Results of EJP RD Joint Transnational Call (JTC2019)

In December 2018 the EJP RD launched its first Joint Transnational Call (JTC2019) co-funded with the European Commission to fund multilateral “Research projects to accelerate diagnosis and/or explore disease progression and mechanisms of rare diseases”. The aim of the call was to enable scientists in different countries to build an effective collaboration on a common interdisciplinary research project based on complementarities and sharing of expertise, with a clear benefit for patients. Twenty three countries joined this call: Austria, Belgium, Canada (including Québec), Czech Republic, Estonia, Finland, France, Germany, Greece, Hungary, Ireland, Israel, Italy, Lithuania, Luxembourg, Poland, Portugal, Slovakia, Spain, Sweden, Switzerland, The Netherlands and Turkey.

The process included a two-step submission and evaluation procedure.

In the first step a total of 217 eligible pre-proposals were submitted. After careful examination by the Scientific Evaluation Committee (SEC), 52 pre-proposals were selected for full submission. Each of the full proposals was then evaluated by at least two additional external experts whose reviews were sent to project coordinators in order to give them the opportunity of studying the assessments and commenting on experts’ arguments and evaluations. Both inputs were taken into account in a second SEC meeting.

Following the second SEC evaluation and ranking of the best projects, 22 consortia with a foreseen budget of about 30,5 Mio € were selected for funding, including almost 6 Mio € of co-funding from the European Commission.

The list of funded projects is detailed below. More information on the funded projects and the outcomes of the call (lay summaries, statistics, etc.) will be provided soon.

Selected Projects

 

Partners 

 

Country 

Di Donato, Nataliya (Coordinator) 

TU Dresden 

Germany 

Reymann, Anne-Cecile 

Institute of Genetics and Molecular and Cellular Biology (IGBMC), Illkirch Cedex 

France 

Manstein, Dietmar J 

Hannover Medical School 

Germany 

Bianco, Pasquale 

University oFlorence 

Italy 

Miklós, Kellermayer 

Semmelweis University 

Hungary 

Abstract
Actins are abundantly produced proteins playing crucial roles in critical cellular processes. Mutations in ACTB and ACTG1 (beta- and gamma-cytoskeletal actin isoforms) cause a broad spectrum of rare disorders – Nonmuscle actinopathies (NMAs). NMAs show high clinical variability. The underlying mechanisms remain to be resolved. We assume that the clinical outcome of NMAs is associated with the specific site/type of mutation, thus affecting actin’s role as transcriptional co-factor and as major component of the cytoskeleton, binding substrate for multiple partners, and track for molecular motors. Our preliminary data show mutation specific cellular phenomena that can be used as a functional readout to predict the clinical outcome in a patient. We propose to systemize clinical information, providing reliable genotype-phenotype correlation, explore cellular disease mechanisms on a multiple- scale level spanning from single molecules to model organism, and develop praxis-oriented screening methods for the functional interpretation of rare actin variants. We bring together five research groups with outstanding expertise, which includes actomyosin physiology, molecular genetics and structure, cell force spectroscopy, high-resolution light and atomic force microscopy, in vivo imaging, C. elegans model system, as well as unique knowledge of the NMA clinical spectrum. Our results will allow a substantial revision of current management strategies, lay out the basis for future clinical studies and provide broadly applicable functional assays allowing for genotype-phenotype correlation. 

 

Partners

Country

Hoenderop, Joost (Coordinator)

RUMC

The Netherlands

de Baaij, Jeroen

RUMC

The Netherlands

Tremblay, Michel

MGU

Canada

Müller, Dominik

Charité University Medicine Berlin

Germany

Martinez-Cruz, Alfonso

CIC bioGUNE

Spain

Aldámiz-Echevarría, Luis

Cruces University Hospital

Spain

Patient Advocacy Organisation

Country

HIPOFAM

Spain

Abstract

Mutations in CNNM2 membrane proteins were identified to be causative for hypomagnesemia, intellectual disability and seizures. CNNM2 mutations are the most common genetic cause for rare dominant hypomagnesemia. Currently, there are no clinical protocols for the diagnosis and follow-up of patients with CNNM2 mutations. Although it has been described that CNNM2 mutations impair renal magnesium reabsorption, the mechanisms that explain the disease are poorly understood. In this proposal, we aim to improve diagnostics and understanding of CNNM2-associated disease by integrated structural, functional and biochemical techniques. Our international network of researchers will address the following objectives: – Key objective 1: CNNM2 Diagnostics. By systematic phenotyping of CNNM2 patients, a novel diagnostics protocol will be developed. Patient-derived stem cells will be stored in a biobank. – Key objective 2: CNNM2 Structure. The CNNM2 protein structure will be uncovered to understand the impact of patient mutations on protein folding and activity. – Key objective 3: CNNM2 Interactome. By proteomic analysis, we will map the complete CNNM2 interactome and examine the role of interacting proteins on CNNM2 function and cell signalling. – Key objective 4: CNNM2 Function. Using advanced cell, tissue and animal models, the CNNM2 function will be discovered to understand disturbed Mg2+ transport function in patients harboring CNNM2 mutations. Altogether, these findings will improve diagnostics, screening and understanding of rare hypomagnesemia in patients with CNNM2 mutations.

