PROBLEM – The drug development cycle, from basic research to testing efficacy, toxicity, and safety of new therapeutics, is largely depending on animal models. However animal biology and pathology differ from human biology at crucial points. The sector is aware of the significant complications in their usage, but lacks better alternatives. Highly advanced technology exists for the culture of cell systems, organs, tumors, etc. outside the body (‘in vitro’). However, the existing culture models lack functional blood vessels – a vital structure inside the body (‘in vivo’). There is a great unmet need for better models of human biology, to speed up both basic research on human biology as well as the development of novel, much needed therapeutic solutions. SOLUTION – OrganoPlate Graft involves the development to market readiness of the first high-throughput in vitro culture method for vascularized tissue that is unrivalled by the available in vitro options. An extensive proof of concept (PoC) for this method has been obtained. The new product will be launched within 6-months post-project and, for the first time, allow for the study and manipulation of human tissues with functional human vascularization. COMPANY – Founded in 2013, the Dutch SME MIMETAS was the first party to commercially exploit organ-on-a-chip technology that enables accurately controlled and monitored in vitro cultivation 3D ‘mini-organs’. MIMETAS currently employs > 60 professionals, generates year-on year multi-million revenues, and is projected to be profitable as of 2020. RESULTS – The results of the 2-year OrganoPlate Graft project will empower Users by aiding them to grow tissues with human vascularization in vitro – enabling the replacement of a wealth of animal experiments and the design of completely novel experiments in research, development and clinical settings. OrganoPlate Graft will cost €3M, employ 10 new FTEs, and is projected to add 40 FTE and >€50M annual revenues to MIMETAS by 2022.

MIMIC is an interdisciplinary European Industrial Doctorate at the interface of cell biology, engineering and drug development. MIMIC aims to develop and improve novel “organs on chips” technology. This technology combines modern cell biology with microfluidics and chip-based techniques with the goal to mimic organ functionality. There is a high demand by the pharmaceutical industry for more reliable tissue models to test drug toxicity and drug efficiency at early stages of drug development. Early reliable drug testing will have a major impact on drug development costs and human health. Furthermore, ethical considerations urge for the search for alternatives to replace animal tests in drug development and basic research. Organs on chips are a new exciting possibility to closer mimic human organ functionality in vitro than conventional 2D or 3D cell cultures. Organs on chips allow both, the emulation of healthy organs as well as the emulation of specific disease conditions using corresponding engineered or patient derived human cells. Moreover, organs on chips are ideally suited for high-throughput drug screening. The EID-MIMIC will develop novel organs on chips prototypes, and validate their suitability for end-users for high throughput drug screening or basic research. MIMIC will train early stage researchers in cutting edge technologies, like novel chip based technologies e.g. cell micropatterning, soft-lithography and microfluidics technology, as well as state of the art microscopy like super resolution- and confocal spinning disc microscopy and modern genome editing techniques like CRISPR-technology. In addition, MIMIC has developed a 3 year modular curriculum including workshops on creativity and business skills, summer schools, business plan competitions and international conferences with a specific agenda of transferable skill training elements highly relevant for scientific communication, translational research and, in particular, entrepreneurship.

