Our current R&D program within Predictive 3D Cell Models will use three-dimensional (3D) cell culture technologies to design and generate highly relevant models for liver toxicity and cancer models for investigating Mode-of-Action of cancer drug candidates. 3D Bioprinting will be implemented as a key technology to generate highly reproducible 3D models relevant for industrial use.
The R&D groups involved in the activities of Predictive 3D Cell Models are located both at the Bioneer:FARMA unit at the Department of Pharmacy at University of Copenhagen in Copenhagen as well as the Bioneer headquarter facilities in Hørsholm. Thus, having access to all central infrastructure, instruments and technologies essential for the pharmaceutical R&D programs including the gene editing and iPSC core facility.
Predictive 3D Cell Models
Using as in vivo-like models as possible early on in the drug development will lead to an accelerated drug development process. By having access to 3D bioprinted human cell models, the effects and safety of different pharmaceutical drugs can be documented in a setting that will provide the prerequisites to better predict and assess a drug’s potential.
Bioneer will implement and develop a range of different technological platforms within 3D cell modelling including 3D cell bioprinting. Within the coming years, Bioneer will establish the necessary generic technological competences as well as infrastructure for 3D cell and tissue printing.
Bioneer will develop complex 3D cell models that mimic the microenvironment in cancer tumors for testing the effects of different pharmaceutical drugs and immune therapies and their Modes of Action. The tumor models will initially be based on cells from healthy donors, subsequently different specialized and tumor-infiltrating immune cells from patients will be used. The 3D cancer model will be analyzed via immunohistochemistry and flow cytometry, and validated with known cancer drugs like checkpoint inhibitors as well as cell therapy products.
Bioneer will continue on the long track record of working with induced pluripotent stem cells, and will with this R&D activity establish a 3D liver cell model to measure drug metabolism and toxicity. The model will include different variants of the CYP450 enzyme, resembling the differences of CYP450 activities seen in different population groups. Bioneer will perform a full analysis of structure and functionality of the model, and through bioprinting the value of other supporting cell types included to promote maturing can be investigated. Furthermore, Bioneer:FARMA will develop a 3D liver model based on primary cells from rodents, to investigate the transportation of drug substances in liver cells.
Bioneer has large experience in building neurodegenerative models based on patient specific induced Pluripotent Stem Cells (iPSC). To advance these models to express more mature in vivo like phenotypes, differentiation in 3D organoid structures are exploited.
Several Alzheimers disease (PSEN1, APP, APOE) and frontotemporal dementia (MAPT, CHMP2B, GRN) models are being perused. In addition, to enhance the differentiation to specific neuronal subtypes, Bioneer is utilizing systems based on controlled expression of specific transcriptions factors.
Gene editing technology has turned out to be the new breakthrough in tailored DNA engineering for research and target validation. Using custom designed and sequence specific double DNA strand cutting enzymes, like the CRISPR/CAS9 system or TALENs, gene engineering in human cells has become an elegant tool to generate new disease models. Bioneer has during the last few years build a whole collection of isogenic cell lines to study the phenotype of disease causing mutations. Many of these lines are stored in the European Bank for induced pluripotent Stem Cell, EBiSC.
> Cryopreservation and Large-Scale Screening
Bioneer has initiated a strategic collaboration with Frauenhofer Institute for Biomedical Engineering to implement solutions covering needs for automated processing of living cells by jointly developing technology for storage and large-scale automated cell based screening in 3D.
> European Bank for Induced pluripotent Stem Cells
Bioneer has since 2014 been part of the European Bank for induced pluripotent Stem Cells (EBiSC). EBiSC is a large European public-private partnership project coordinated by Pfizer Ltd and managed by Roslin Cells Siences Ltd. and supported jointly by the Innovative Medicines Initiative (IMI) and members of the European Federation of Pharmaceutical Industries and Associations (EFPIA). The purpose of EBiSC is to establish a robust, reliable supply chain from the generation of human iPS cell lines, covering many different diseases. The bank builds on internationally accepted quality criteria and their resources are available worldwide to any qualified user. Read more here.
Bioneer is part of BrainStem, which has been granted 24 MDKK by the Innovation Fund Denmark and will do research in neurodegenerative diseases over a 6 year period – from 2015 until 2020. BrainStem is a Stem Cell Center of Excellence in Neurology. To learn more about the project, read here.
Rasmussen, MA., Holst, B., Tümer, Z., Johnsen, MG., Zhou, S., Stummann, TC., Hyttel, P., Clausen, C. (2014) Transient p53 Suppression Increases Reprogramming of Human Fibroblasts without Affecting Apoptosis and DNA Damage. Stem Cell Reports 3, 404-413
EBiSC, Innovative Medicines Initiative project:
De Sousa PA. et al. (2017) Rapid establishment of the European Bank for induced Pluripotent Stem Cells (EBiSC) – the Hot Start experience. Stem Cell Research 20, 105-114
- Zhang, Y., Schmid, B., Nikolaisen, NK., Rasmussen, MA., Aldana, BI., Agger, M., Calloe, K., Stummann, TC., Larsen, HM., Nielsen, TT., Huang, J., Xu, F., Liu, X., Bolund, L., Meyer, M. Bak, LK., Waagepetersen, HS., Luo, Y., Nielsen, JE., The FReJA Consortium, Holst, B., Clausen, C., Hyttel, P., Freude, KK. (2017) Patient iPSC-Derived Neurons for Disease Modeling of Frontotemporal Dementia with Mutation in CHMP2B. Stem Cell Reports 8, 1-11
- Ochalek et al. (2017) Neurons derived from sporadic Alzheimer’s disease iPSCs reveal elevated TAU hyperphosphorylation, increased amyloid levels, and GSK3B activation. Alzheimer’s Research & Therapy 9:90
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