 

Partners

 

Country

Le Grand, Fabien (Coordinator) Institut National pour la Santé et la Recherche Médicale (INSERM)

France

Rudnicki, Michael

University of Ottawa

Canada

Ruegg, Markus

University of Basel

Switzerland

Previtali, Stefano

IRCCS Ospedale San Raffaele

Italy

Bava, Alessio

Université Paris Sud

France

Abstract

Duchenne Muscular Dystrophy (DMD) and LAMA2-related Muscular Dystrophy (LAMA2 MD) are rare and devastating genetic disease of childhood manifested by progressive skeletal muscle wasting and ultimately death. In both diseases, muscle undergoes constant cycles of degeneration-regeneration exacerbated by intrinsic muscle stem cell (MuSC) dysfunction and their impaired ability to support long-term regeneration. The overall goal of the project is to use a combination of single-cell transcriptomics (RNA-sequencing) and proteomics (mass cytometry, CyTOF) to define the cellular composition of diseased muscle tissues at the single- cell resolution. We will delineate the different cell populations that pre-exist and arise during disease progression and classify the novel cellular subsets involved in this process. This data, in combination with genetic lineage tracing will allow reconstruction of the MuSC lineage hierarchy. We will further characterize cellular subpopulations associated with human muscle dystrophies by performing 3-Dimensional intact-tissue RNA sequencing on patient biopsies The unbiased elucidation of the cellular events underlying the different steps of muscle disease progression at the single-cell level represents crucial missing information, which will push forward our current knowledge on muscle dystrophies. Ultimately, our goal is to develop new biomarkers and eventually new pharmacological approaches to enhance therapy by stimulating intrinsic muscle tissue repair and capitalize on our single cell expertise to uncover disease-related subsets in human biopsies.

 

Partners

 

Country

Udd, Bjarne (Coordinator)

Folkhälsan Research Center/Tampere University Hospital

Finland

Linari, Marco

Universita´ di Firenze

Italy

Laporte, Jocelyn

CERBM

France

Mártonfalvi, Zsolt

Semmelweis University

Hungary

Munell, Francina

Hospital Universitari Vall d’Hebron

Spain

Ottenheijm, Coen

Stichting VUMC

The Netherlands

Õunap, Katrin

University of Tartu

Estonia

Gautel, Mathias

King’s College London

United Kingdom

 

Patient Advocacy Organisation

 

Country

Lihastautiliitto ry – The Finnish Neuromuscular Disorders Association

Finland

Abstract

Inherited myopathies are genetically determined diseases affecting voluntary muscles (skeletal muscle disorders or SMDs). SMDs include a wide spectrum of disorders characterized by a different age of onset, disease progression, and muscle involvement. The phenotypic variability seen in SMDs, the lack of clear-cut genotype–phenotype correlations and the sheer size of the SMD-associated genes (e.g., TTN or NEB) make the diagnostic process complex. Half of the patients do not receive a molecular diagnosis despite a workflow including clinical, histological, imaging and genetic tests. The molecular diagnosis is crucial for SMD patients in order to receive optimal care, correct prognosis and proper genetic counseling. Furthermore, the functional consequences of the genetic variations in these genes are nearly unknown. This project, which brings to life a synergistic cooperation between clinicians, geneticists, pathologists, physiologists, biophysicists and patient advocacy organizations, aims at improving the diagnostic pipeline for skeletal muscle disorders caused by mutations in large genes like TTN (titin) and NEB (nebulin), using novel techniques through five complementary work-packages. Our goal is to design and validate new tools available to a larger community of clinicians and researchers working in this field, and to characterize in depth genotype- functional-phenotype correlations.

 

Partners

 

Country

Volkmann, Jens (Coordinator)

University Hospital of Wuerzburg

Germany

Oliveira-Maia, Albino Fundação D. Anna Sommer Champalimaud e Dr. Carlos Montez Champalimaud, Champalimaud Research

Portugal

Pisani, Antonio

IRCCS Fondazione Santa Lucia

Italy

Kühn, Andrea

Charité, University Medicine Berlin

Germany

Jech, Robert

Charles University

Czech Republic

Vidailhet, Marie

Department of Neurology, and ICM

research Center, Hôpital Salpêtrière

France

Abstract

The dystonias are rare movement disorders. Despite diverse underlying etiopathogeneses, dystonias share a common clinical presentation, with motor deficits that result from brain circuit dysfunction caused by various gene defects, brain lesions, or environmental factors, or which may emerge idiopathically. It is unclear how different inherited molecular defects cause neuronal dysfunction on the microcircuit and large scale network level, leading to the manifestation of dystonia as a common final symptom pathway. Gene-environmental interaction in dystonia pathogenesis is discussed in hereditary forms with reduced penetrance. Based on the “second hit” hypothesis, we have generated endogenously predisposed DYT1 and DYT12 models with trauma-triggered dystonia-like movements, allowing us to discern transcriptomic, metabolic and physiological CNS alterations related to the predisposition and the onset of dystonia after an environmental trigger. The EurDyscover consortium combines outstanding expertise from across Europe in molecular neurobiology, cellular and system pathophysiology, and behavioural and clinical neurosciences to map the entire disease pathway of dystonia from the molecular to the brain network level in mice and humans and to identify new targets for treatment. Methods such as multi-omic, fMRI, MEG, TMS, LFP, LTP/LTD, PAS, optogenetics and in-vivo calcium imaging to characterise brain network changes in rodent models and human dystonia will be used. For clinical studies, patients will be recruited from various European countries and the German dystonia registry.

