Better and cheaper drugs in less time: Aarhus University and industry are joining forces in six new open research collaboration projects
ODIN has reserved DKK 23.9 million for six new research projects that will pave the way for new drugs to treat a wide range of medical conditions – e.g. Parkinson's disease, schizophrenia, diabetes, renal diseases and cancer.
- Biomarkers can be measured with certainty and they can tell us about the state of an organism. Biomarkers can be anything from molecules, enzymes and other proteins, cells, intestinal bacteria, DNA and RNA, to MR and CT scans and X-rays
- Targets include receptors, enzymes or other specific proteins, as well as DNA, RNA and lipids.
In the quest for biomarkers and targets, efforts are complicated by the fact that biomarkers and targets cannot always be “translated” from laboratory animals to humans or from human cell cultures in the lab to the entire organism.
Despite substantial progress, medical researchers and the pharmaceutical industry are still working hard to find reliable biomarkers and targets for a number of medical conditions and treatments (see Fact box), and to develop new methods of analysis to identify and verify them.
The aim is not only to develop better drugs; it is very much also to accelerate the process and lower the costs.
The reason is that, even though they seem promising in the lab, many new drug candidates fail when, finally and after a long and challenging process, they enter the clinical trial phase. This is a waste of time and money for industry as well as society, because it adds to the costs and slows down the introduction of the new drugs that doctors and patients are waiting for.
Six new research projects, with funding totalling DKK 23.9 million from ODIN (the Open Discovery Science Network), will respond to these challenges by developing solutions in the form of new and better knowledge bases that are unpatented and freely accessible to everyone. The six projects have been selected from among 13 applicants in this round, which is the second round after the Novo Nordisk Foundation granted DKK 54.5 million to the ODIN pilot project in February 2020.
A fundamental requirement for the research projects is that they generate broad value – i.e. benefit more than just the individual company – and that the results are shared with the public. The road through the eye of the needle first passed through a project assessment committee, then an international panel of experts, and finally the ODIN steering committee, who chose the most promising projects.
Below is a presentation of the six projects and their participants. Names of project managers are in bold:
Fresh Human Kidney Tissue: Exploring biomarkers and intervention targets in chronic kidney disease (FRIGG)
need: Long-standing, progressive deterioration of renal function, or chronic kidney disease (CKD), affects 10-15% of the adult population and is a major socioeconomic burden. The incidence and prevalence of CKD is increasing concurrent with the increase in diabetes, hypertension, obesity and longer lifespan. There is an urgent, unmet need for:
- Translatable targets to treat CKD and reduce disease progression
- Model systems for intervention strategies that bridge laboratory testing and patients in order to increase translatability.
- Biomarkers that accurately detect CKD (at early stages) and predict the risk of progression.
Using fresh, live human kidney slices (HKS) forced into archetypical CKD disease processes, fibrosis and inflammation, the team aims to 1) Profile downstream molecular and cellular changes involved in CKD development and progression and thus, suggest novel targets, 2) Evaluate translatability between the HKS CKD model and a mouse CKD model and 3) Explore biomarkers to detect CKD earlier and predict disease progression.
Live HKS in combination with the most advanced OMICs platforms will provide unprecedented detail into critical pathophysiological processes that drive CKD and generate an openly-accessible platform, which can be used to classify human CKD-associated pathways. Moreover, the team will provide insight into cross-species translatability between human and mouse. Success criteria/output: Increased knowledge of human renal physiology and of the early stages of human CKD as well as identification of potential CKD biomarkers and targets.
The success criteria is Increased knowledge of human renal physiology and of the early stages of human CKD as well as identification of potential CKD biomarkers and targets.
Relevance to Industry: CKD is a central focus area for numerous pharmaceutical companies who will gain fundamental knowledge of human renal physiology as well as mechanisms driving early CKD development and progression and insights into the translatability between HKS and mouse KS as well as identification and classification of pathways that drive CKD across the different species. This project will be of interest to renal physiologists, clinicians and companies working directly or
indirectly with CKD. Openness:
FRIGG will not be possible in a closed, contracted setting. Multiple OMIC datasets will be generated and deposited in relevant databases making the data rapidly available to both interested academia and companies.
