The adverse effects of pharmaceuticals on the central or peripheral nervous systems are poorly predicted by the current in vitro and in vivo preclinical studies performed during Research and Development (R&D) process. Therefore, increasing the predictivity of the preclinical toolbox is a clear need, and would benefit to human volunteers/patients (safer drugs) and Pharmaceutical Industry (reduced attrition). By combining top level scientists in neurobiology/toxicology with successful software developers, the NeuroDeRisk | Neurotoxicity De-Risking in Preclinical Drug Discovery Consortium will aim at tackling three of the most challenging adverse effects: seizures, psychological/psychiatric changes, and peripheral neuropathies. Our approach will be global, starting with an in-depth evaluation of knowledge on mechanisms of neurotoxicity (biological pathways as well as chemical structures and descriptors, using in particular historical data). Then we will search for innovative tools, assays and studies covering in silico, in vitro and in vivo approaches. This will include in particular: molecular design platform, artificial intelligence, human induced pluripotent stem cells, blood-brain-barrier models, immunohistochemistry, transcriptomics, RNA editing biomarkers, video-monitoring and telemetry of animals, pharmacokinetics, etc. The last step will aim at combining these tools in an integrated platform for better risk-assessment and decision-points throughout R&D process, and thus better protection of human volunteers and patients.
EBiSC2 builds on the achievements of the European Bank for iPSCs (EBiSC1) in centralising existing capacities across Europe in a unique banking and distribution infrastructure for research use in response to the increasing demand for human induced pluripotent stem cells (iPSC). Significant progress towards this aim has been made by EBiSC1; further resources, however, are required to ensure self-sustainability. Key partners of EBiSC1 who have delivered major assets of the current bank, join efforts to establish EBiSC2 as self-sustainable, central bank. Based on a gap analysis of the EBiSC1 endeavours towards sustainability, and focussing on user demand, scientific excellence and productivity, EBiSC2 will deploy a business strategy for a sustainable, non-for-profit bank providing access to disease-relevant and quality-controlled iPSCs, along with comprehensive data and freedom to operate for academic and commercial use. To meet evolving requirements from industry and academia, the cell catalogue will be constantly enriched through on-demand generation of new iPSC lines, including gene-edited lines and isogenic controls, iPSC-derived and progenitor cells. EBiSC2 will distribute cell lines and develop a range of additional cell services (incl. screening panels of disease-relevant iPSC and control lines in ready-to-use-formats) to extend its offer, while reducing operational costs through state-of-the-art upscaling and automation enabling bulk production of standardised high-quality cells. Proof-of-concept studies performed jointly by academia and industry will demonstrate the reliability and robustness of the lines for disease modelling and screening and enrich the EBiSC2 catalogue with extensive data. To bundle resources, EBiSC2 focuses on collaboration with iPSC programmes and aims to serve as central hub for EU-funded projects to bank their iPSC lines, and thus, enable long-term access by the research community to the results of European investments.
The overall aim is to further the understanding of the BBB in health and disease states towards the development of innovative brain delivery systems, especially for biopharmaceuticals (e.g., peptides, antibodies, etc.) and the identification of novel disease drug targets (Alzheimer’s Disease, MS, metabolic disease). The related key deliverables will be as follows: 1.Identification and validation of specific genes and/or mechanisms which are altered in brain endothelial cells in disease. 2. Generation, validation and characterisation of robust and predictive iPSC-derived BBB models: The developed models should be more reflective of the in vivo situation than existing models, in the healthy and disease states. 3. New, efficacious and safe mechanisms and technologies of brain delivery: The output of this topic should also result in an expanded and deepened understanding of the fundamental processes that underpin drug-trafficking across the BBB, which in turn can further support endeavours to elucidate novel and more efficacious brain delivery mechanisms. 4. Characterised new genetic models for the diseases of interest in this topic which are better amenable to evaluate disease-modifying agents. 5. Characterised mechanisms of neurotropic virus-mediated BBB and CNS penetration for development of selective brain delivery systems. 6. Established in silico/mathematical models in predicting BBB penetration of therapeutics (such as receptor-or carrier-mediated transcytosis for delivery across the BBB) and pharmacokinetics of biopharmaceutics in different compartments of CNS. 7. Identification of relevant translational readouts which are better amenable to elucidate the role of the BBB in the pathogenesis of neurodegeneration and could eventually lead to new targets for the treatment of the neurovascular causes of the diseases.