DESCRIPTION OF THE DISEASE AND STATE OF KNOWLEDGE: Idiopathic pulmonary fibrosis (IPF) is a rare, lethal disease with a mean survival of three years. IPF is characterized by the proliferation of myofibroblasts and the accumulation of extracellular-matrix (ECM) in the lungs. Transforming Growth Factor (TGF)-ß1 is the major pro-fibrotic cytokine involved in IPF and is responsible for myofibroblast proliferation, ECM synthesis and transdifferentiation of alveolar epithelial cells into myofibroblasts ( process named EMT). Smad4 is a key TGF-ß1 signal transducer protein Except for pirfenidone and nintedanib that slightly reduce the annual decline in forced vital capacity compared to placebo, no pharmacologic treatment is currently available. Heat shock proteins (HSPs) belong to a group of highly conserved proteins, whose expression is induced by different aggressive situations, including inflammation and reactive oxygen species, allowing the cells to survive in otherwise lethal conditions. During the last 20 years, our laboratory has been studying the role of HSPs in different pathological processes and has constructed a number of HSPs inhibitors. Among the different HSPs, small HSPs (sHSPs) and, in particular, HSPB1 and HSPB5 have strong cytoprotective functions which can be explained by their anti-apoptotic properties but also mainly by their role as molecular chaperones for other proteins. We recently observed that HSPB1 and HSPB5 are strongly overexpressed in human IPF lungs. We have demonstrated that the inhibition of HSPB1 in vivo using the oligonucleotide antisense (ASO) OGX-427, a specific inhibitor of HSPB1 limits pulmonary fibrosis and EMT. We showed that HSPB1 binds to and stabilizes Snail, a major transcription factor involved in EMT. We also demonstrated that the other ubiquitous small chaperone, HSPB5, was essential for the mono-ubiquitination and nuclear translocation of Smad4, a key TGF-ß1 signal transducer protein. We already confirmed the interaction between Smad4 and HSPB5 in vitro. OBJECTIVES: 1) To discover chemical molecules able to inhibit HSPB1 and/or HSPB5 and 2) To design and produce antisense oligonucleoties (ASO) able to inhibit HSPB5 or both HSPB5 and HSPB1 and also 3) To vectorize OGX427 the ASO specific for HSPB1 that we have already. DESCRIPTION OF THE PROJECT METHODOLOGY: (1) Our first aim will be to study and model the interaction of HSPB1 and HSPB5 with Snail and Smad4, respectively, in order to well define the druggable domains. (2) The second aim will be to set up a high throughput screening to identify molecules inhibiting HSPB1 and HSPB5. (3) We will select the possible inhibitors by fast in vitro 96 well plates tests: ability to inhibit the chaperones’ anti-aggregation properties and to block the interaction with Snail or Smad4 (with an Octet optic instrument). In parallel, we will develop antisense oligionucleotides (ASO) targeting HSPB5 alone or both HSPB5 and. (4) We will be to test the possible lead candidates in cultured human IPF fibroblasts, tissues and our animal models. (5) We will Vectorize of the most promising candidates will be done using the Inserm Transfert National Plateform RNA-targeting DRUG. For HSPB1 we have already a second generation ASO: OGX-427 (Bonniaud et al. Patent 2011). HSPB5 ASO and OGX-427 will be autonanovectorized using a lipid-conjugated oligonucleotides modification via « Click Chemistry » in order to improve stability, biodisponibility and delivery of the ASO (Patent CT/IB2013/001517/2013). EXPECTED RESULTS AND IMPACTS: We believe that the discovery of molecules that specifically inhibit HSPB1 and HSPB5 and disrupt their interaction respectively with Snail and with Smad4 may be useful to attenuate or to stop the progression of lung fibrosis. We hope that the combination of these different approaches will allow us at the end of to come out with at least one molecule worth to be tested in clinical trials in IPF therapy

Introduction: Pilot studies are intended to prepare a trial. In population health intervention research (PHIR), they may also focus on intervention preparation. In this context has been introduced the concept of "viability validity" exploring the capability of an intervention to be successful in the real world (along the dimensions of practical, affordable, suitable, evaluable and helpfull). The aim of the VAPS research is to operationalize the concept of viability through conceptual and methodological research. Objectives are: to determine the viable viability criteria for consideration in evaluation process ; to describe and analyze how practitioners and researchers take into account these dimensions during development and evaluation phases and in routinization, transfer or dissemination processes; to develop a guide. Methodology: The VAPS research is articulated in 3 work packages. A mixed meta-narrative review (WP1) will seek (1) to position the concept of viability in relation to other concepts related to the pilot study of public health interventions, (2) to identify the dimensions to be considered in addressing the conditions of viability in public health interventions, (3) to identify how researchers assess and take into account these conditions according to the stages of the project. It will be carried out in a 4-step multidisciplinary approach: scoping review; article selection; data extraction and analysis by research tradition; synthesis across different research traditions. A multiple case study (WP2), in France, Canada and Senegal will be conducted, in an inductive approach. Based on a documentary study and semi-directive interviews with stakeholders in the 6 cases studies, this study will seek to describe, explore and understand in detail how the dimensions of viability are taken into account by stakeholders and how these stakeholders address these issues in order to develop, transfer and scale up their interventions. The triangulation of the results of these two WPs, carried out in parallel from 2021 to 2023, will allow to refine the preparation of the consultation process (WP3). The consultation process (2023-2024) will bring together a panel of international experts to reach a consensus and produce a guide explaining the dimensions of viability to be considered in the development of the intervention and the methods to evaluate them in pilot studies. For this, a first step will be done remotely using the e-Delphi method, then a seminar will be organized in person. The scientific consortium, composed of French and Canadian research teams, in a multidisciplinary approach, will be solicited in a transversal way for each WP. Its mobilization will be articulated around 6 workshops. Impact/finality: Population health intervention research has been described as "the science of solutions". Viability is an integral part of PHIR issues, to develop interventions that can be deployed and scaled up in common practice. While the interest of the viability during pilot studies in the development of public health interventions is recognized by many researchers, a clear definition of the concepts that make it up, their operationalization and the existence of standards still need to be clarified and developed. This project aims to support applied research by developing evaluation methods adapted to PHIR.