Over the past two decades, cells isolated from human perinatal (or birth-associated) tissues (amniotic membrane, umbilical cord tissue and cells from amniotic fluid), have been shown to provide tremendous pro-regenerative activities. Amongst others, the application of these cells or of components of their secretome, including extracellular vesicles (EVs), have been found to improve myocardial infarction (MI), ischemic stroke (IS) and multiple sclerosis (MS) symptoms in various animal models. Currently, cell-free therapies represent a frontier for innovation in regenerative medicine for clinical unmet needs, however, very few scientists are trained for their clinical translation. “Exploring the therapeutic potential of perinatal cell SECRETomes - SECRET” sets out with the ambition to train 10 doctoral candidates (DCs) to disentangle the inherent therapeutic potential of perinatal cell secretomes (either as a whole or as fractionated small EVs) in order to possibile translate novel biologics into the clinic. Their specific focus will be the characterisation, the delivery and the preclinical evaluation of these perinatal secretomes as an innovative therapeutic approaches for MI, IS and MS. To achieve this goal, Università Cattolica del Sacro Cuore (Prof. Ornella Parolini, Italy) unites internationally-renowned academic and non-academic institutions from Italy, The Netherlands, Germany, Belgium, Portugal and Switzerland, to deliver an inter-disciplinary programme that goes beyond current state-of-the-art research in next generation medicinal product development and validation. These include the development and use of iPSC-derived organoids and organ-on-a-chip models to identify the most efficient perinatal cell secretome in terms of immunomodulation, angiogenesis, anti-fibrotic, cardio-protective and neuro-trophic properties, as well as the assessment of their in vivo cardiac reparative and neuro-regenerative potential using novel delivery methods.

Gene therapy has transitioned from a distant hope to reality. To date 3 rAAV gene therapies are approved in the EU, >30 phase III clinical trials ongoing, and exciting developments in therapeutic gene editing in the pipeline. However, fundamental limitations in the bioprocessing of gene therapy vectors limit broader application. Manufacturing is not automated, with an open process environment, limited scalability and robustness, and inefficient downstream processing, resulting in huge footprint and exceedingly high cost of goods. The field requires scalable manufacturing technology with modular design to produce high doses for large patient groups at a fraction of cost. Improved delivery approaches with increased specificity and efficacy at lower doses are needed to overcome emerging safety concerns observed in clinical trials. Prediction of therapeutic efficacy in man is challenging due to a species barrier, underlining the need for humanized models to reduce attrition rates in the development pipeline. To overcome these challenges, innovation driven by multidisciplinary approaches is direly needed. GET-IN is a doctoral network of 7 academic and 8 non-academic partners, with expertise in vectorology, genome editing, process engineering, biomanufacturing and innovative humanized models. Together, they provide an excellent training framework for 10 Doctoral Candidates (DCs) who will be the future innovators in the gene therapy field. Research in GET-IN will investigate disruptive innovations including optimised bioprocessing, digital simulation, novel and improved vectors and genome editors, targeted delivery systems, and human organ-on-chip models for more relevant safety and efficacy evaluation. The joint training programme will emphasise responsible, cooperative research and innovation, creativity, and entrepreneurship to maximize the career potential of the DCs.

The overall objective of this project is to identify novel drug candidates capable of slowing down the progression of neurodegeneration in the subset of Parkinson’s disease (PD) patients with overt mitochondrial dysfunction. Multi-modal phenotypic characterisation of cohorts of monogenic PD patients with overt mitochondrial dysfunction will be used as an anchor for the discovery of two extreme cohorts of idiopathic PD patients: with and without detectable mitochondrial dysfunction. A suite of personalised in vitro, in vivo, and in silico models will be generated using induced pluripotent stem cells (iPSCs) from selected subjects and controls. An industrial quality 3D microfluidic cell culture product, specifically designed for the culture of iPSC-derived dopaminergic neurons, will be developed for use in a morphological and bioanalytical screen for lead compounds reduce mitochondrial dysfunction. By monitoring motor behaviour and in situ striatal neurochemistry at high temporal resolution, the in vivo response to lead compounds will be characterised in humanised mouse models with striatally transplants of iPSC-derived dopaminergic neurons derived from PD patients. Personalised computational models of dopaminergic neuronal metabolism and mitochondrial morphology will be developed. These in silico models will be used to accelerate drug development by prioritising pathways for metabolomic assay optimisation, stratifying idiopathic PD patients by degree of mitochondrial dysfunction, predicting new new targets to reduce mitochondrial dysfunction and mechanistic interpretation in vitro and in vivo experimental results. SysMedPD unites a highly experienced multidisciplinary consortium in an ambitious project to develop and apply a systems biomedicine approach to preclinically identify candidate neuroprotectants, for the estimated 1-2 million people worldwide who suffer from PD with mitochondrial dysfunction.