data access or to the sharing the expertise of the TNEs to promote problem by focusing on mechanical of healthy myocardium. therapy to prevent cardiomyocyte designers of the Fondation Leducq’s of resources like animals, biological internetwork collaboration. failure of the titin cytoskeleton as a This network is tightly focused on the death in the setting of disease. new website are setting up a listserv samples, and images. The audience for

6 7 A GREAT LADY!

ylviane Leducq passed away in December 2013. She was 88. Until she was diagnosed Swith cancer in early 2013 she was very active in the management and oversight of the foundation that she had created with her husband Jean 17 years ago. She was tremendously dedicated to the foundation, and deeply recognizant of and grateful for the participation of the scientific community in foundation activities. Members of the SAC and investigators attending the 2013 fall and spring meetings will remember that she attended, and spoke at, the social events surrounding the meetings, despite her ongoing chemotherapy treatment. After Jean Leducq passed away in 2002, Sylviane Leducq carried on the work of the foundation as President of the Board of Directors. She oversaw the implementation of the Transatlantic Networks Program, and the development of the venture philanthropy program Broadview Ventures, Inc. In 2009, she was awarded the French Legion of Honor in recognition of her generosity and leadership of the foundation. Her work helped to assure that the foundation will remain a family legacy in perpetuity, dedicated to its mission in cardiovascular and neurovascular research. We would like to thank all the wonderful tributes to Sylviane that were sent to the Fondation Leducq following the announcement of her death. Costantino Iadecola, Cornell Medical College, New York, has agreed to let us publish his text in our Newsletter. It gives a good idea of the esteem and gratitude expressed by all the people who had the chance to know Sylviane personnally. «The impact of the Fondation Leducq on the international scientific scene has been substantial and continues to grow from year to year. The Fondation has enabled hundreds of scientists to explore new ideas and to test groundbreaking hypotheses that could not otherwise be done within the boundaries of conventional funding agencies and foundations. In the prescient mind of Jean and Sylviane Leducq it was clear that new, game-changing discoveries in cardiovascular medicine, as in other disciplines, require efforts that go beyond individual laboratories, departments, universities, and even countries. Drawing from their transatlantic experience and with the help and guidance of dedicated scientists and administrators, they conceived and implemented the “Transatlantic Leducq Network” concept. Now the foundation provides vital support to the foremost centers of cardiovascular and neuro-vascular research throughout the world. The research portfolio is spectacular in depth and breadth, the discoveries breathtaking, and the number of publications in high impact journals is impressive. Leducq investigators are opening new avenues in cardiovascular research, which are now starting to bear fruit in the clinical arena, leading to new drugs, new medical devices and new surgical procedures to alleviate human suffering. This is exactly what Sylviane and Jean hoped to achieve. In truth, when I joined the Leducq Scientific Advisory Committee (SAC) in 2007, I was not aware of the Fondation. Now, I cannot attend a scientific meeting or visit a university without being asked about it. Being in a Leducq network has become a sign of distinction: investigators list their Leducq funding as a badge of honor on their curriculum vitae, and Medical School Deans seek it as a mark of distinction for their institutions. I often wondered how the Fondation became so successful in such a short time. As I got to know Sylviane a little I started to see a glimpse of a few driving principles: keep uncompromisingly high standards, foster a harmonious interaction among research teams, invest in the next generation, and provide unconditional support. It is not “throwing enough money at the problem”, but creating the conditions in which culturally and scientifically diverse groups of out-standing individuals work together in harmony, keeping in mind that their ultimate goal is to improve the lives of our patients. As Sylviane rejoins Jean, she leaves us with a long lasting legacy that will continue to inspire the lives of a growing number of scientists on both side of the Atlantic, who work together under the Leducq aegis to alleviate human suffering. Sylviane we miss you.»

For more information about the Fondation Leducq, please visit our website at www.flcq.org or contact our Executive Director, Dr. David Tancredi at [email protected]