- AU: Rikke Nørregaard and Lene N. Nejsum, Department of Clinical Medicine,
- AU: Lin Lin, Department of Biomedicine,
- AU: Rick Mutsaers, Department of Clinical Medicine
- AU: Jørgen Kjems, iNANO/Department of Molecular Biology and Genetics
- AU: Gitte Albinus Pedersen, Department of Clinical Medicine
- AU: Camilla Merrild, Department of Clinical Medicine
- Novo Nordisk A/S: Peter Helding Kvist and Agnès Bènardeau
- AstraZeneca AB: Pernille Lærkegaard Hansen and Timo Haschler
- Nordic Bioscience A/S: Federica Genovese and Daniel Guldager Kring Rasmussen
Identification of biomarkers in the human psychiatric brain - focusing on non-coding RNAs and sex differences (BioPsych)
Mental disorders, like schizophrenia (SZ), bipolar disorder (BD), and depression (DE) are leading causes of disability worldwide. The diagnoses are based only on symptoms, which is problematic, as these are partly overlapping. Sex differences in prevalence, symptoms, and responses to treatment have also been reported, supporting the complexity of the disorders.
Therefore, there is an unmet need to identify biomarkers. This project will identify RNA targets that can bind radiotracers for in vivo imaging and function as leads for innovative stratified treatment. The team is highly interdisciplinary, where in-depth knowledge about the human brains and neurological diseases are combined with expertise in non-coding RNA (ncRNA) sequencing, in situ hybridization (ISH), and in vivo imaging.
The strategy is to identify deregulated ncRNAs, such as microRNA (miRNA) and circular RNA (circRNA) in core brain areas of psychiatric disorders (hippocampus and prefrontal cortex) using unbiased profiling.
The brain tissue stem from patients (60 males/60 females) diagnosed with SZ, BD and DE from the Human Brain Bank in DK. Proof-of-concept unbiased profiling of miRNA has been conducted and data will be available for the project, ensuring a successful outcome of the proposed project. In collaboration with Omiics, deregulated circRNAs will be identified. Candidate top-5 lists with miRNAs and circRNAs will be generated distinguishing between diagnoses and sex differences. In collaboration with Bioneer, ISH will be performed using state-of-the-art techniques. Based on the ISH results two superior miRNA/circRNA biomarkers will be selected. Anti-miRNA and anti-circRNA will be radiolabeled and tested in vitro followed by ex vivo rat distribution studies. Finally, in vivo pig emission tomography studies will be conducted. The project will create value for a broad audience by 1) providing knowledge about techniques, that can be used to develop solutions for other disease groups and 2) identifying putative ncRNA targets, therapeutically relevant for e.g. Lundbeck and RICC.
Hence, the project will benefit from an open research platform where any company can buy-in on a particular field of use, and the gained knowledge can be translated into novel treatment regimes by involvement of additional experts in a commercialized environment
- AU: Betina Elfving, Translational Neuropsychiatry Unit (TNU), Department of Clinical Medicine
- AU: Jørgen Kjems, iNANO/Department of Molecular Biology and Genetics
- AU: Lasse S. Kristensen, Department of Biomedicine
- AU: Dirk Bender, Department of Clinical Medicine
- AU: Erik Kaadt, TNU, Department of Clinical Medicine
- omiics Aps: Morten Venø
- Bioneer A/S: Boye Schnack Nielsen
Bayesian AnaLysis of Diabetes for Enhanced biomarkeR and drug target (BALDER)
Type 2 diabetes mellitus (T2DM) is a common disease with a prevalence in Denmark of 250.000 diagnosed patients. T2DM has a strong underlying genetic component; for example, having a parent with T2DM, your risk is approximately 40%.
Genetic variants associated with T2DM currently only explain 3% of the disease risk. Increased power to detect variants is mainly obtained by increasing sample size, or – as the team propose – better use of existing data. The team will increase detection power by developing a multitrait and multi-component Bayesian Linear Regression (MT-BLR) model that combine information on multiple correlated traits and information on groups of genetic variants located within functional units (e.g., pathways).
