Characterization and novel therapeutic options for pigmented villonodular synovitis – PVNS

Thus, this project aims to first explore the mechanisms leading to the development of synovitis using high-throughput technologies (WP1). The recent development of cell-level studies methods will allow us to identify abnormal fibroblastic cells, dissect the phenotype of inflammatory cells (mostly macrophages) and characterize the associated pathological vasculature. Using synovial tissue from patients with PVNS, we will study the key factors involved in the communication between these cells in order to identify new therapeutic targets. We then wish to evaluate in vitro the biological activity of several drugs, in particular those targeting the CSF1 pathway, on tissues from patients with PVNS (WP2). For this, we will use tissue from patients included in our cohort (cell culture, explants or organoids) to better understand the effects and mechanisms of action of treatments and to explain the heterogeneity of responses observed between patients. We hope that this will be the first step towards the development of personalized medicine in PVNS. Finally, our goal is to be able to rapidly transfer our discoveries for the development of new treatments for the patient. For this, relevant animal models of the disease are
needed. We have already set up and will develop different complementary animal models of the disease to evaluate the in vivo efficacy of drugs targeting CSF-1 and new therapeutic
targets. The interest of using local delivery systems of molecules will also be evaluated (WP3).

PVNS is a rare but debilitating disease with no current curative therapy. Despite a better understanding of the pathophysiology of the disease, most of the patients underwent multiple surgeries and are treated with systemic treatment with partial efficacy and poor tolerance. Our approach is original as we will use high throughputs technics to better characterize the cells to find new potential therapeutic targets. We will use in vitro explants and cells and original animal models to study the efficacy and mode of action of CSF1 drugs as well as treatments targeting the inflammatory or vascular compartment. We will also develop new local delivery modes. Our translational project is therefore in line with the 2020 Generic call and CE17 objectives as it aims at a better understanding of the pathophysiology of PVNS to develop new therapeutic targets and delivery.

The PVNS project is particularly innovative, with a multidisciplinary combination of expertise ranging from clinical expertise, biology, the physiopathology of PVNS conditions, the design of local drug delivery systems, and translational research.
The emergence of high-throughput technologies has transformed the way we approach and understand diseases pathophysiology. To date, very few studies have focused on a multimodal characterization of the synovial tissue in PVNS. It remains a heterogeneous disease in terms of causal mutation, phenotype, aggressiveness and prognosis. The expertise of the 3 teams will be combined to characterize in depth the synovial tissues of the patients at the genetic and cellular level (proteins, gene expression, intercellular communication). The combination of these data with the clinical evolution and therapeutic responses will probably modify the way with understand this disease. These results could also be useful to other synovial pathologies such as inflammatory or crystal related rheumatic diseases.

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Pigmented villonodular synovitis (PVNS) is a rare joint disease with an estimated incidence of 14 per million per year. Most PVNS are diagnosed between 20 and 50 years and affect large joints. PVNS is a benign proliferative lesion arising from synovia that results in a secondary inflammatory joint response, pain and destruction. PVNS is associated with abnormal fibroblastic cells, often involving a specific chromosomal translocation resulting in the overexpression of colony-stimulating factor 1 (CSF1 or M-CSF), recruitment of CSF1 receptor (CSF1R) macrophages and fusion in giant cells. PVNS is the articular form of tenosynovial giant cell tumor (TGCT). Most of the synovial tissue is infiltrated by inflammatory cells (mostly macrophages) that drives the synovium hypertrophy and hyperplasia leading to the symptoms and joint destruction. PVNS shows clinical, histological and genetic similarities with rheumatoid arthritis. Surgery remains currently the first line therapy in most patients. However, if it may be curative in nodular forms, it is much more complex in diffuse forms inducing potential joint sequelae. In recent years, systemic treatments have been used in addition to surgery with their main target being the CSF-1 pathway. However, despite therapeutic options such as surgery and/or systemic treatments, the risk of recurrence of synovitis remains high, estimated at more than 50%. Thus, PVNS continues to have a major impact on the quality of life of patients. There is currently a clear medical need to improve the management of patients with new systemic treatments, or better, local injections. For this, a better understanding of the pathophysiology of the disease, the identification of new therapeutic targets and the evaluation of the efficacy of new therapies in relevant preclinical animal models are required. Thus, this project aims to first explore the mechanisms leading to the development of synovitis using high-throughput technologies (WP1). The recent development of cell-level studies methods will allow us to identify abnormal fibroblastic cells, dissect the phenotype of inflammatory cells (mostly macrophages) and characterize the associated pathological vasculature. Using synovial tissue from patients with PVNS, we will study the key factors involved in the communication between these cells in order to identify new therapeutic targets. We then wish to evaluate in vitro the biological activity of several drugs, in particular those targeting the CSF1 pathway, on tissues from patients with PVNS (WP2). For this, we will use tissue from patients included in our cohort (cell culture, explants or organoids) to better understand the effects and mechanisms of action of treatments and to explain the heterogeneity of responses observed between patients. We hope that this will be the first step towards the development of personalized medicine in PVNS. Finally, our goal is to be able to rapidly transfer our discoveries for the development of new treatments for the patient. For this, relevant animal models of the disease are needed. We have already set up and will develop different complementary animal models of the disease to evaluate the in vivo efficacy of drugs targeting CSF-1 and new therapeutic targets. The interest of using local delivery systems of molecules will also be evaluated (WP3). Our consortium, thanks to the expertise of each partner, will allow us to study this disease from different and complementary angles and could lead to major discoveries in PVNS.