Sickle cell disease (SCD) is one of the most prevalent monogenic diseases in Europe. A single amino acid substitution in the beta-globin chain of the adult hemoglobin (Hb) drives red blood cell sickling and multi-organ damage. The clinical severity of SCD is alleviated by the co-inheritance of mutations causing expression of fetal gamma-globin in adult life ? a condition termed hereditary persistence of fetal hemoglobin (HPFH). Transplantation of autologous, genetically modified hematopoietic stem/progenitor cells (HSPCs) is an attractive therapeutic option for SCD patients. To this end, genome editing approaches based on the use of site-specific nucleases or, more recently, base editors have been explored by many groups, including teams in our consortium. These approaches either correct the single point mutation causing SCD or reactivate fetal gamma-globin expression by mimicking HPFH mutations. On the other hand, (pre)clinical data from SCD patients or SCD mouse models, as well as preliminary data from our labs suggest that SCD HSPCs are characterized by a high mutational burden, oxidative stress and expression of inflammatory genes. This can alter HSPC properties as well as their interactions within the bone marrow niche. In the context of gene therapy, it is essential to understand the mechanisms underlying SCD HSPC dysfunction and assess the impact of genome editing approaches on SCD HSPCs. In this proposal, we have assembled a multidisciplinary team to: (i) understand the molecular and cellular mechanisms underlying SCD HSPC autonomous and non-cell-autonomous dysfunctions and (ii) evaluate the impact of established and novel genome editing approaches on SCD HSPC properties and genome integrity. This study will lay the foundation of an improved gene therapy strategy to treat SCD and provide best practice tools and protocols for genome editing-based therapies in HSPCs.

Structured understanding of the drivers of irreproducibility and presenting concrete solutions of tools and interventions will help to increase the quality, reliability and re-usability of scientific evidence. To this end, iRISE proposes to provide theoretical and empirical evidence of the effectiveness of specific interventions, and a framework for a robust, evidence-based road map for the development, assessment and implementation of interventions intended to improve reproducibility. iRISE brings together qualitative and quantitative expertise, from academia and SMEs, including meta-science, statistics, economics, artificial intelligence, research ethics and integrity, quality assurance, and project management. iRISE proposes the development of a general framework for diagnosing and addressing reproducibility problems using analytical and computational modelling, simulations and meta-studies. Data on existing interventions will be systematically curated and evaluated, and stakeholders will be consulted to collaboratively identify practices and tools that should be prioritised for implementation. iRISE proposes to conduct empirical studies of both technical and practice-based solutions to increase reproducibility. Across all iRISE activities, the influences of research culture will be investigated, with a focus on mainstreaming systematic integration of equity, diversity and inclusion practices. A comprehensive Stakeholder Forum will be engaged to provide advice, and iRISE will commit to open and reproducible practices. The different types of evidence generated will be integrated into an open knowledge base to support the community in decision-making to identify, test, and implement effective and feasible solutions for reproducibility. The members of iRISE have made pivotal scientific and policy contributions relating to robustness, rigour and reproducibility in the past and have the skills and tools to succeed in this ambitious project that has potential scientific, economic and societal gains both in Europe and beyond.

HEAL will focus on general bottlenecks to induced pluripotent stem cell therapies with a particular focus on heart failure, which remains a major cause of morbidity and mortality with very few treatment options. HLA-homozygous cell line derived cardiomyocyte aggregates offer the prospect of a restorative heart therapy applicable to large patient populations and to overcome economic barriers associated with autologous approaches. By developing solutions for their mass-production and cryopreservation we will enable allogeneic treatment with minimum requirements for immunosuppression. Assays for assessment of immunogenicity will provide data for the development of an artificial intelligence powered algorithm to predict recipients's immune responses for personalised design of immunosuppression protocols. A potency assay to assure product effectiveness will be developed together with assays of tumorigenicity in vitro and in vivo that meet and exceed current regulatory requirements. A genetic integrity pipeline defining the most sensitive assays for rigorous assessment will be developed and a rescue tool in the form of a biallelic suicide gene for programmed cell death will add to the safety toolbox for the therapy. Optimisation of cell-product administration in terms of retention and engraftment, including catheter-based delivery as minimally invasive alternative to surgical application, and assessment of risks of graft-induced arrhythmia will be determined in a pig model. Early dialogues, via established links, to the regulatory authorities will ensure proper development according to GMP requirements. Freedom to operate and licensing strategies with a health technology and infrastructure assessment of European centres will set the scene for approval of the cell product and related assays and protocols for storage and distribution required to progress towards a first in man study of cell-based heart repair.

There has never been a greater need for skilled managers and operators of research infrastructure (RI). Europe must develop the workforce that will turn ~50 nascent RIs with sites in different countries into powerhouses of support for major projects comparable to understanding the blueprint of life or discovering new subatomic particles. RItrain will develop a flagship training programme enabling RIs across all domains to gain expertise on governance, organisation, financial and staff management, funding, IP, service provision and outreach in an international context. It will be designed and delivered by experts who have set up and managed RIs from concept to maturity. We will define competencies required by RIs through consultation with their senior managers. The resulting competency framework will underpin a Bologna-compliant degree, the Master in Research Infrastructure Management, with three delivery routes. (1) Professionals working in RIs (or organisations representing them) can dip into the content, focusing on areas where there is most need. (2) Management teams can take the course as an organisation, dividing modules between them to gain a certificate for the RI. This will flag the RI as an organisation that values staff development, improving its attractiveness as an employer. (3) Recent graduates and others wishing to enhance their employability can take a full master’s degree. Course content will include webinars led by senior managers of RIs. A staff-exchange programme will catalyse exchange of best practice and foster cooperation to develop a mobile work force effective across many RIs. By the end of the project we will be delivering a master’s curriculum funded through course fees. Others with an interest in adopting it will be encouraged to do so, providing a means of expanding the programme. Europe’s research community and global collaborators will gain from world-class facilities to support excellent, high-impact research to benefit humankind.