Periodic Reporting for period 3 - TECHNOBEAT (Tools and TECHNOlogies for Breakthrough in hEArt Therapies)
Période du rapport: 2019-01-01 au 2019-12-31
Ischemic heart diseases including myocardial infarction (MI), which entails the irreversible loss of function heart muscle tissue, constitute a major socio-economic burden in global healthcare. The costs related to sickness, morbidity and the productivity losses resulting from ischemic heart diseases alone amounts to about €45 billion/year in the EU (http://www.who.int/cardiovascular_diseases/en/).
Consequently, the overall objective of the project is developing innovative tools and technologies enabling a curative, cell-based therapy for damaged hearts. Achieving this goal will have a considerable socio-economic impact on Europe’s healthcare system and on patients’ personal well-being.
Through its interdisciplinary excellence, TECHNOBEAT’s consortium of leading European stem cell researchers, clinicians, tissue-, bioprocess-, and technical- engineers in industry and academia is ideally positioned to address this ambitious objective(s).
Currently, heart transplantation is the only treatment option for end-stage heart failure patients; this option is strongly restricted by the availability of donor organs and the requirement of life-long medication with immunosuppressing drugs. In contrast, TECHNOBEAT aims at establishing advanced cell therapies aimed at the functional reconstitution of damaged hearts thereby preventing heart failure and the need for organ replacement.
Human induced pluripotent stem cells (hiPSCs) can be derived by a recent technology known as “reprogramming” from patients’ own somatic cells. hiPSCs have outstanding features with respect to their utility for advanced cell therapies that is an unlimited expandability and differentiation potential into all relevant cell types in a dish, including functional human cardiomyocytes (heart muscle cells), endothelial cells (lining the blood vessels), and connective tissue-forming cells. These features make hiPSC highly attractive as a universal cell source for organ repair. However, technologies for the robust production of hiPSC-derived progenies in line with GMP standards and at reasonable cost are currently lacking.
In the total 4 years of project funding TECHNOBEAT has made ground breaking progress in establishing technologies for the production of human heart muscle cells and their preclinical testing. Particularly, the concept of generating mass-produced, bioreactor-derived µ-tissues which can be directly applied for transplantation into the heart has been proven very successful. These team-driven efforts have paved the way for leaping forward towards novel therapies for heart repair.
Consequently, the overall objective of the project is developing innovative tools and technologies enabling a curative, cell-based therapy for damaged hearts. Achieving this goal will have a considerable socio-economic impact on Europe’s healthcare system and on patients’ personal well-being.
Through its interdisciplinary excellence, TECHNOBEAT’s consortium of leading European stem cell researchers, clinicians, tissue-, bioprocess-, and technical- engineers in industry and academia is ideally positioned to address this ambitious objective(s).
Currently, heart transplantation is the only treatment option for end-stage heart failure patients; this option is strongly restricted by the availability of donor organs and the requirement of life-long medication with immunosuppressing drugs. In contrast, TECHNOBEAT aims at establishing advanced cell therapies aimed at the functional reconstitution of damaged hearts thereby preventing heart failure and the need for organ replacement.
Human induced pluripotent stem cells (hiPSCs) can be derived by a recent technology known as “reprogramming” from patients’ own somatic cells. hiPSCs have outstanding features with respect to their utility for advanced cell therapies that is an unlimited expandability and differentiation potential into all relevant cell types in a dish, including functional human cardiomyocytes (heart muscle cells), endothelial cells (lining the blood vessels), and connective tissue-forming cells. These features make hiPSC highly attractive as a universal cell source for organ repair. However, technologies for the robust production of hiPSC-derived progenies in line with GMP standards and at reasonable cost are currently lacking.
In the total 4 years of project funding TECHNOBEAT has made ground breaking progress in establishing technologies for the production of human heart muscle cells and their preclinical testing. Particularly, the concept of generating mass-produced, bioreactor-derived µ-tissues which can be directly applied for transplantation into the heart has been proven very successful. These team-driven efforts have paved the way for leaping forward towards novel therapies for heart repair.
