Published on 28.06.2022
(*) Institut Imagine (France), Annarita Miccio ; Ospedale San Raffaele SRL (Italy), Giuliana Ferrari ; Universitaetsklinikum Freiburg (Germany), Claudio Mussolino, Toni Cathomen ; Bar Ilan University (Israel), Ayal Hendel; Inserm (France), Mario Amendola ; Eidgenoessische Technische Hochschule Zuerich (Switzerland) Jacob Corn, Astrazeneca AB (Sweden), Marcello Maresca ; Eatris Eric (Netherlands), Anton Ussi
Innovative approaches of gene therapy for sickle cell disease
Sickle cell disease (SCD) is the most common genetic disorder, with 350,000 new cases diagnosed worldwide each year. It results in severe anemia, extremely painful crises, increased risk of infections, and progressive loss of organ function. SCD affects hemoglobin, the main component of red blood cells, which carries oxygen in the blood, and is caused by a mutation of the β-globin gene coding one of the key constituent proteins of hemoglobin. The only curative treatments for SCD to date are the transplantation of blood (hematopoietic) stem cells from the bone marrow of a healthy donor (an approach limited by the lack of compatible donors, i.e. less than 30% of cases only), and still experimental, lentivirus-based gene transfer. Other available treatments reduce symptoms and pain but do not target the cause of the disease.
Annarita Miccio's team and the members of the consortium are developing cutting edge methodologies in gene therapy for hematological disorders, using site-specific nucleases or base editors. EDITSCD will benefit from this expertise, as innovative CRISPR-Cas9-based approaches will be used specifically for SCD to reactivate the expression of fetal hemoglobin, naturally produced before birth, to compensate for the deficit of functional adult hemoglobin, or to correct the SCD-causing mutation.
Collaborate to assess the efficacy and safety of these approaches
Data from sickle cell diseases patients or SCD mouse models suggest that SCD hematopoietic stem cells (HSCs), the target cell population in gene therapy approaches, are characterized by a high mutational burden, oxidative stress and expression of inflammatory genes.
"For this project, we have brought together a multidisciplinary team composed of eight partners from seven countries. Thanks to their expertise and collaboration, we want to better understand the molecular and cellular mechanisms underlying HSC autonomous and non-cell-autonomous dysfunctions in SCD. We also want to evaluate the impact of established and novel genome editing approaches on SCD hematopoietic stem cells’ properties and genome integrity. We hope that this study will lay the foundation for an improved gene therapy strategy to treat SCD and provide best practice tools and protocols for genome editing-based therapies using HSCs. Ultimately addressed to patients, it is important to us to establish within EDITSCD project a dialogue around these novel therapies with patients’ communities. For this, the European Reference Network on Rare Hematological Diseases (ERN-EuroBloodNet) will accompany our consortium in patients-directed actions, and support dissemination activities on these innovative strategies", explains Annarita Miccio, project coordinator.
Responding to European health and innovation needs
This project is funded by Horizon Europe, the European Union’s key research and innovation program, which aims to increase the visibility of cutting-edge European research and innovation and to attract and mobilize excellent talents. projects should contribute to a more innovative, resilient, competitive and healthy Europe.
"Institut Imagine, together with its partners, is proud of its involvement in this ambitious European program of excellence. Widening collaborations at the European level is one of our priorities. Horizon Europe brings together the key players of technological and therapeutic innovation, from industrial, academic research, and healthcare sectors, to accelerate scientific development, find treatments, and ultimately contribute to a better health. Mobilized through multidisciplinary and multi-partner projects, these actors demonstrate the importance of public-private collaborations to collectively contribute, at a European level, to the development of innovative treatments for diseases that represent real public health challenges.", concludes Prof. Stanislas Lyonnet, Director of Institut Imagine.
► About Institut Imagine
Institut Imagine is the first European center for research, care and teaching on genetic diseases. With the mission of understanding and finding a cure for these diseases, the Institute brings together 1000 of the best clinicians, researchers and healthcare personnel in an architecture that creates synergies between teams. It is this All these expertisesfrom the proximity with patients, that allows Imagine to make discoveries for patients. The 8,000 genetic diseases that have been identified affect 35 million patients in Europe, and almost 3 million in France, where 30,000 new cases are diagnosed each year. Nearly 50% of children leave consultation without a genetic diagnosis and 85% of genetic diseases have no cure. Faced with this major public health issue, the challenge is doubled: to diagnose and find a cure.
