SmallDrugRheuma · Discovery of Immune Therapeutic Targets and Immunomodulators for the Development of Novel Therapies in Rheumatoid Arthritis.
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2018-06-29 → 2020-09-11
- EU contribution
- €170,122
- Participants
- 1
- Scheme
- MSCA-IF-EF-ST
Lines connect the coordinator with its partners.
Results in brief
Discovery of Immune Therapeutic Targets and Immunomodulators for the Development of Novel Therapies in Rheumatoid Arthritis.
Rheumatoid Arthritis (RA) is an autoimmune chronic disease, characterized by inflammation in multiple joints, ultimately leading to joint deformity, pain and swelling. A high percentage of patients do not respond to currently available therapies; these mostly constitute of big-sized molecules incapable of crossing cellular membranes, and therefore do not target intracellular components of immune/inflammation-related pathways, which are altered in RA. Therefore, finding new drugs targeting these other RA-related intracellular components would widen the catalogue of therapies available to treat RA, potentially obtaining a higher success rate in patients. The SmallDrugRheuma project aimed to identify novel small drugs for RA, capable of crossing cellular membranes and therefore targeting intracellular components, using a drug-centric, rather than a target-centric, approach; this is, focusing on first identifying a drug causing the desired effect (anti-inflammatory) and only then asking what the intracellular route and target are, to make a more clever use of human, time and monetary resources in drug discovery processes. We developed an in vitro inflammation model in human primary immune cells, and tested on it 3,000 different small molecules (including both approved and novel lead-like drugs), covering the whole chemical space. We identified a portfolio of small molecules capable of reducing the secretion of proinflammatory cytokines while do not altering cell viability (n=25). We validated them in several donors and at different concentrations. The extensive screening effort led to 2 strong candidates (repurposing drugs), which allow for 30-50% reduction of IL-1β and/or TNF-α secretion by inflamed PBMCs. Further, we validated this reduction in cytokine secretion in PBMCs from newly diagnosed RA patients which have not yet received any treatment, and identified the intracellular pathways being targeted. In summary, we identified novel compounds capable of reducing IL-1β and TNF-α secretion in both in vitro inflamed HD PBMCs and PBMCs from naïve RA patients.
Data: CORDIS, © European Union
Project objective
Rheumatoid Arthritis (RA) is an autoimmune chronic disease, characterized by inflammation in multiple joints, ultimately leading to joint deformity, pain and swelling. RA is one of the most frequent inflammatory arthropathies, with a prevalence of 0.3%-1%, striking during the most productive years of adulthood, and is a chronic disabling condition. No therapies exist to prevent RA, and a high percentage of patients do not respond to currently available therapies. Our research aims to integrate expertise on immunology and cutting-edge screening technologies to identify novel immunotherapeutics for RA based on immune modulation mechanisms. The project makes use of an extensive screening effort using a chemical library (60,000 compounds) containing repurposing drugs (drugs already approved for their use for the treatment of other diseases), targeted libraries and lead-like compounds. The aim of the project is to identify novel small molecules capable to modulate the immune response, counterbalancing the altered inflammatory environment that characterizes RA. Elucidation of the mechanism of action of the candidates (cell type, pathway and target) will take place through state-of-the art technologies such as chemoproteomics, RNASeq or CRISPR/Cas9. Ultimately, the most promising candidates will be tested ex vivo in cells from RA patients, providing a proof-of-concept of the therapeutic utility of the identified mechanism. The project is interdisciplinary and will make progress beyond the state of the art, as the identified immunotherapeutics could also be employed to treat other (auto)immune diseases, as well as being potentially translated to immunotherapy of cancer and cardiovascular diseases. The high-quality and originality of this proposal will open up the best career possibilities for the experienced researcher, and will be carried out under the umbrella of a public-private partnership with a pharmaceutical company, boosting European competitiveness.
Original text from CORDIS.
Participants
- UNIVERSIDAD DE SANTIAGO DE COMPOSTELA · Santiago De CompostelaCoordinatorSpain
Links
Data: CORDIS, © European Union