Their modelling approach allow better use of existing data such as functional marker information in biological databases, and availability of large independently collected genotype and phenotype data sets for a range of diseases, including T2DM. The team will use these existing data to develop statistical models that better use information on correlated traits and disease for detecting genetic signals underlying T2DM. The team anticipates that their modelling approach will generate novel biological insight into T2DM disease aetiology. Importantly, the discovery of novel genetic markers associated with T2DM can help identify potential drug targets for T2DM including genes and regulatory elements located nearby disease-associated variants or biological pathway. The team will gather this information in a database for T2DM for genomic informed drug target identification, and the corresponding statistical methodologies will be implemented in open-source software packages allowing for open sharing with other research groups in academia and the pharmaceutical industry.
While the focus in this project is on improving the drug target discovery process, the team’s modelling approach can also be used for developing more accurate genetic risk predictors for complex diseases. The team is convinced that their novel statistical modelling approaches and genomic informed drug target identification strategy can be applied to other complex diseases (e.g., cardiovascular disease) contributing to the identification of potential drug targets for a range complex diseases.
- AU: Peter Sørensen, Center for Quantitative Genetics and Genomics
- AU: Mads Fuglsang Kjølby, Department of Biomedicine, Department of Clinical Pharmacology and Steno Diabetes Center, Aarhus University Hospital.
- Novo Nordisk Research Centre Oxford: Dr. Joanna Howson, Senior Director Genetics
Optimization of cell-penetrating peptides to enable therapeutics with intracellular targets (P2P CPP)
In 2009, there were 25 FDA-approved biologics. Ten years later, almost 300 biologics accounted for seven of the ten top-selling drugs in the US. This success is despite biologics being confined to targets outside the cell, which account for only about a third of the proteome. Numerous bioactive molecules with therapeutic potential have been developed for intracellular targets. Still, if the drug is unable to pass the cell membrane, like, e.g., most peptides and nucleic acids, it will never reach its target. Thus, there is a huge unmet need for methods that make the majority of the proteome, the intracellular targets, drugable by biologics.
An extensively studied way for macromolecules to reach the cytoplasm is to conjugate them to a small cell-penetrating peptide (CPP). This method is simple to use and safe and effective in cultures, but no CPP-conjugated drug has yet obtained marketing approval despite its great potential. In contrast to cell culture studies, intravenously injected conjugated CPPs have shown acute toxicity.
The team has developed two initial assays using physiologically relevant concentrations and timescales to reflect the toxicity, determining a reversible inward current and induction of vasodilation in a rat resistance artery. By testing an array of CPP conjugates, the team will look for a correlation between the peptide physicochemical properties and its safety profile. The first success criterion will be to determine if their in vitro assays are indeed predictive of toxicity. That would enable improved safety, and, ultimately, the best possible direct outcome would be a CPP-based novel cancer therapy.
The project is, in its essence, an open collaboration initiated by STipe when they recognized the need for an improved basic molecular and physiological understanding of how CPPs work. Frequent meetings between the applicants representing pharma, the toxicology testing industry, and two academic faculties have let the team to develop their current assays and hypotheses. The academic objective is to gain a molecular understanding of how (conjugated) CPPs penetrate the membrane, and what effects that has on the cell, the organ, and the organism. For pharmaceutical companies, this would lay the groundwork for toxicological testing and developing biologics for intracellular targets and thus novel treatments of, e.g., inflammation, diabetes, and cancers.
- AU: Hanne Poulsen, Department of Molecular Biology and Genetics
- AU: Ulf Simonsen, Department of Biomedicine
- AU: Daniel Otzen, iNANO/Department of Molecular Biology and Genetics
- STipe Therapeutics ApS: Claus Olesen and Richard Bethell
- ApconiX Ltd: Michael Morton
Immune-related biomarkers and targets in Parkinson's disease (IMPAD)
Parkinson’s disease (PD) is characterized by a-synuclein (asyn) aggregates in neurons and immune activation. PD has no cure, and therapeutic development is limited by the lack of novel targets and the absence of good accessible biomarkers that can be used for diagnosis and assessment of PD progression.
