Neutrophil Vesicles as a novel autologous regenerative therapeutic for joint disease.

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There is an unmet need for the treatment of rheumatoid arthritis since a significant proportion of patients do not respond to current therapies (~30%): this is evident from clinical trials and is even more acute in the community, where patients are 'not chosen' and comorbidities like obesity and diabetes increment the extent of therapeutic failures. As such, new approaches to improve prognosis and impact on patient quality of life are necessary. At the same time, as RA is diffuse in the adult population (1 in 20) better disease control can reduce the current health economic burden to our society (between 1 and 2.5% of GDP), determined by medicine and care costs as well as by loss of working hours.To address this clinical need, we propose herein a research project to establish the biology to underpin the future development of an innovative autologous therapy for rheumatoid arthritis patients. This therapeutic opportunity comes from the use of vesicles (bubbles) that can be generated from white blood cells that circulate in the blood together with red blood cells and can also reach the inflamed joint. In fact, we have quantified an enrichment of specific bubbles in the joint of rheumatoid arthritis patients and, to our surprise, reported that they protected the joint from inflammation and the cartilage from degradation.With this grant application we propose to study in experimental settings how these bubbles work; definition of the mechanisms activated by these bubbles to protect the joint can open avenues for developing an innovative autologous therapy: that is, we envisage a future scenario where rheumatoid arthritis patients will come to an out-patient clinic to donate their own white blood cells for the generation of bubbles which will then be injected into their own inflamed joint to exert anti-arthritic and analgesic effects. However, to accomplish this futuristic vision we must - 1) Understand the processes activated/modulated by the bubbles in the arthritic joint; 2) Define how many bubbles are required, an how often must be administered, to produce the beneficial effects on the joint;3) Establish efficacy of the bubbles not only in experimental animals but also on human cartilage.Completion of this project with a successful outcome will pave the way to the development phase for this innovative therapy, a path we will take with the guidance and advice of important players in the field, like the Cell and Gene Therapy Catapult and the MHRA, both of which have already been engaged.