►About Assistance Publique - Hôpitaux de Paris / Greater Paris University Hospitals:
The leading hospital and university centre (CHU) in Europe, Greater Paris University Hospitals and its 38 hospitals are organised into six hospital-university groups (AP-HP. Centre - Université Paris Cité ; AP-HP. Sorbonne Université ; AP-HP. Nord - Université Paris Cité ; AP-HP. Université Paris Saclay ; AP-HP. Hôpitaux Universitaires Henri Mondor et AP-HP. Hôpitaux Universitaires Paris Seine-Saint-Denis) and are centered around five universities in the Île-de-France region. Closely linked to large research bodies, Greater Paris University Hospitals include four international hospital-university institutes (Institut du Cerveau, ICAN, IMAGINE, FOReSIGHT) and the largest French health data repository (EDS). As a major stakeholder in applied research and health innovation, Greater Paris University Hospitals hold a portfolio of 650 active patents, and each year its clinicians sign off nearly 10000 scientific publications and over 4,000 research projects are under development, all promoters combined. In 2020, Greater Paris University Hospitals were awarded the Institut Carnot label, which is recognition of the quality of partner research: Carnot@AP-HP offers industrial stakeholders applied and clinical research solutions in the health sector. In 2015, Greater Paris University Hospitals also founded the Greater Paris University Hospitals Foundation to support the biomedical and health research performed in all its hospitals.
► About Université Paris Cité
Université Paris Cité is a multidisciplinary research-intensive university in the heart of the capital, which has reached the highest international level thanks to its research, the diversity of its training courses, its support for innovation, and its active participation in the construction of the European research and training area. Université Paris Cité is made up of three faculties (Health, Sciences and Societies, and Humanities), a component institution, the Institut de Physique du Globe de Paris, and a partner research organization, the Institut Pasteur. Université Paris Cité has 63,000 students, 7,500 teacher-researchers and researchers, 2,700 administrative and technical staff, 21 doctoral schools and 119 research units.
► About Bar-Ilan University
Bar-Ilan University, founded in 1955, is one of Israel's leading institutions of higher education, with nine faculties that are active partners in the country's national science and technology initiatives. The university's milestone achievements in the sciences and humanities and all fields of human endeavor have made an indelible imprint on the landscape of the State of Israel.
A microcosm of Israeli society, Bar-Ilan has a diverse student body of close to 19,000. Serving as a bridge between Israel's diverse sectors, Bar-Ilan University, with its multicultural campus environment, provides a singular forum for free thought and open discussion.
► About EATRIS
EATRIS, the European Research Infrastructure for Translational Medicine, is one of the leading permanent European infrastructures for translational sciences. The infrastructure provides access to excellent academic expertise and facilities across Europe to accelerate early medicine development and advance promising medical research for the benefit of patients. EATRIS is active in the preclinical and very early clinical phases of the development of medicines, diagnostics and vaccines. Central to its mission is to support the development of innovative next generation therapies including cell and gene therapy products. This is achieved by facilitating the development of safer and more efficient next generation tools, protocols and approaches to gene therapy which is the goal of the EDITSCD project.
EATRIS is a non-profit organisation based in Amsterdam, NL, supported by 14 European countries and representing 127 leading academic and non-profit biomedical research institutions. EATRIS collaborates with a wide range of users and stakeholders, including academia, SMEs and large pharma/biotech, as well as patient organisations and research funding organisations.
► About ETH Zurich – Where the future begins
Freedom and individual responsibility, entrepreneurial spirit and open-mindedness: ETH Zurich stands on a bedrock of true Swiss values. Our university for science and technology dates back to the year 1855, when the founders of modern-day Switzerland created it as a centre of innovation and knowledge. At ETH Zurich, students discover an ideal environment for independent thinking, researchers a climate which inspires top performance. Situated in the heart of Europe, yet forging connections all over the world, ETH Zurich is pioneering effective solutions to the global challenges of today and tomorrow.
► About Medical Center – University of Freiburg
With roughly 14,000 employees, the Medical Center – University of Freiburg is among the largest university medical centers in Germany. Around 1,700 doctors and more than 3,900 nurses provide care to more than 90,000 inpatients and around 820,000 outpatients per year. The Medical Center – University of Freiburg engages in research, teaching, and healthcare as its core responsibilities, always with the goal of offering its patients treatment informed by the latest scientific findings – today and in the future.
► About Ospedale San Raffaele SRL
IRCCS Ospedale San Raffaele is a university and research hospital established in 1971, capable of offering specialised care for the most complex medical conditions. In 1972, the hospital was officially recognised as a research hospital (Istituto di Ricovero e Cura a Carattere Scientifico, IRCCS), and in 2012 it became part of Gruppo San Donato. With over 60 clinical units and 100 research laboratories, IRCCS Ospedale San Raffaele combines both clinical and scientific activities through a translational approach whereby discoveries made in the laboratory inform clinical practice and research is driven by clinical needs.
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Marie de Bazelaire, Director of Communication