 

Partners

 

Country

Prokisch, Holger (Coordinator)

Klinikum rechts der Isar der Technischen Universität München

Germany

Mayr, Johannes

Paracelsus Medical University

Austria

Rötig, Agnes

Institut Imagine

France

Lamperti, Costanza

Foundation Neurological Institute C. Besta

Italy

Klopstock, Thomas

Klinikum der Universität München

Germany

Mancuso, Michelangelo

University of Pisa

Italy

Murayama, Kei

Chiba Children’s Hospital

Japan

McFarland, Robert

Newcastle University

United Kingdom

 

Patient Advocacy Organisation

 

Country

Deutsche Gesellschaft für Muskelkranke e.V. (DGM) Diagnosegruppe Mitochondriale Erkrankungen

Germany

Mitocon, insieme per lo studio e la cura delle Malattie Mitocondriali, Onlus

Italy

The Lily Foundation

UK

AMMi (Association against michondrial diseases)

France

Abstract

Mitochondrial disorders are a genetically diverse group of individually rare, but severe human diseases for which no causal treatments are available so far. The GENOMIT consortium assembles the national networks from Germany, Italy, UK and Japan and the main centers for mitochondrial diseases in Austria and France, collectively following more than 6,000 patients. GENOMIT acts in close collaboration with the national patient organizations to improve diagnosis and care of mitochondrial disease patients. GENOMIT will i) further develop its global mitochondrial patient registry and establish disease- specific outcome measures and natural history data to prepare for clinical trials, ii) boost genome-wide diagnostics and optimize interpretation of genomic data by aggregating >3,000 exome and RNA sequencing datasets, iii) extend functional studies on novel variants, genes and pathways involved in the pathophysiology of mitochondrial diseases. GENOMIT partners are established national hubs for molecular diagnosis and state-of-the-art care for patients with mitochondrial disease. They leverage on national networks collaborating on a global registry and the largest collection of genomic data pertaining to mitochondrial disease world-wide. Each partner has also developed unique expertise that will be shared synergistically within the network. GENOMIT will thus create the critical mass to expand knowledge on the natural history, to identify novel mitochondrial disease genes, to gain insight into disease mechanisms and will be an invaluable resource for clinical trials.

 

Partners

 

Country

Bezzina, Connie (Coordinator)

Amsterdam University Medical Center

The Netherlands

Barc, Julien

l’institut du thorax

France

Schwartz, Peter

Istituto Auxologico Italiano IRCCS

Italy

Schulze-Bahr, Eric

University Hospital Münster

Germany

Keck, Andreas

Syte Capital GmbH

Germany

Abstract

The discovery of genes underlying the rare inherited cardiac disorders associated with sudden cardiac death (SCD) in the young has led to the routine implementation of genetic testing in the clinical care of patients with these disorders. Yet, with few exceptions, genetic testing has had a relatively modest impact on the ability to predict major clinical events such as SCD. LQTS-NEXT will focus on the Long QT Syndrome (LQTS) as a model to test the hypotheses that (1) additional genetic factors as well as non-genetic factors (clinical, ECG) conspire with the mutation to modulate disease severity, and (2) the incorporation of such additional genetic and non-genetic factors in a risk prediction algorithm will provide a refined, personalized, assessment of risk. LQTS-NEXT brings together researchers at the forefront of research and clinical care of LQTS patients with experts in deep learning, to test these hypotheses in the largest cohort of LQTS patients worldwide (>6,000 patients). Importantly, when successful, this project will serve as a template for large-scale genetic and clinical modifier studies in other rare disorders. Furthermore, LQTS-NEXT will apply cutting edge genomic and bioinformatics approaches to identify the genetic defect underlying LQTS in patients that have remained mutation-negative after extensive gene panel testing. The extensive preliminary work that has been conducted by the project partners ensures the feasibility of the project. The standing of the project partners and their network ensures optimal dissemination and implementation of the findings.

 

Partners

 

Country

Kurth, Ingo (Coordinator)

RWTH Aachen University Hospital

Germany

Senderek, Jan

University Hospital, LMU Munich

Germany

Laššuthová, Petra

Charles University in Prague

Czech Republic

Auer-Grumbach, Michaela

Medical University of Vienna

Austria

Hornemann, Thorsten

University Hospital Zurich

Switzerland

Chrast, Roman

Karolinska Institutet

Sweden

Parman, Yesim

Istanbul University Medical School

Turkey

 

Patient Advocacy Organisation

 

