Therapeutic innovations in SSc

In this part, we want to rely on our models to assess innovative treatment targeting inflammation and firbosis in this incurable disease. We plan to assess the role of extracorporeal photopheresis (ECP) in the treatment of fibrosis in an experimental model of systemic sclerosis. ECP is an immunomodulatory procedure based on in vitro 8MOP photosensitization and UV-A irradiation of patient’s PBMC, leading to cells apoptosis. Here, we propose to assess ECP efficacy in mouse model of SSc induced by HOCl. ECP impacts on inflammation, fibrosis and immune system dysregulation induced by HOCl will be assessed at different stages of the disease, by histological, cytometric and transcriptomic methods. The use of this animal model will permit us to test different treatment strategies, such as different timepoints of injection of the ECP-treated cells, different number of injections, and different sources of irradiated cells (i.e., from healthy or from HOCl-treated mice). We also aim to study the ability, in mice, to mount an antigen specific immune response during the ECP procedure. The results will clarify the role of ECP in SSc, the kinetic of therapeutic strategy in patients and will help to better understand the potential infectious risk that may be associated with ECP through impact on vaccine response. The project has secured 150 k€ from Therakos. We will complete by assessing the role of JAK inhibitors, to parallel the objectives of WP2 and FRM team. We aim to evaluate ex vivo the efficacy of selected therapies and their combination in experimental model of inflammatory fibrosis. The JAK inhibitor chosen will be the JAK1/3 inhibitor (Tofacitinib), which will be compared to those of PPARγ agonists (e.g., rosiglitazone) and nintedanib alone and to combination of these drugs. FB and human organoids derived from healthy or SSc or IBD patients will be expanded and treated with tofacitinib, PPARγ agonist or nintedanib alone or in combination. The most promising drugs and/or combination will be validated in murine models (HOCl for SSc, dextran sulfate sodium for IBD), both in preventive or curative mode. Specific readouts for establishing the anti-fibrotic potential will be, in vitro, the evaluation of expression profile of main markers of fibrosis (αSMA, Collagen, Fibronectin the TGF- β/Smad system as in Task 1 and 2) and of markers of epithelial cells (E-Cadherin and Occludin) for organoids cultures, using qRT-PCR and WB. In vivo we will evaluate specific clinical features for each murine model in response to selected treatments, histological parameters (e.g., collagen deposition), as well as tissue levels of pivotal pro-fibrotic markers (hydroxyproline, αSMA, collagen…). JAK inhibitors are perfect example of drugs possibly working both on inflammation and fibrosis through direct action on immune cells and FB.

Finally, throughout this part of the project, we anticipate finding innovative drug targets both on the immune and fibrotic part of SSc. We want to develop innovative treatment or reposition drug starting from these new targets. To achieve this goal, we will rely both on WP4 expertise on drug discovery and partnerships with Pharma. We have already developed successful partnerships with Servier (Portfolio item 4) and Therakos. We have ongoing discussions with Boehringer-Ingelheim, which we previously applied to an RHU grant with, and AstraZeneca to apply for competitive grants and collaborate.