Project: Development of non-human primate models for preclinical assessment of osteoarthritis treatments

Inflammatory osteoarthritis (OA) is characterized by painful and destructive inflammatory flares of a single joint, COly at the back, knees, wrists or hips. In industrialized countries, more than 150 million patients suffer from some form of joint pain of osteoarthritic or arthritic origins. Today there is no available cure for OA and current treatment goals are COly focused on reducing pain and limiting functional impairment. Two classes of intra-articular injectable products are currently commercialized for OA: corticosteroids and hyaluronan preparations. Conflicting results are reported in the literature concerning their use with some implying little benefit and others showing excellent results. For example, if the short-term benefits of intra-articular corticosteroids in mono-arthritis flares are well established, their longer term benefits have not been confirmed._x000D_We are of the opinion that the development of effective treatments for OA has been partially hindered by the lack of both robust preclinical models – relevant to human – and sufficiently sensitive techniques to probe early stage of OA evolution. Many models of induced OA are described in literature, most of them in small animals. The limitations of these models, in adequately mimicking a condition as complex as human OA, need to be fully considered. Indeed, these models are rather ineffective in evaluating new treatments and especially in transposing observations to human disease considering the big genetic, phenotypic and pathophysiological heterogeneity between human and rodent. _x000D_OA that closely resembles the human condition occurs naturally in primate. The histological lesions of OA in human and monkey knee joints include articular cartilage fibrillation and clefting. These lesions coincide with an increase in the thickness of the subcondral bone plate in both species and it has been suggested that this thickening may precede cartilage breakdown. These similarities make that these animals are useful to model the human disease. Nevertheless, spontaneous OA appears in monkeys as a function of age making this model less usable due to the long time necessary to obtain OA lesions. _x000D_Because of that, we propose, in addition to the naturally occurring OA model in aging primate, to develop a chemically induced OA model in adult primate that hopefully could be available much more quickly._x000D_Histology or biochemical assays are considered as gold standard to evaluate articular cartilage changes during OA. However, they are time-consuming, destructive and do not give three-dimensional (3D) information. Non invasive techniques to measure and qualify in-vivo the cartilage thickness in animal model of OA has been developed and have greatly improve existing strategy to assess OA treatments and cartilage repair strategies. Established reproducibility confirmed that 3D HR-MRI could directly assess the cartilage thickness on guinea pigs and recent instrumental developments demonstrated that volume quantification in the different compartments of the cartilage can be achieve on rat models of OA. Nonetheless, 7T µMRI techniques (only usable on animal model smaller than the rabbit) are very challenging due to relatively limited spatial resolution compared to other modalities. Based on these considerations we plan to develop a µ-CT imaging technique (known as X-ray arthro-scanner in human medicine) adapted to primate model of OA to achieve a ten time more sensitive description of the cartilage layer. Moreover this new technique will be relevant also to tackle other OA associated clinical symptoms such as sub-chondral bone mineral content reduction. _x000D_PRIM-OA will be structured in two work-packages, corresponding respectively the development of new primate models of OA and of new µCT based imaging techniques (WP1) and the validation by real drug (i.e., regenerative treatment) testing (WP2) . Each WP will be itself divided in a series of tasks supported on the basis of specific know-how and technical skills of each P._x000D_The objective of WP1 is to develop and characterise a new preclinical model of OA and to develop and validate with respect to 7T µ-MRI the µ-arthroscanner technique. It is subdivided in 3 tasks: _x000D_1) Investigation of spontaneous osteoarthritis in old primates._x000D_2) Development of the µ-arthroscanner method and result cross-correlation with µ-MRI technique _x000D_3) Development of a chemically induced model of OA in young primate. _x000D_The objective of WP2 is to validate by real drug testing these new models using OA treatments based on known therapeutic approaches but also using innovating treatments aiming at restoring, the integrity of the joint. It is subdivided in 2 tasks: _x000D_1) Assessment of the efficacy of conventional and new intra-articular therapeutic approaches on the new preclinical model. _x000D_2) Assessment of the efficacy of cell therapy on the new OA model developed. As consequence, this second task implies the development of articular cell therapy_x000D_

Acronym	PRIM-OA (Reference Number: 5671)
Duration	01/09/2011 - 30/04/2013
Project Topic	The aim of PRIM-OA project is to provide the first structurally but also clinically relevant preclinical model of OA. This project will be structured in two work-packages, corresponding respectively to the development of a new primate model of OA and to its validation.
Project Results (after finalisation)	During this project, Bone Therapeutics has optimized a chemically induced model of OA in rats (MIA intra-joint injection). This was confirmed by knee joint histological analysis. This model will be used to assess the effectiveness of the new products that Bone Therapeutics is developing to treat OA._x000D_Moreover, one of Bone Therapeutics product has been tested on the non-human primate (NHP) model which was developed by the French Ps. The obtained results are encouraging as the product seems to be more efficient that the commercialized one to reduce the loss of cartilage (as seen by imagery) and might slow down the venue of OA (as seen by the Department of Rheumatology - ULB with the biomarker analysis). However, more data are needed to confirm these results: histological analysis, detailed individual imagery data (not yet given by the French Ps)… _x000D_
Network	Eurostars
Call	Eurostars Cut-Off 4

Project partner

Number	Name	Role	Country
5	Bone Therapeutics	Partner	Belgium
5	Cynbiose SAS	Coordinator	France
5	The Laboratory of Rheumatology of Erasme Hospital, Université Libre de Bruxelles	Partner	Belgium
5	Université Claude Bernard Lyon 1	Partner	France
5	Voxcan sarl	Partner	France