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

类风湿关节炎的治疗需求尚未得到满足，因为相当大比例的患者对目前的治疗没有反应（约30%）：这从临床试验中可以明显看出，在社区中甚至更为严重，患者“未被选择”，肥胖和糖尿病等合并症增加了治疗失败的程度。因此，改善预后和影响患者生活质量的新方法是必要的。与此同时，由于类风湿性关节炎在成年人中是弥漫性的（1 / 20），更好的疾病控制可以减少当前社会的卫生经济负担（占GDP的1%至2.5%），这是由药品和护理费用以及工作时间损失决定的。为了满足这一临床需求，我们在此提出一项研究项目，以建立生物学基础，以支持未来发展一种创新的自体治疗类风湿性关节炎患者。这种治疗机会来自于使用由白细胞产生的囊泡（气泡），这些白细胞与红细胞一起在血液中循环，也可以到达发炎的关节。事实上，我们已经量化了类风湿关节炎患者关节中特定气泡的富集，令我们惊讶的是，它们可以保护关节免受炎症和软骨降解。通过这项拨款申请，我们建议在实验环境中研究这些气泡是如何工作的；通过这些气泡激活保护关节的机制的定义可以为开发创新的自体治疗开辟道路：也就是说，我们设想未来的场景，类风湿关节炎患者将来到门诊捐献自己的白细胞来产生气泡，然后将其注射到他们自己发炎的关节中，以发挥抗关节炎和镇痛作用。然而，为了实现这一未来的愿景，我们必须- 1)了解关节炎关节中的气泡激活/调节的过程；2)确定需要多少气泡，以及必须多久注射一次，才能对关节产生有益的影响；3)建立气泡在实验动物和人体软骨上的功效。该项目的成功完成将为这种创新疗法的开发阶段铺平道路，我们将在该领域重要参与者的指导和建议下走这条道路，如细胞和基因治疗弹弓和MHRA，两者都已经参与其中。

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.