Country

Spolecnost C-M-T

Czech Republic

CMT-Austria

Austria

Abstract

Patients with monogenic pain-insensitivity disorders do not respond to painful stimuli and sustain repeated trauma with potentially fatal complications. Limited awareness of these rare conditions, small patient cohorts, lack of standardized phenotype information, low diagnostic yield of genetic testing and only partial recognition of disease mechanisms have been largely precluding clinical research. ENISNIP, a European network of clinicians, geneticists and basic scientists will tackle these hurdles and (1) ensure rapid diagnosis for pain-insensitivity disorders, (2) gather cross-sectional data, (3) advance genetic diagnosis and gene discovery through state-of-the-art genomics and innovative variant filtering procedures integrating additional omics levels, disease modelling and regular re-evaluation of variants’ impact on disease, and (4) track disease mechanisms. ENISNIP will bring accurate genetic diagnosis and counselling to individuals with pain-insensitivity disorders and support establishing standards of diagnosis and care. We envision delivering meaningfully sized, well-phenotyped and – genotyped patient cohorts, new insights into the molecular basis of pain-insensitivity disorders, paving the way for preclinical experimental treatment trials and clinical research. With regard to further translational capacity, genes and mechanisms related to rare Mendelian pain- insensitivity disorders are exceptional in their potential to uncover novel molecular targets to treat chronic pain, which constitutes one of the major global socioeconomic and health care burdens.

 

Partners

 

Country

Synofzik, Matthis (Coordinator)

University of Tuebingen

Germany

Brais, Bernard

The Royal Institution for the Advancement of Learning – McGill University

Canada

van de Warrenburg, Bart

Radboud University

The Netherlands

Santorelli, Filippo

IRCCS Fondazione Stella Maris

Italy

Elena, Rugarli

University of Cologne

Germany

Nazli, Basak

Koç University

Turkey

Tezenaz du Montcel, Sophie

Sorbonne Université

France

Horvath, Rita

University of Cambridge

United

Kindgdom

 

Patient Advocacy Organisation

 

Country

Ataxia Charlevoix-Saguenay Foundation

Canada

Deutsche Heredo-Ataxie Gesellschaft Bundesverband e.V. (DHAG e.V.)

Germany

Euro-HSP

France

Abstract

Spastic ataxias present an expanding group of >100 rare neurodegenerative diseases with joined damage of cerebellum and corticospinal tract (CST). While rapid genetic stratification facilitates current development of molecular therapies, effective trial-planning for SPAX is hampered by a lack of valid outcome measures and natural history studies. Uniting all major European ataxia and spastic paraplegia networks, and building on our prior networks and pilot data-sets, PROSPAX will establish a paradigmatic IRDiRC-guided integrated trial-ready model of disease progression and mechanistic evolution in SPAX. In a 2-year natural history study we will validate clinician- and patient-reported, digital and molecular outcomes. In addition, PROSPAX will improve existing and develop new outcome parameters that show superior sensitivity to change. These include a novel SPAX composite score, a smartphone mHealth toolbox combining remote assessment of daily living by wearable sensors with app- based patient-entered outcomes, and multimodal MRI radiomics with an innovative machine learning approach for multisite MRI analysis. Longitudinal validation of candidate biomarkers will be complemented by single-cell multi-omic studies in mouse By focusing on the two most prevalent recessive SPAX (SPG7, ARSACS), PROSPAX will create a paradigmatic trial-readiness pathway for charting disease progression and multimodal outcome measures that will be applicable to many of the >100 SPAX diseases alike.

 

Partners

 

Country

Scheffold, Alexander (Coordinator)

Christian-Albrechts-Universität zu Kiel

Germany

Elinav, Eran

Weizmann Institute of Science

Israel

Marignier, Romain

Lyon University Hospital

France

Martin, Roland

Neuroimmunology and MS Research

Switzerland

Fillatreau, Simon

Institut Necker-Enfants Malades, INSERM U115-CNRS UMR 8253

France

Mario, Assenmacher

Miltenyi Biotec

Germany

Abstract

Neuromyelitis optica spectrum of disorders (NMOSD) form a rare group of severe antibody- mediated autoimmune diseases (AID) requiring livelong therapy with severe side effects. The identification of aquaporin-4 (AQP4) as a specific target autoantigen in NMO differentiated it from multiple sclerosis (MS). Autoantigen-specific T cells are centrally involved in the pathogenesis of these diseases via the regulation of pathogenic antibodies. However, their NMOSD-associated phenotypic and functional alterations are still enigmatic. The characterization of autoreactive T cells provides a unique opportunity for the development of novel specific diagnosis and therapies targeting the disease cause rather than the symptoms. Members of our consortium have established powerful technologies for unbiased identification and molecular characterization of autoantigen-specific CD4 T cells. In a proof of principle experiment we identified a unique and discriminative phenotype of ex vivo isolated AQP4-specific T cells in AQP4 antibody positive but not -negative NMOSD patients. We will deeply characterize T cells against AQP4- and myelin oligodendrocyte glycoprotein (MOG) in large NMOSD patient cohorts and screen for cross-reactivity to microbiota as potential pathogenic trigger mechanism. A biotech industry partner will develop analysis tools optimized for rare auto-antigen-specific T cells and for their rapid application in clinical routine. Our project will pursue a unique technical approach to provide a basis for the development of auto-antigen-specific diagnostics and therapeutics.

