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

类风湿性关节炎的治疗需求尚未得到满足，因为相当大一部分患者对当前的治疗方法没有反应(约30%)：从临床试验中可以明显看出这一点，在社区中，这一点甚至更加严重，在那里，患者不是被选中的，肥胖和糖尿病等共病增加了治疗失败的程度。因此，新的方法来改善预后和对患者生活质量的影响是必要的。同时，由于类风湿性关节炎在成人人群中扩散(1/20)，更好的疾病控制可以减轻当前社会的健康经济负担(占GDP的1%至2.5%)，这是由药物和护理成本以及工作时间损失决定的。为了解决这一临床需求，我们在此提出一项研究项目，以建立生物学基础，以支持类风湿性关节炎患者创新的自体疗法的未来发展。这种治疗机会来自于使用囊泡(气泡)，这种囊泡可以由在血液中与红细胞一起循环的白细胞产生，也可以到达发炎的关节。事实上，我们已经量化了类风湿性关节炎患者关节中特定气泡的丰富，令我们惊讶的是，报告称它们保护关节免受炎症和软骨的退化。通过这项拨款申请，我们建议在实验环境中研究这些气泡如何工作；定义这些气泡激活保护关节的机制可以为开发创新的自体疗法开辟道路：即，我们设想未来的场景，类风湿性关节炎患者将来到门诊捐献他们自己的白细胞来生成气泡，然后将这些气泡注射到他们自己的炎症关节中发挥抗炎和止痛作用。然而，为了实现这一未来主义的愿景，我们必须-1)了解关节炎关节中气泡激活/调节的过程；2)确定需要多少气泡，以及必须多久给药一次，才能对关节产生有益的影响；3)不仅在实验动物身上，而且在人类软骨上建立气泡的功效。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采取这条道路，如细胞和基因治疗弹射器和MHRA，这两个项目都已经投入使用。

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.