Project: Preclinical Efficacy Models for Osteoarthritis To Repair Articular Cartilage

Human osteoarthritis (OA) is a heterogeneous disease that includes degeneration of the joints. OA is a complex process that involves multiple changes in joint structure and turnover. OA is characterized by progressive destruction of articular cartilage and articular structures, such as bones, synovial and fibrous joint capsules, and the destruction of peri-articular muscles. _x000D__x000D_Cartilage has limited repair capabilities. Since chondrocytes are bound in lacunae they cannot migrate to damaged areas. Therefore, if cartilage is damaged, it is difficult to heal. Also, because hyaline cartilage does not have a blood supply, the deposition of new matrix is slow. Damaged hyaline cartilage is usually replaced by fibrocartilage scar tissue. The current approach to therapy is the use of bioengineering techniques to generate new cartilage, using cellular "scaffolding" material and cultured cells to grow artificial cartilage. However, the problem in the current approach is that the industry lacks understanding of the complete developmental and organisational processes of cartilage. Therefore, the cell lines that are used currently are irrelevant because they address calcified cartilage, while the real problem in OA sufferers is articular cartilage damage._x000D__x000D_Due to the heterogeneous nature of OA, no animal model fully resembles the human disease. Different models have their own merits for evaluation of certain elements of human OA. The mechanisms of OA are believed to involve both mechanical and chemical inflammatory processes, so models for both of these should be developed. There are several different models that have been described in the literature, and the goals of this project are to test several different models and find the most optimal chemically and surgically induced models that can be offered commercially. After this has been determined, the selected models will be optimized and validated._x000D__x000D_Currently, the only drugs available on the market are designed to treat the symptoms (e.g. pain, inflammation, joint stiffness), but no disease modifying OA drugs (DMOADs) are available. A complete lack of relevant preclinical models for OA has been a burden in this healthcare area. Percuros and Pharmatest hereby put forward a proposal for developing new preclinical efficacy models and markers for OA to address the needs of OA patients and pharmaceutical industry developing DMOADs. Models that will be developed include in vitro assays transplanted to in vivo assays for studying articular cartilage with more relevance to the pathology of osteoarthritis, an ex vivo metatarsal assay for studying the process of skeletal development with a focus on articular and growth plate cartilage, and chemically induced and surgically induced small animal models of OA. _x000D__x000D_Our proposal will address these unmet needs with innovative tools which include 1) a chondrocyte mesenchymal progenitor cell line 2) a recent, newly derived immortalised murine chondrocyte cell line with a doublecortin (DCX) - red fluorescent protein (RFP) gene reporter to distinguish articular cartilage 3) a transgenic DCX-RFP gene reporter mouse and methods to induce OA both chemically and surgically in vivo 4) further novel biomarkers for cartilage differentiation, one of which is a putative therapeutic target for Percuros. _x000D__x000D_Tools that have already been derived from our ongoing studies are now being proposed to be developed further for OA. These will have a particular impact on how the industry will look at the quality of and ability to distinguish articular over non-articular cartilage, and how to develop relevant OA biological models and screening assays. _x000D__x000D_Such models would a) help the pharmaceutical industry to develop novel therapeutic interventions for OA that would repair articular cartilage and b) bring an understanding of the mechanism of action of both articular cartilage growth and degradation. _x000D__x000D_This project will be performed by two Ps, Percuros in The Netherlands led by the CEO, Dr. Alan Chan and Pharmatest in Finland led by the CEO, Dr. Jussi Halleen. Percuros will use the expertise of Prof. Clemens Lowik's research group at Leiden University Medical Center (LUMC), The Netherlands. Pharmatest will use the expertise of Prof. Kalervo Väänänen's group at the University of Turku (UTu), Finland. Both LUMC and UTu will be subcontracted to perform some parts of the work. Percuros would use the models primarily in their own OA drug development, and Pharmatest for offering them as contract research services to the pharmaceutical industry._x000D_

Acronym	PORAC (Reference Number: 5257)
Duration	01/04/2010 - 31/03/2013
Project Topic	The goal of this project is to develop preclinical efficacy models for osteoarthritis (OA) that would be relevant for the pathophysiology of adult human articular cartilage and human OA. Our proposal addresses an unmet need which would characterize the progressive destruction of articular cartilage.
Project Results (after finalisation)	New preclinical test models of osteoarthritis
Network	Eurostars
Call	Eurostars Cut-Off 3

Project partner

Number	Name	Role	Country
2	Percuros	Coordinator	Netherlands
2	Pharmatest Services Ltd	Partner	Finland