 

Partners

 

Country

Vaglio, Augusto (Coordinator)

Meyer’s Children Hospital

Italy

Little, Mark

Trinity College Dublin

Ireland

Terrier, Benjamin

Assistance Publique Hopitaux de Paris

France

Mohammad, Aladdin

Lund University

Sweden

Lamprecht, Peter

Universitaet zu Luebeck

Germany

Musial, Jacek

Jagiellonian University Krakow

Poland

Hruskova, Zdenka

General University Hospital in Prague

Czech Republic

Basu, Neil

University of Glasgow

United

Kindgdom

 

Patient Advocacy Organisation

 

Country

Vasculitis Stichting

The Netherlands

Abstract

Research into vasculitis needs large enough quantities of data to be able to draw well- informed conclusions about treatments and possible cures. However, there are relatively few vasculitis patients in any one European country. It is essential to combine the databases of patient information (‘registries’) of several countries, to build a large enough dataset to enable impactful research. FAIRVASC is a research project of the European Vasculitis Society (EUVAS), bringing together leading scientists, clinicians and patient organisations. FAIRVASC will use modern semantic-web technologies to link vasculitis registries across Europe into a ‘single European dataset’, and thus open the door to new research into these challenging diseases. Importantly, the legal and ethical aspects of such international data sharing are a high priority – a dedicated legal team will ensure that all activities comply with GDPR and other regulations, while the main European vasculitis patient organisation will be active throughout, ensuring that patient priorities are respected. In FAIRVASC, this large new European dataset will be analysed to identify clusters of clinical features that predict how a patient’s illness will develop, and what their major health risks are. Using artificial intelligence approaches, these clinical features can then be used to develop predictive clinical tools that allow a personalised approach to healthcare delivery.

 

Partners

 

Country

Vivi, Heine (Coordinator)

VU University Medical Center

The Netherlands

Gritti, Angela

Ospedale San Raffaele

Italy

Brustle, Oliver

Universitätsklinikum Bonn

Germany

Angulo, Maria Cecilia

INSERM

France

Sousa, Monica

University of Porto

Portugal

 

Patient Advocacy Organisation

 

Country

ELA International – GEIE

Luxembourg

Abstract

Genetic brain white matter disorders, also called leukodystrophies, lead to considerable clinical handicap, ranging from mild to severe. Patients are most often children and die early in life. As yet, the majority of leukodystrophies lack an effective treatment. While all leukodystrophies share major pathological traits (i.e. white matter disruption), our understanding of the cascade of events leading from the genetic defect to this detrimental outcome is still poor. Recent evidences suggest that besides white matter and myelin, also the nerve cells (neurons, also called grey matter) and their processes (axons) are damaged from early disease stages on. In our project, we want to explore this grey matter involvement in different types of leukodystrophies with an innovative approach. We will combine modern –OMICS and high-resolution imaging with advanced 2D and 3D induced pluripotent stem cell (iPSC)-based cellular models. We want to study patient grey and white matter cells using different model systems, from reductive in vitro cultures up to complex in vivo microenvironments, to know how they influence each other, and whether different patients present with common defects. In the future, this might be a good approach to study for drug screening for leukodystrophies. To reach this goal, the project will combine the expertise of (i) recognized European research teams working in the field of white matter diseases and (ii) leukodystrophy patients and families associations devoted to leukodystrophies.

 

Partners

 

Country

Eriksson, Maria (Coordinator)

Karolinska Institute

Sweden

d’Adda di Fagagna, Fabrizio

IFOM – Fondazione Istituto FIRC di Oncologia Molecolare

Italy

Foisner, Roland

Medical University Vienna

Austria

Djabali, Karima

Technical University of Munich

Germany

Pia, Bernasconi

Fondazione IRCCS Instituto Neurologico “Carlo Besta”

Italy

 

Patient Advocacy Organisation

 

Country

The Progeria Research Foundation

USA

Abstract

Hutchinson-Gilford Progeria Syndrome (HGPS), is rare genetic disorder affecting one in 18 million live births. The disorder is commonly referred to as “Progeria”, or “Progeria of the childhood”. With the striking appearance of children resembling an elderly person, its classified as a premature aging syndrome. Babies are normal at birth but during their first years of life, they start developing symptoms including severe growth retardation, loss of fat and hair, sclerotic skin and osteoporosis. Death occurs on average at age 13, usually resulting from cardiac diseases. HGPS is almost exclusively caused by a de novo point mutation in exon 11 (c.1824C>T, p.G608G) of the LMNA gene. The mutation leads to the production of a truncated lamin A protein, named progerin. Lamins play roles in nuclear shape, replication, transcription and chromatin organization. Even though the genetic cause of the disorder was defined 15 years ago, the underlying mechanisms responsible for the pathophysiology of HGPS remain less clear. Here we have put together a transnational research consortia, including partners with a long-standing interest and significant contribution to the research on this specific disease and/or on mechanisms proven central to the disease. Published and preliminary results from the investigators strongly support the involvement of non-coding RNAs in HGPS. The transnational consortia will unify their resources and networks in order to elucidate the role of non-coding RNAs in the progeria disease pathogenesis, using established models and state-of-the-art technologies.

