Translational Models in IBD

Strategic drug development in IBD

A drug development route for success is key but often challenging and full of uncertainties. Strategies that can increase the likelihood of success are vital. The FDA and EMA recognize that biomarker-based drug development strategies could be the solution in combination with translation research. This approach offers a biology-focused pathway that reduces time and cost and enhances the overall likelihood of success.

Nordic Bioscience combines innovative translational models with the Nordic ProteinFingerPrint Technology™ to translate findings effectively. This is facilitated by utilizing the same biomarkers across different clinical stages of development, creating a link between the preclinical model and the clinic. This strategically selected development route greatly enhances the efficiency of drug development pipelines.

In essence, the integration of biomarker-based drug development strategies in translational research not only accelerates the progression of therapeutics but also increases the likelihood of success. Through advanced translational models combined with the ProteinFingerPrint™ biomarkers, Nordic Bioscience contributes significantly to optimizing decision-making processes in clinical development, ultimately ensuring better patient treatments.

Browse our GI biomarkers

Translational biomarkers in gastroenterology research

Our major cornerstone is combining translational models with clinically validated biomarkers to enhance drug development. For this purpose, we have assessed the ability of our biomarkers to bridge the gap between patients with gastrointestinal disease and our various model systems.

Our investigations have revealed that ProteinFingerPrint™ biomarkers, such as the nordicPRO-C3™ (PRO-C3) and nordicC3M (C3M), reflecting tissue formation and destruction, can be modulated by anti-inflammatory treatments.  We have assessed the biomarkers in the supernatants from our in-vitro models, the blood from in-vivo models, and the blood of patients with IBD (Figure 1.) These findings underline the use of the Nordic ProteinFingerPrint TechnologyTM pharmacodynamically and translationally.

Figure 1. Nordic Bioscience’s IBD biomarkers reflect tissue fibrogenesis and mucosal damage

In Vivo—colitis models

Various in vivo models mimicking IBD, such as the acute and chronic dextran-sodium sulphate (DSS) model, represent important translational tools to study intestinal inflammation and fibrosis in vivo. By collecting blood from these animals, intestinal tissue remodeling can be evaluated using the Nordic ProteinFingerPrint™ biomarkers to assess drug efficacy and pharmacodynamic effects in preparation for clinical trials.

In two studies using the acute (Figure 2A) and chronic (Figure 2B) DSS rodent model for the induction of colitis, the biomarkers C3M, PRO-C3 (nordicPRO-C3™), and PRO-C16 were evaluated. In the acute model, DSS induced significant mucosal damage quantified using C3M and PRO-C3 (nordicPRO-C3™). The induction of chronic intestinal damage, an elevation of type XVI collagen and fibrogenesis was observed using the PRO-C16 biomarker.

 

In Vitro Model—Scar-in-a-Jar

The prolonged Scar-in-a-Jar is a novel model that employs macro-molecular crowding to promote extracellular matrix formation, maturation, and deposition in vitro(Figure 3).

The extracellular matrix plays a crucial role in providing structural support to cells and regulating tissue repair and regeneration by acting as a reservoir for growth factors and cytokines.

Understanding the extracellular matrix dynamics is vital for developing therapeutic strategies. Using macromolecular crowding, the model becomes more 3D-like and increases complexity, making it a suitable translational model.

Figure 3. Extracellular matrix remodeling in-vitro Scar-in-a-Jar model

In vitro modeling of intestinal fibrosis

By stimulating intestinal fibroblasts with pro-fibrogenic cytokines, we can model intestinal fibrosis in vitro and evaluate the efficacy of direct anti-fibrotic treatment using the Nordic ProteinFingerPrint™ biomarkers. Thus, we can determine efficacy by measuring collagen formation in the supernatants, allowing direct translation to clinical settings.

 

Figure 4. Nordic Bioscience’s biomarkers demonstrate fibrotic burden and anti-fibrotic effects of compounds

For example, by the addition of TGF-β, IL-6, and soluble IL-6R we can mimic the pathological pathways of systemic sclerosis (Figure 4A), demonstrating differences in the fibrotic burden by quantifying type VI collagen formation (nordicPRO-C6™). Moreover, the anti-fibrotic effects of compounds, such as the JAK-STAT inhibitor Tofactinib (Figure 4B+C), can be evaluated. Here, we demonstrated the anti-fibrotic effects of Tofacitinib inhibiting type III and VI collagen formation, showcasing the biomarkers applicability as efficacy biomarkers in the in-vitro setting.

 

Figure 5. Scar-in-a-Jar (SiaJ) demonstrates fibrogenesis driven by activated macrophages, measured by PRO-C3

  • 1. D’Haens, G., Maddux, R., Wu, C., Hu, Y., Sands, B. E., Mortensen, J. H., Zhang, J., Petersen, A., & Harris, S. (2024). P653 Impact of ozanimod on type III collagen turnover biomarkers and the association with ozanimod efficacy in patients with moderately to severely active ulcerative colitis: Results from the phase 3 True North study. Journal of Crohn’s and Colitis, 18(Supplement_1), i1244–i1245. https://doi.org/10.1093/ecco-jcc/jjad212.0783

    2. Lindholm, M., Manon-Jensen, T., Madsen, G. I., Krag, A., Karsdal, M. A., Kjeldsen, J., & Mortensen, J. H. (2019). Extracellular Matrix Fragments of the Basement Membrane and the Interstitial Matrix Are Serological Markers of Intestinal Tissue Remodeling and Disease Activity in Dextran Sulfate Sodium Colitis. Digestive Diseases and Sciences, 64(11), 3134–3142. https://doi.org/10.1007/s10620-019-05676-6

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