Identification of patients at risk of OA who will benefit from Agrin treatment

Cartilage covers the ends of the bones to maintain frictionless motion. Cartilage defects are found in 61% patients undergoing arthroscopy and if left untreated, up to 51% of these defects lead to osteoarthritis (OA). OA affects up to 1/3 of people over the age of 60yrs. It is a leading cause of chronic disability and the main cause of work-absenteeism in the UK. Patients with OA have joint pain, reduced mobility and independence. Despite this, there is no treatment that can prevent or reverse cartilage loss. Pain-relief and physiotherapy provides some benefit; however, joint replacement is often needed- which only restores partial joint function, has a limited lifespan, and revision surgery is often complex and not risk-free. In 2011, we discovered a molecule called Agrin in the cartilage. Further studies showed that only healthy patients have Agrin in the cartilage, and a loss of Agrin is correlated with the severity of OA. We went on to uncover that treating with Agrin can increase the amount of cartilage produced in cells in the lab and in pre-clinical animal studies. Since 2011, we have prioritised research on Agrin and its suitability as a treatment for cartilage defects. We have published its cartilage and bone repairing capabilities, uncovered the molecular mechanism, and revealed its exciting pain-relieving properties in mice and sheep. Additionally, sheep we treated with Agrin for their cartilage defects had reduced secondary osteoarthritis, compared to the control treated animals, in keeping with the human statistics. We have now pin-pointed the ‘active’ portion of Agrin and have manufactured it, validated it in vivo and made a “patient-ready” version. To enter clinical testing in patients, we need to confirm efficacy of the “patient-ready” version and identify subsets of patients that are most likely to benefit. We seek the funding in this application to complete the pre-clinical package required to take Agrin to regulatory bodies for approval. Before regulatory approval is given, a product must undergo a tightly regulated series of tests–many of which we have obtained funding for-including efficacy in rodents, but for Agrin to be approved for patient use, we must test our “patient-ready” Agrin in large animal models. As part of our newly funded Biomedical Research Centre, we are recruiting a cohort of patients who, following joint trauma, are at high risk to develop osteoarthritis within one year. This will enable us to determine which patients progress to ‘early OA’ and which are protected. Biological sample analysis (bloods, synovial fluid, Xray, MRI, pain levels, muscle function etc) will help us determine which patients are likely to progress and therefore who is suitable for treatment with Agrin. In addition to our annual Research Showcase days, using our newly developed App, we will keep our patients and the public updated on our research and seek their input throughout the project. The funding requested in this application would enable early detection of patients at risk of developing OA and, importantly, will bring us closer to obtaining regulatory approval and start clinical testing of Agrin.