 

Partners

 

Country

Kekäläinen, Eliisa (Coordinator)

University of Helsinki

Finland

Arstila, T. Petteri

University of Helsinki

Finland

Guillonneau, Carole

INSERM

France

Giraud, Matthieu

INSERM

France

Peterson, Pärt

University of Tartu

Estonia

Graca, Luis

Universidade de Lisboa

Portugal

Abstract

Many rare diseases are caused by a malfunctioning immune system attacking the patient’s own tissues, but treatment options are limited by the fact that the origin of such malfunctioning is poorly understood. In the TARID project we study some of these immunological diseases, united by similar pathogenetic events and pathological findings. Common to the diseases we study is an inherited or acquired defect of AIRE-protein that normally works in the thymus organ. In the thymus AIRE takes part in the development and education of T cells, the cells responsible for cellular immunity. Our hypothesis is that when AIRE is lost in the thymus some unknown harmful mechanism allows T and B lymphocytes to collaborate and together create an abnormal response to structures found in other parts of the human body. This response results in production of antibodies reacting to body’s own structures, so-called autoantibodies that are common in rare immunological diseases. We will identify key steps leading to this abnormal response, and aim to find therapeutic targets that can be manipulated to put the brakes on the pathological production of autoantibodies. The results will be tested in an AIRE-deficient animal model and validated in human tissue culture assays and patient samples. Our ultimate goal is to provide information facilitating the development and use of new modes of treatment in rare immunological diseases.

 

Partners

 

Country

Tartaglia, Marco (Coordinator) Ospedale Pediatrico Bambino Gesù, IRCCS

Italy

Zenker, Martin

Otto-von-Guericke University Magdeburg

Germany

Ahmadian, Reza

Heinrich-Heine University

Germany

den Hertog, Jeroen

Koninklijke Nederlandse Akademie van

Wetenschappen

The Netherlands

Cavé, Hélène

CHU Hôpital Robert Debré

France

Yart, Armelle

INSERM

France

Gos, Monika

Instytut Matki i Dziecka

Poland

Gelb, Bruce D

Icahn School of Medicine at Mount Sinai

United States of

America

Abstract

RASopathies constitute the most common family of non-chromosomal disorders affecting development. This group of rare diseases includes an increasing number of conditions characterized by reduced growth, heart defects, cognitive deficits, dysmorphisms and variable predisposition to malignancies. RASopathies share upregulated RAS-MAPK and/or PI3K-AKT-mTOR signaling as pathogenetic mechanism. Past work of the NSEuroNet partners has significantly contributed to our understanding of the molecular causes underlying these diseases and to their clinical characterization. However, we are still far from a full understanding of the impact of mutations on protein function, intracellular signaling, and cell physiology. Considering the availability of molecules targeting the signaling pathways altered in RASopathies, a deeper knowledge of the functional impact of individual mutations is required for designing effective therapies. Finally, a significant number of patients remains molecularly unexplained. The planned work, which is the natural follow-up of a previously funded E-Rare project, is directed to resolve the functional consequences of a large panel of uncharacterized mutations, generate in vitro and in vivo gene/mutation-specific models, characterize novel circuits modulating RAS signaling, explore the pathophysiology of key complications of these diseases, and identify novel disease genes. Work will also be directed to populate a dedicated database that will be used for clinically oriented studies to help clinicians towards a timely diagnosis and a more effective patient care.

 

Partners

 

Country

Ris, Laurence (Coordinator)

University of Mons

Belgium

Fumagalli, Fabio

University of Milan

Italy

Caiazzo, Massimiliano

Utrecht University

The Netherlands

Salahpour, Ali

University of Toronto

Canada

Razumienè, Julija

Vilnius University

Lithuania

Abstract

Dopamine Transporter Deficiency Syndrome (DTDS) is a rare genetic disease affecting children with a deficit in the Dopamine Transporter (DAT), which regulates dopamine homeostasis and motor control. These children show severe motor symptoms from early infancy and worsening throughout childhood. At present, no effective treatments exist. Animal models allow to reveal mechanisms in depth using invasive methods that ethically cannot be applied to humans. Our consortium has multi-year experience in the study of rats lacking, totally or partially, the DAT, which is defective in DTDS patients. Strikingly, mutant animals replicate major symptoms found in children with DTDS, providing an excellent tool to identify novel pathophysiological pathways. To this end, by using these animals, as well as in vitro stem cell-based models reproducing DTDS mutations, we will study pathological mechanisms related to the glutamate system, the major excitatory neurotransmitter. We hypothesize that alteration of glutamate homeostasis, as shown by our preliminary data, could be rescued by memantine or bupropion. Since these drugs are commercially available, this would speed up the potential benefit for DTDS patients. Notably, our results could benefit other diseases characterized by altered dopamine-glutamate interactions such as Schizophrenia, Attention Deficit Hyperactive Disorder and Parkinson’s Disease. In the end, URGENT, via its well-integrated translational approach, holds the potential to identify meaningful markers of DTDS that could serve as guidance for more effective DTDS treatments.