Within the second funding period TECHNOBEAT partners made substantial scientific progress along the defined aims and timelines. In particular, this includes the successful:
- hiPSC genome editing via homologous transgene targeting “safe harbour” genomic loci
- Process development for GMP compliant hiPSC mass production in stirred tank bioreactors and process scale up towards 1 liter process scale
- Advanced hiPSC processing-specific bioreactor design and in-process cell monitoring technologies
- Improving tools for monitoring genetic variants in hPSC including labelling of isogenic clonal variants
- Establishing advanced chemically defined cardiomyogenic differentiation processes in stirred tank bioreactors, process upscaling and cell production for pre-clinical testing
- Establishing methods for larger-scale cardiac µ-tissue production
- Developing novel protocols and reporter lines for differentiating endothelia cells, epicardial-like cells and hPSC-derived cardiac fibroblasts
- Advancing processes for the production of mesenchamal stromal cells in clinical scale under good manufacturing production (GMP) compliant conditions
- Establishing and performing large animal studies including acute cell retention experiments and establishing immunosuppression enabling engraftment of hiPSC-derived progenies in xenogeneic model of heart failure
- Extensively promoted outreach activities to ensure dissemination of projects achievement within the scientific community and to the public.
- All management and communication goals have been met as well.
- hiPSC genome editing via homologous transgene targeting “safe harbour” genomic loci
- Process development for GMP compliant hiPSC mass production in stirred tank bioreactors and process scale up towards 1 liter process scale
- Advanced hiPSC processing-specific bioreactor design and in-process cell monitoring technologies
- Improving tools for monitoring genetic variants in hPSC including labelling of isogenic clonal variants
- Establishing advanced chemically defined cardiomyogenic differentiation processes in stirred tank bioreactors, process upscaling and cell production for pre-clinical testing
- Establishing methods for larger-scale cardiac µ-tissue production
- Developing novel protocols and reporter lines for differentiating endothelia cells, epicardial-like cells and hPSC-derived cardiac fibroblasts
- Advancing processes for the production of mesenchamal stromal cells in clinical scale under good manufacturing production (GMP) compliant conditions
- Establishing and performing large animal studies including acute cell retention experiments and establishing immunosuppression enabling engraftment of hiPSC-derived progenies in xenogeneic model of heart failure
- Extensively promoted outreach activities to ensure dissemination of projects achievement within the scientific community and to the public.
- All management and communication goals have been met as well.
TECHNOBEAT’s contribution to achieving the expected impacts which range from:
• Short-term impact: development of improved bioreactor systems, cell monitoring and characterisation tools, large scale process for GMP-compliant stem cell -production, -differentiation, and µ-tissue engineering. These are all marketable tools, technologies, and cell-based products including µ-tissue based 3D assays of broad commercial value that will immediately strengthen Europe’s lead on biotechnology markets.
• Mid-term impact: will in particular include the robust proof of concept for the functional engraftment of transplanted hiPSC-progenies (applied as injectable µ-tissues) in physiological relevant preclinical models of myocardial infarctions. Moreover, the regulatory framework for hiPSC-based cell therapies will be shaped in close exchange with the national, European and global competent authorities as well as other stakeholders and networks thereby preparing the ground for the clinical translation of the hiPSC technology.
• Wider, long-term impact (TECHNOBEAT and beyond): will include the proof that hiPSC-based therapies can be safely applied to patients in clinical trials, can substantially support or even cure diseased hearts and thus help to overcome the shortage of donor organs. As a consequence, the approach might provide a substantial socio-economic benefit to the wellbeing of the aging European and global population.
• Short-term impact: development of improved bioreactor systems, cell monitoring and characterisation tools, large scale process for GMP-compliant stem cell -production, -differentiation, and µ-tissue engineering. These are all marketable tools, technologies, and cell-based products including µ-tissue based 3D assays of broad commercial value that will immediately strengthen Europe’s lead on biotechnology markets.
• Mid-term impact: will in particular include the robust proof of concept for the functional engraftment of transplanted hiPSC-progenies (applied as injectable µ-tissues) in physiological relevant preclinical models of myocardial infarctions. Moreover, the regulatory framework for hiPSC-based cell therapies will be shaped in close exchange with the national, European and global competent authorities as well as other stakeholders and networks thereby preparing the ground for the clinical translation of the hiPSC technology.
• Wider, long-term impact (TECHNOBEAT and beyond): will include the proof that hiPSC-based therapies can be safely applied to patients in clinical trials, can substantially support or even cure diseased hearts and thus help to overcome the shortage of donor organs. As a consequence, the approach might provide a substantial socio-economic benefit to the wellbeing of the aging European and global population.