Title: Are synovitis-associated lncRNAs central regulators of inflammatory pain in patients with knee OA: A route to identifying a novel analgesic drug for OA patients
Funder: Versus Arthritis

Abstract: Background Synovial inflammation (synovitis) is a contributory factor in the severity of OA pain due to the sensitizing action of inflammatory cytokines and chemokines on joint nociceptors. Importantly, in knee OA patients, distinct patterns of inflamed synovial joint tissue are associated with pain. Therefore, determining the key cellular regulators of the inflammatory response within these regions of synovial tissue is critical so that novel drug targets can be identified and pain-relieving drugs can be developed. We have demonstrated that long non-coding RNAs (lncRNAs) act as central regulators of the inflammatory response. Critically, we have now identified through next generation sequencing (NGS) specific lncRNAs that are associated with inflammatory OA synovial tissue, and which regulate the production of inflammatory pain mediators. We hypothesise that these synovitis-associated lncRNAs are key regulators of nociceptive pain in patients with knee OA, and that modulating their activity will inhibit the production of inflammatory pain mediators and alleviate pain. Focus and Objectives This proposal will determine whether: specific “synovitis-associated lncRNAs” are localised to areas of synovial tissue associated with OA pain; these lncRNAs are associated with greater pain intensity; modulating their activity mitigates the production of pain mediators and alleviates pain. Proposed Techniques Patients with either early OA or end-stage OA (n=41) will be recruited, undertake a pain assessment, and anatomical pain maps will be generated. Following MRI analysis, synovial tissue biopsies will be collected from regions of the joint associated with pain, and from regions not associated with pain. The synovial tissue expression of 20 synovitis-associated lncRNAs will be examined by qRTPCR and their cellular localisation determined by in-situ hybridisation. The synovial fluid profile of inflammatory pain mediators will be determined by ELISA and Luminex assays. Loss of function (LOF) studies using LNA inhibitors (Exiqon) will determine the functional role of lncRNAs in the regulating the production of inflammatory pain mediators in primary human OA and murine synovial fibroblasts. The murine MIA model of OA pain will be used to determine the in vivo analgesic efficacy of novel lncRNA modulators. Exploitation of Results Results will be disseminated to commercial, academic, patient and public beneficiaries. For academics, results will be presented at national and international meetings, and published in high impact peer-reviewed journals. To reach public sector and clinical beneficiaries, we will engage with clinical collaborators and service providers via our three national centres of excellence, the MRC-ARUK Centre for Musculoskeletal Ageing, the ARUK Rheumatoid Arthritis Pathogenesis Centre of Excellence and the ARUK Pain Centre in order to highlight the research outputs and the clinical implications. Engagement with the Birmingham Rheumatology Research Patient Partnership (R2P2) will facilitate dissemination to patient groups. To exploit the commercial potential of our results we will engage with the University of Birmingham’s dedicated Technology Transfer Team to determine IP and commercial development opportunities and strategies. The University has its own External Commercialisation Board, which includes leading industry experts. This board is linked to the University's own dedicated commercialisation company, Alta Innovations, who support the patent process and facilitate commercial opportunities.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: MUSCULOSKELETAL