Periodic Reporting for period 2 - SINERGIA (advanced technologieS for drug dIscovery and precisioN mEdicine: in vitRo modellinG human physiology and diseAse)
Okres sprawozdawczy: 2021-11-01 do 2024-02-29
A key step in the drug development process is to predict information on safety, efficacy and mechanisms of action of a candidate molecule as early as possible in the pipeline (drug screening). To accomplish this aim, physiological and pathological pre-clinical models that closely approximate the human body are required. The limited capabilities of most of the existing pre-clinical screening tools, unable to meet the physiological relevance required to screen out failing drug candidates, reflect in the current weak performances of drug discovery: high attrition rates indeed affect the process of taking drugs from lab to market. Despite emerging new technologies exist with potential for advancing the field of in vitro modelling, their successfully implementation in the drug discovery pipeline to make it more efficient is still challenging. This is also imputable to a lack of structured dialogue between academic technology providers, market-oriented and regulatory-aware CROs, Biotech and Pharma companies, which finally affects the research, training and development pipeline. SINERGIA aimed at integrating a training network where academic and non-academic actors contribute to unravel the potential of the synergistic and rational use of four key bioengineering technologies. SINERGIA involved academic leading experts of i) organs-on-chip and microfabrication technologies; ii) bioreactor and tissue engineering; iii) 3D Bioprinting; iv) induced-pluripotent human stem cells. These techniques are deployed to CROs and Biotech Consortium members that will ensure rational development, exploitation, validation and compliancy with regulatory and industrial aspects. This concerted action lead to advanced models of human physiology and diseases to be introduced in preclinical stages of an innovative and improved drug discovery pipeline.
SINERGIA aimed to provide breakthrough strategies for the implementation of new in vitro preclinical platforms in terms of innovative technologies, biological models and drug screening approaches in the effort of bridging the gap between current, simplistic in vitro cultures and faithful and effective future physiological models.
SINERGIA aimed at improving the dialogue among the main stakeholders in the drug discovery field, and at developing advanced models of human physiology and diseases, to be ultimately introduced in the preclinical stages of the drug discovery pipeline.
SINERGIA provided career development and training opportunities for 15 young researchers. The Consortium enrolled 15 Early Stage Researchers (ESRs): 9 ESRs based at Universities, 4 ESRs at companies, and 2 ESRs at hospitals.
SINERGIA aimed to provide breakthrough strategies for the implementation of new in vitro preclinical platforms in terms of innovative technologies, biological models and drug screening approaches in the effort of bridging the gap between current, simplistic in vitro cultures and faithful and effective future physiological models.
SINERGIA aimed at improving the dialogue among the main stakeholders in the drug discovery field, and at developing advanced models of human physiology and diseases, to be ultimately introduced in the preclinical stages of the drug discovery pipeline.
SINERGIA provided career development and training opportunities for 15 young researchers. The Consortium enrolled 15 Early Stage Researchers (ESRs): 9 ESRs based at Universities, 4 ESRs at companies, and 2 ESRs at hospitals.
SINERGIA had 3 Research Objectives (ROs), tackling open issues of the drug development pipeline from different angles, namely "Drug benefit", "Drug safety" and "Precision medicine". All ROs included the development of 5 paradigmatic models, each carried out by an ESR. By using the enabling technologies available in the Consortium, ESRs built these models in the framework of specific PhD programs. In the first year ESRs defined the technical requirements, in the second year they carried out the preliminary validation, while in the third year ESRs exploited the newly developed platforms for biological/clinical validations.
RO1 “Drug Benefit”:
- RO1.1: Andrea Mazzoleni (University of Basel), developed a novel in-vitro model to discover new potential targets for prostate cancer;
- RO1.2: Francesco Niro (ICRC Brno), studied the cardiac fibroblast contribution to myocardial fibrosis in a 3D microscale model;
- RO1.3: Gabriele Addario (University of Maastricht), used bioprinting techniques to to manufacture a tubulointerstitium model to be used in-vitro;
- RO1.4: Riccardo Francescato (Ente Ospedaliero Cantonale), developed an in-vitro model of skeletal muscle tissue to test anti-fibrotic therapies;
- RO1.5: Karol Kugiejko (Politecnico di Milano), developed a multi-compartment microfluidic model to improve gut microbiome-mediated immunotherapy efficiency.
RO2 “Drug Safety”:
- RO2.1: Helen Kearney (University of Maastricht), coupled bioprinting and microfluidics to advance current kidney organoid protocols;
- RO2.2: Ferran Lozano (BiomimX), validated the heart-on-chip device “uHeart” as drug cardiotoxicity screening platform for in-vitro tests;
- RO2.3: Elisa Cauli (Accelera), developed a liver-on-chip model which recapitulated the hepatobiliary environment;
- RO2.4: Hélia Cristina de Barros Fernandes (MTTLab), developed a reusable insert to generate thousands of liver spheroids for drug screening;
- RO2.5: Alicia Ruppelt (LifeTec), developed an ex-vivo perfusion platform able to preserve slaughterhouse-obtained porcine livers in a physiological state.
