Periodic Reporting for period 2 - FLAMIN-GO (From pathobioLogy to synoviA on chip: driving rheuMatoId arthritis to the precisioN medicine GOal)
Période du rapport: 2022-07-01 au 2023-12-31
Rheumatoid arthritis (RA) is an autoimmune inflammatory disease affecting the joints, characterised by inflammation that can lead to cartilage and bone damage, resulting in long-term disability. Despite research efforts, there is currently no cure for RA. Available treatments face two main challenges: 1) many patients do not respond well to initial therapies, leading to prolonged exposure to potentially harmful medications and delayed disease control; 2) expensive RA treatments pose a great burden on the global economy. Cuts in healthcare budgets hinder efforts to strengthen rheumatological care networks, preventing the implementation of measures that could reduce long-term costs associated with untreated complications of RA. Moreover, conventional clinical trials are time-consuming and raise ethical concerns. It’s thus crucial to explore alternative approaches that can facilitate innovative trials and reduce costs for pharmaceutical companies as well as financial burdens on patients and families, but also on healthcare systems. Based on the above assumptions, FLAMIN-GO aims to tackle the following key challenges:1) improving the screening of new RA drugs; 2) minimising the occurrence of side effects in RA patients; 3) discovering new biomarkers or therapeutic targets for RA. The main goal of FLAMIN-GO is thus to create an advanced, personalized joint-on-chip platform designed to faithfully replicate the complex characteristics of RA-affected joints, enabling personalised clinical trials-on-chip. OoC platforms provide controlled microenvironments with vasculature-like perfusion, integrating human multicellular structures that mimic the physiological architecture and function of tissues and organs. Such a technology offers an ideal platform for studying disease mechanisms and advancing precision medicine, in order to replace traditional in vitro and animal models which do not accurately represent human physiology. FLAMIN-GO joint-on-chip platform will serve for: 1) personalising treatment by identifying the most effective drug for each individual patient; 2) accelerating the discovery and testing of novel therapeutic targets, paving the way for the development of new drugs. Joint-on-chip will be built using the cells isolated from the patients who usually undergo biopsy, required for the follow-up of their RA. Such cells will form the basis of a multi-compartment microfluidic platform, enabling 3D culture and perfusion of relevant joint tissues, including synovia, synovial fluid, immune components (blood vessels, leukocytes), cartilage, and bone. Upon identifying the most effective drug, it could potentially be administered to the patient within 1-2 months. FLAMIN-GO is pursuing these objectives thanks to a multidisciplinary and international consortium mobilising 14 partners from 6 EU countries and 3 non-EU countries (UK, Switzerland, Turkey) with experts from hospitals, academia, and industry, covering the entire value chain with complementary expertise. Specialists in rheumatology, material science, tissue engineering, nanotechnology, cell biology, and 3D modelling will collaborate in a cohesive, transdisciplinary, multi-sectoral approach for advancing personalised care for RA.
During the first reporting period (M1-18) FLAMIN-GO aimed at conceiving, fabricating and testing the RA Synovial Unit (RA Syn-U), the Inflamed Blood Vessel Unit (Vas-U) and the Osteochondral Unit (OC-U), to be assembled in the next project phases to create a functional Synovia-on-Chip (SoC). To detect the cell activity within the chip, nanosensors were also developed. During the second reporting period (M19-36) FLAMIN-GO aimed at finalising the creation and completing the biological testing of the three units mentioned above in an inflamed environment (typical of RA). Preclinical drug testing on the inflamed units was performed by using methotrexate (MTX), the first line DMARD used in the treatment of RA patients. To closely follow the physiological process in the chip, advanced sensing technologies for real-time evaluation of SoC were developed. For Syn-U, the primary goal was deepening the biological characterisation of RA Syn-U on a chip using the most effective hydrogel formulation identified in RP1. The effect of mechanical stress was also tested by incorporating an actuator. The impact of the MTX on inflamed Syn-U was evaluated as well. The work on Vas-U focused on a complete biological assessment, with functional characterisation of inflamed endothelial cells inside the Vas-U. Production of NO and PBMCs extravasation was evaluated as an effect of MTX on inflamed blood vessel. For OC-U, the primary objective was to create and validate a functional OC-U under inflammatory conditions. Additionally, the impact of the MTX on inflamed OC-U was evaluated. Sensing tools for continuous monitoring of physical and biochemical parameters associated with the functionality of each cell compartment were fully developed: 1) microsensors for monitoring the culture environment (pH/O2 levels); 2) microsensors for monitoring mechanical stresses; 3) two different LoCs: a microELISA (LoC1) and a microplate array (LoC2), to detect disease-relevant cell-secreted molecules like cytokines and metalloproteinases. In order to facilitate the technological transfer of the achieved results, a start-up company was been established (AI-TWIN) in November 2023 and 2 patents are under preparation.
By starting from individual patient biopsies, the FLAMIN-GO project aims to replicate each patient’s joint, enabling the testing and allocation of the most suitable drug for that patient. This approach reduces the risk of side effects, minimizes healthcare costs, and enhances patients’ quality of life. Implementing personalised treatment for RA can lead to reducing both healthcare costs and socioeconomic impacts. By administering the appropriate drug to each patient and achieving early remission, long-term treatment, disability, and low quality-of-life can be avoided, thereby lessening the burden on both patients and the society. In Europe around 3 million people are diagnosed with RA, with estimated total costs to society reaching €45.3 billion (such costs amount for €41.6 billion in the US). In EU, costs increased from approximately €5,000 for patients with minimal functional disability to €20,000 for those with severe disease, of which up to 40% leave the workforce entirely within 5 years of diagnosis. It is estimated that the OoC technology could reduce costs by 10–26% per new drug brought to market. Thus, the FLAMIN-GO joint-on-chip solution offers a promising approach to optimising drug allocation in the context of RA treatment.