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Innovative Fibrosis Medicine Discovery by HDB Comprehensive Collection of Disease Models
Fibrosis, characterized by tissue scarring, is usually chronic and progressive as clinical symptom. It could be caused by diseases, iatrogenic injury or trauma. Those fibrosis-associated diseases include cirrhosis (LF), hepatitis, nonalcoholic steatohepatitis (NASH), chronic kidney disease (CKD), myocardial infarction, heart failure, diabetes, celiac disease, scleroderma and idiopathic pulmonary fibrosis (IPF), etc. The relevant abnormalities affect about one fourth of population in world, but with no such effective drugs available until now. [1, 2]. The establishment and application of animal models related to human diseases have attracted more and more industry’s attention and become an indispensable
part in pathogenesis research and therapeutic drug discovery.
HDB Fibrosis Disease Model Summary
HD Biosciences (HDB), a Biology-focused Business Unit at WuXi AppTec RSD with integrated and comprehensive biology service platforms, has accumulated over 15 years of experience to support clients during research and development. Over the years, we have successfully built many comprehensive service platforms, including fibrosis related disease models and evaluation platform compose of a wide range of animal models, with the endpoints measured from various aspects. Hundreds of projects have been successfully conducted by HDB, with the key results to support clients’ decision making during R&D, as
well IND/CTA application of many innovative medicines crossing the world.
As listed in Table 1 below, our fibrosis models cover liver fibrosis, lung fibrosis, kidney fibrosis, skin fibrosis, peritoneal fibrosis and ocular retinal fibrosis, etc. All pathology and biochemical endpoints are relevant to those appeared as the clinical characteristics. With the advantage of assay technology, especially qPCR, ELISA, western blotting, flow cytometry, LC-MS/MS, etc., the mechanism of drug action and biomarkers can be
evaluated at both protein and gene levels.
Table 1: List of HDB Fibrosis Animal Models and the relevant test parameters
As the cases showing below, data within some typical models are briefly described and shared, i.e. liver fibrosis models from mouse and rat; lung fibrosis model in mouse, the
peritoneal fibrosis model, and few samples of cellular models in vitro.
Case Studies
1. CCl4-induced liver fibrosis in mice
CCl4-induced liver fibrosis model in C57/BL6J mice is well-recognition and widely used. Based on the requirement from our clients, HDB has provided a variety of models with different single dose treatment cycle, from 4 weeks up to 20 weeks, with the different CCl4-induced dose ranges, by co-induction with the specific diets. We have accumulated many practical experience for clients during compound efficacy evaluation for liver fibrosis.
Figure 1. OCA as a positive reference drug, significantly reduces hepatic fibrosis induced by CCl4 in C57/BL6J mice
2. Bile duct ligation (BDL) -induced liver fibrosis in rats
This BDL induced model in SD rats, has been widely used for severe liver fibrosis. Based on the requirements from clients, our HDB refined the surgical steps of bile duct ligation (BDL) and reduced the mortality rate to 10%. This was superior to the mortality rate (50%), which was reported in the literature. The reference drug, Tropifexor, as below, showed
good efficacy.
Figure 2a. Reference drug, Tropifexor, significantly improve liver function by measuring
Figure 2b. Reference drug, Tropifecor, significantly reduced liver fibrosis
3. Bleomycin (BLM) -induced pulmonary fibrosis model in mice
BLM -induced fibrosis in C57/BL6J mice is widely used and very popular for the research in pulmonary fibrosis. After optimization, the mortality of the model was improved, and reduced significantly to <10%, compared to the literature which is 30-50%. The reference
drug, Nintedanib, showed good efficacy as below.
Figure 3. Nintedanib 60mpk PO/QD significantly reduced lung fibrosis in BLM model.
4. Peritoneal fibrosis model induced by chlorhexidine gluconate
By using ICR mice, this model has been recognized and widely used for peritoneal fibrosis. Its stability and high reliability have been demonstrated through our work with clients.
Below, as a typical data after the treatment with TGFβ inhibitors.
Figure 4. TGFβ inhibitors significantly reduced peritoneal fibrosis in a chlorhexidine gluconate-induced mouse model.
5. In vitro cell culture models
In addition to animal models, we have also established in vitro cell models by using human and rodent cells, either primary fibroblast cells or cell line. It becomes more feasible, cost
effective, and more throughput using in vitro platform for drug screening and evaluation.
Figure 5. Antifibrotic effects of compounds by measuring the changes in CTGF gene expression in human hepatic stellate cells (LX-2) and lung fibroblasts (MRC-5) (pre-stimulated with TGF-β1).
If you’re interested in the field of fibrotic disease models, please don’t hesitate to contact us at and connect with our experts for further scientific
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Tel: +86 (21) 5116 3700
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