 

Partners

 

Country

DE BAERE, Elfride (Coordinator)

UGent

Belgium

CREMERS, Frans

RUMC

The Netherlands

DOLLFUS, Hélène

INSERM

France

LISKOVA, Petra

CUNI

Czech Republic

RIVOLTA, Carlo

UNIBAS

Switzerland

BANFI, Sandro

TIGEM

Italy

SPIELMANN, Malte

MPIMG

Germany

GÓMEZ-SKARMETA, José Luis

CSIC

Spain

 

Patient Advocacy Organisation

 

Country

Retina International

Switzerland

Abstract

Inherited retinal diseases (IRD) represent a clinically and genetically heterogeneous group of rare diseases that are a major cause of early-onset blindness in 350,000 people in Europe. Our group has discovered almost 30 percent of over 260 IRD genes. These significant advances have culminated in novel therapies entering the clinic. Despite this progress, there are important knowledge gaps that hamper a molecular diagnosis in half of the cases. We have provided proof-of-concept for an emerging role of non-coding DNA variation in unsolved IRD. We demonstrated there is an unmet need for a shift from classical coding genomics to integrative omics. Here, it is our main goal to establish a framework to solve missing heritability in IRD using multi-omics and gene editing in human cellular and animal models. First, we will dissect the regulation of IRD genes in human retina to improve functional genome annotation. Second, we will revisit clinical diagnoses and generate relevant cellular models derived from unsolved monoallelic cases with suspected recessive IRD. Third, we will integrate omics performed on these cells to accelerate diagnosis in unsolved IRD. Fourth, we will unravel novel regulatory mechanisms underlying dominant IRD in human cellular and animal models. Finally, we will transfer research findings to the clinic. Our multidisciplinary approach combined with a strong track record and international network offer a unique opportunity to address unmet needs to accelerate diagnosis and to understand mechanisms of IRD, and to pave the way to precision medicine in IRD.

 

Partners

 

Country

Ditadi, Andrea (Coordinator)

Ospedale San Raffaele

Italy

O’Donohue, Marie-Françoise

Université de Toulouse

France

Schwartz, Schraga

Weizmann Institute of Science

Israel

Flygare, Johan

Lund University

Sweden

Pospisilova, Dagmar

University Hospital Olomouc

Czech Republic

Jovanovic, Marko

Columbia University

United States

Abstract

Ribosomes are the essential molecular machines that translate the genetic code into proteins in our cells. Mutation in the component ribosomal proteins can cause diseases, termed ribosomopathies, of which the best known is Diamond-Blackfan Anemia (DBA), which affects the production of red blood cells (RBCs). RBCs are the most abundant cell type in the body and an essential component for life. Thus, RBCs are constantly produced throughout embryonic, fetal and postnatal life. However, DBA patients present hematological symptoms and die from anemia if not treated only after birth, indicating that only RBCs produced postnatally are sensitive to DBA mutations. Our goal is to understand what determines the difference in sensitivity to a DBA mutation across the different RBCs produced before and after birth. We hypothesize that impaired RBC production observed after birth may be caused by altered ribosome availability or by the acquisition of a developmental-specific ribosome repertoire (i.e. a “ribosome code”) postnatally. To distinguish between these possibilities, We will generate embryonic, fetal and adult RBC from human embryonic stem cells carrying DBA mutations in which we will compare potential changes in ribosome composition and function. This genetically tractable system will allow us to address the dynamics and potential functional role of specialized ribosomes during RBC development. Our combined expertise will identify lineage-specific “translational targets”, which will be tested as novel targeted therapeutic avenues for patients affected by DBA.

 

Partners

 

Country

Hol, Elly (Coordinator)

University Medical Center Utrecht

The Netherlands

Pekny, Milos

University of Gothenburg

Sweden

Kubista, Mikael

Czech Academy of Sciences (CAS)

Czech Republic

Harel, Itamar

The Hebrew University of Jerusalem

Israel

Ahlenius, Henrik

Lund University

Sweden

Pérez-Sala Gozalo, Dolores

Spanish National Research Council (CSIC)

Spain

 

Patient Advocacy Organisation

 

Country

ELA International

Luxembourg

Patiëntenvereniging VKS

The Netherlands

Abstract

Alexander disease (AxD) is a rare genetic brain disease with no cure. AxD patients show white matter degeneration and extensive loss of brain tissue. AxD is often diagnosed before the age of 2, sometimes in later childhood or in adults. Symptoms include mental retardation, epilepsy, muscle stiffness, and AxD leads to death. About 500 AxD cases have been reported worldwide. AxD is caused by mutations in GFAP, an astrocyte intermediate filament (nanofilament) protein. The disease starts in astrocytes, cells that control many neuronal functions and homeostatic mechanisms of the brain. However, it is not known how AxD astrocytes cause the disease, and the available animal models are imperfect. ALEXANDER consortium partners have complementary expertise, and unique technologies to determine the cellular and molecular mechanisms leading to AxD and to design future treatment strategies. We will use induced pluripotent stem cells from AxD patients to derive astrocytes, neurons, and other glial cell types and to generate brain organoids. We will also generate an AxD killifish model. We will elucidate the effects of AxD astrocytes on neurons, and other aspects of AxD pathogenesis using a range of experimental systems and approaches. We will test compounds previously identified by the consortium partners as modulators of astrocyte activation, for their ability to reduce the detrimental activation of AxD astrocytes. Our aim is to understand the pathogenesis of AxD and possibly other diseases with the maladaptive responses of reactive astrocytes as the core underlying mechanism.