RO3 “Precision Medicine”:
- RO3.1: Daniel Pereira de Sousa (ICRC Brno), generated patient-specific in-vitro models for a personalized recognition of the key pathway of cardiac fibrosis;
- RO3.2: Evrim Ceren Kabak (University of Basel), coupled in-vivo and in-vitro approaches to study metastatic breast cancer dormancy in bones;
- RO3.3: Anaïs Lamouline (Ente Ospedaliero Cantonale), developed microfluidic bone chips to personalize the therapeutic regimen of bone metastatic tumours;
- RO3.4: Konstantinos Karyniotakis (Aachen University), validated in-vitro models of kidney diseases through specific animal experiments and cell culture trials;
- RO3.5: Rodrigo Torres Garcia (Politecnico di Milano), developed a platform combining electrophysiological, and force contractile measurement in 3D cardiac tissue models.
In SINERGIA, 91 scientific products have been disseminated; of them, 11 are articles in international journals, 42 are abstracts in Conference proceedings. In 8 of the articles, our ESRs were named as first authors or equal-contributing first authors, and more papers are in press.
We provided the ESRs with 3 Summer Schools, and supplementary online training and meetings during Covid. SINERGIA organised a final Workshop event which was open to PhD students from outside the Consortium.
RO1 “Drug Benefit”:
- RO1.1: Andrea Mazzoleni (University of Basel), developed a novel in-vitro model to discover new potential targets for prostate cancer;
- RO1.2: Francesco Niro (ICRC Brno), studied the cardiac fibroblast contribution to myocardial fibrosis in a 3D microscale model;
- RO1.3: Gabriele Addario (University of Maastricht), used bioprinting techniques to to manufacture a tubulointerstitium model to be used in-vitro;
- RO1.4: Riccardo Francescato (Ente Ospedaliero Cantonale), developed an in-vitro model of skeletal muscle tissue to test anti-fibrotic therapies;
- RO1.5: Karol Kugiejko (Politecnico di Milano), developed a multi-compartment microfluidic model to improve gut microbiome-mediated immunotherapy efficiency.
RO2 “Drug Safety”:
- RO2.1: Helen Kearney (University of Maastricht), coupled bioprinting and microfluidics to advance current kidney organoid protocols;
- RO2.2: Ferran Lozano (BiomimX), validated the heart-on-chip device “uHeart” as drug cardiotoxicity screening platform for in-vitro tests;
- RO2.3: Elisa Cauli (Accelera), developed a liver-on-chip model which recapitulated the hepatobiliary environment;
- RO2.4: Hélia Cristina de Barros Fernandes (MTTLab), developed a reusable insert to generate thousands of liver spheroids for drug screening;
- RO2.5: Alicia Ruppelt (LifeTec), developed an ex-vivo perfusion platform able to preserve slaughterhouse-obtained porcine livers in a physiological state.
RO3 “Precision Medicine”:
- RO3.1: Daniel Pereira de Sousa (ICRC Brno), generated patient-specific in-vitro models for a personalized recognition of the key pathway of cardiac fibrosis;
- RO3.2: Evrim Ceren Kabak (University of Basel), coupled in-vivo and in-vitro approaches to study metastatic breast cancer dormancy in bones;
- RO3.3: Anaïs Lamouline (Ente Ospedaliero Cantonale), developed microfluidic bone chips to personalize the therapeutic regimen of bone metastatic tumours;
- RO3.4: Konstantinos Karyniotakis (Aachen University), validated in-vitro models of kidney diseases through specific animal experiments and cell culture trials;
- RO3.5: Rodrigo Torres Garcia (Politecnico di Milano), developed a platform combining electrophysiological, and force contractile measurement in 3D cardiac tissue models.
In SINERGIA, 91 scientific products have been disseminated; of them, 11 are articles in international journals, 42 are abstracts in Conference proceedings. In 8 of the articles, our ESRs were named as first authors or equal-contributing first authors, and more papers are in press.
We provided the ESRs with 3 Summer Schools, and supplementary online training and meetings during Covid. SINERGIA organised a final Workshop event which was open to PhD students from outside the Consortium.
The SINERGIA consortium included experts in in-vitro drug screening models at different scales and using diverse emerging technologies (macro-scale bioreactors, meso-scale 3D bioprinting, micro-scale organs-on-chip, cell-scale iPSCs). In all work packages, substantial progress has been made with respect both to the state of the art and to the original research program. The progress of SINERGIA ESRs has been multifaceted. Some of them published results of their research in high-impact journals: more are to come, especially for those (11 out of 15) who are still finalizing their PhD research.
ESRs were exposed to a broad range of cutting-edge equipment and methodologies and they thus received a comprehensive multidisciplinary research training, not readily achievable through standard PhD programmes. This will substantially enhance career perspectives and prospects of ESRs recruited in SINERGIA. Soft skills training, solid hard science competences and cell biological lab training for all of them the foundations for brilliant career prospects, not only in academia, but also in industry or the public sector. Noteworthy, 5 ESRs have already started working in the private sector.
ESRs were exposed to a broad range of cutting-edge equipment and methodologies and they thus received a comprehensive multidisciplinary research training, not readily achievable through standard PhD programmes. This will substantially enhance career perspectives and prospects of ESRs recruited in SINERGIA. Soft skills training, solid hard science competences and cell biological lab training for all of them the foundations for brilliant career prospects, not only in academia, but also in industry or the public sector. Noteworthy, 5 ESRs have already started working in the private sector.