The team aim to define immune related biomarkers in blood that can be used as proxies for brain events, markers of progression and possible targets in PD; while in parallel assessing the translational potential of PD models for future pre-clinical studies. Team data suggest that peripheral immune cells and proteins change during PD stages in association to brain events, and also influenced by sex. The team has recently proposed two PD subtypes with different site of onset and progression (body-first & brain-first), which they hypothesize have distinct immune differences. But little is known about which factors in the peripheral immune system plays a role in PD and how immune changes correlate to PD subtypes, stages or sex.
IMPAD will analyze the transcriptome of immune cells by single cell sequencing and characterize immuneassociated proteins using a novel aptamer based proteomic method, APTASHAPE, in blood from differently affected PD patients. The cohort will be clinically evaluated and neuronal integrity analyzed by PET to determine PD subtypes and stages. The data from blood will be correlated to clinical and PET scores to identify novel biomarkers and putative targets that can later be tested in pre-clinical models.
In parallel, the academic partners and H.Lundbeck A/S will jointly analyze the immune response in an asyn based PD rat model and human iPSC-derived microglia, and by comparing datasets across our complementary studies identify common pathways in animal and human systems thus validating the models for further studies.
IMPAD will describe translatable biomarkers across patients and PD models and define specific biomarkers to support development of new drugs for disease-modifying treatments. The data will be of interest for companies focusing on PD, synucleinopathies and other brain diseases and the interplay with the immune system; aiming to develop diagnostic tools and interested in PD personalized medicine. The open sharing approach by clinicians, basic scientists and pharma, will secure efficient progression of knowledge towards patient care.
- AU: Marina Romero-Ramos, Department of Biomedicine
- AU: Per Borghammer, Department of Clinical Medicine
- AU: Jørgen Kjems, iNANO/Department of Molecular Biology and Genetics
- AU: Sara Almeida Ferreira, Department of Biomedicine
- AU: Ankita Singh, Department of Biomedicine
- H. Lundbeck A/S: Karina Fog, Director of Cell Biology, Neuroscience
Advanced 2D cell culture for improved phenotype assays (CELPPLUS)
This project addresses the relevance of in vitro assays used for early drug screening by developing a technology based on ligand patterns to allow 2D culture assays with better phenotype.
Importantly a proof of principle of the application will show the potential market and kick-start future closed projects (cell culture manufacturers and pharma companies).
The objective of this project is to demonstrate a novel 2D cell culture technology for improving the phenotype of cell assays for early drug discovery and target exploration. Better early high throughput assays will contribute to better candidates and reduced fall out during pre-clinical and clinical trials.
In vitro culture technologies try to mimic in vivo components to allow screening/identification of drug candidates in high throughput. Increased complexity of culture, e.g. 2D, 3D, spheroid/organoid can improve phenotype but at the cost of readout speed/quality. Recent scientific advances in the field of biomaterials utilize micro and nanopatterns of ligands to better represent the in vivo microenvironment in 2D culture.
Here, these approaches will be made available in a 96 well format and demonstrated for improving the phenotype of 2D assays by improving a current assay at Leo Pharma A/S in the area of skin inflammation. The phenotype of the primary human keratinocytes will be monitored by the expression of biomarkers and single cell RNA seq and compared to existing in vivo data and the original assay.
Success in this project will demonstrate robust and generic cell culture technology to display patterns of ligands in a 96 well plate format and provide proof of principle of the application to improve the phenotype of 2D assays with a collaboration between Leo Pharma A/S and two faculties at AU.
The value creation for pharmaceutical companies will be realized with the future development and use of better assays in a broad range of disease areas. This open project will enable closed scale up projects between manufacturers/pharma.
- AU: Duncan Sutherland, iNANO
- AU: Claus Johansen, Department of Clinical Medicine
- Leo-Pharma A/S: Christine Brender Read