 

Partners

 

Country

Guenther, Andreas (Coordinator)

Justus-Liebig-University Giessen

Germany

Crestani, Bruno

University Paris Descartes

France

Eils, Roland

Charité

Germany

Molina Molina, Maria

Bellvitge Biomedical Research Institute – IDIBELL

Spain

Haick, Hossam

Technion

Israel

Brun, Virginie

CEA/Inserm/UGA

France

Walsh, Simon

Imperial College

United Kingdom

Abstract

Pediatric and adult Interstitial Lung Diseases (ILD) are a heterogenous group of >100 different, rare diseases, which share the fate of progressive scarring and, ultimately, death. Apart from two novel anti-fibrotic drugs authorized only for IPF and steroids/immunosuppressants used for inflammatory-driven ILDs, therapeutic options are scarce and lung transplantation represents the only curative option. Similarly, settling a correct diagnosis is difficult in most cases, especially when patients are too sick to undergo invasive procedures. Drawn against this background, leading experts in their fields joined this initiative to i) develop novel, primarily non-invasive, diagnostic algorithms and biomarkers, to ii) better understand the natural course and the role of intermittent exacerbations, to iii) develop better prognostic models and biomarkers, to iv) better understand genotype / phenotype relationships and v) to a priori predict response to therapy via novel therapeutic biomarkers. Based on already existing pediatric (chILD-EU) and adult (eurIPFreg) registries / biobanks, we aim to include another 5000 ILD patients and > 100.000 biomaterials. Next to deep phenotyping, we intend to conduct daily hand-held spirometry, accelerometry and saturation measurement, periodic capture of volatile organic solvent (VOC) based signatures (via awarded “Sniffphone”), apply proteomics/genomics in exhaled breath condensates (EBC)s and deep sequencing in EDTA blood, use artificial intelligence for CT interpretation and, finally, establish disease models on the basis of big data analyses.

 

Partners

 

Country

Gleizes, Pierre-Emmanuel (Coordinator) Centre National de la Recherche Scientifique

France

Lafontaine, Denis

Université Libre de Bruxelles

Belgium

Boztug, Kaan

Ludwig Boltzmann Institute for Rare and

Undiagnosed Diseases

Austria

Erlacher, Miriam

University of Freiburg

Germany

Houtkooper, Riekelt

Amsterdam University Medical Center

The Netherlands

Da Costa, Lydie

Robert Debré Hospital

France

Albrecht, Katarzyna

Medical University of Warsaw

Poland

Cetinkaya, Arda

Hacettepe University

Turkey

Abstract

The ribosome is a fundamental piece of molecular machinery that is responsible for translating messages containing instructions for the synthesis of protein chains. A group of rare diseases, known as “ribosomopathies”, occur when inherited genetic mutations impair the synthesis and function of ribosomes. The EuroDBA consortium was created in 2012 to bring together clinical and biological researchers of the ribosomopathy Diamond-Blackfan anemia (DBA). This new phase of the consortium, titled RiboEurope, will broaden the focus of the rare diseases we study to include other inherited bone marrow failures linked to impairment ribosome synthesis or function. We have been successful in biobanking cell lines from over 100 patients that have a known ribosomopathy such as DBA or Shwachman-Diamond syndrome (SDS), as well as about 1/3 of these who remain “unknown”. One major goal of this proposal is to perform in-depth profiling of all our biobanked cell lines. We will profile their metabolic signatures, the specific way ribosome biogenesis is impaired, and how the cells respond to death signals. The goal here is to develop standardized diagnostic profiles that can be used to rapidly predict specific gene mutations. We will also bring a special focus to the groups of “unknown” patients in our registries where a ribosomopathy is suspected but no indicative gene mutation is evident. We have a pipeline in place for “solving the unsolved” which has already been successful in finding and characterizing several new genes that drive ribosomopathies and diseases that look like them.

 

Partners

 

Country

Murshed, Monzur (Coordinator)

McGill University

Canada

Kempf, Hervé

CNRS-Université de Lorraine

France

Cancela, M Leonor

University of Algarve

Portugal

Cucchiarini Madry, Magali

Saarland University Medical Center

Germany

Abstract

Keutel Syndrome (KS) is a rare genetic disease caused by mutations in MGP gene. The major KS traits include inborn facial disfigurements, cross-bites and serious respiratory complications, which may lead to premature deaths. Our studies on MGP-deficient mice, a faithful model of KS, show that pathologic mineral deposition (ectopic calcification) in cartilaginous tissues is the primary cause underlying these abnormalities. At present only symptomatic treatments are available, which often fail to prevent the progression of KS pathology. Our lack of understanding of how MGP prevents pathologic calcification of various cartilages is still missing. This lack of information is seriously hampering the process of novel drug development and treatment strategies for KS patients. We will use cutting-edge genetics and analytical techniques to address this gap of knowledge.This mechanistic study using genetically modified mouse and zebrafish models will identify the relevant functional domains in MGP required for the prevention of abnormal cartilage calcification and provide information about the nature of the critical sites of mineral accumulation associated with the major KS traits. Understanding the mechanism of action of MGP as a mineralization inhibitor will have important implications for the treatment of KS patients in future.