SINPAIN: A game changer for the treatment of osteoarthritis: a cost effective combined advanced therapy to treat knee osteoarthritis (SINPAIN)

根据世界卫生组织的说法，骨关节炎(OA)是老年人残疾生活的主要病程之一，被认为是一种高负担疾病，这使其成为欧洲的研究重点。骨性关节炎是无法治愈的，SOA治疗需要重新考虑。目前的药理干预措施包括止痛药、抗炎药以及关节内类固醇和透明质酸(IA-HA)，疗效中等，并伴随着长期副作用。因此，需要新的药物来缓解疼痛和减缓疾病的进展。利用过去几年RNA技术的爆炸性增长，SINPAIN的目标是开发一条基于siRNA的治疗管道，该管道建立在当前技术(动态IA-HA和纳米载体)组合的基础上，将逐步设计，以实现对炎症的成功管理和用于治疗早期(0-1级)和晚期(3-4级)膝骨性关节炎(OA)的神经治疗。为此，将开发一种由可负载载体的功能性IA-HA和纳米载体组成的纳米制剂，用于传递针对IL1？和NGF的siRNA。同时，大量的工作将集中在了解骨关节炎的病理机制上。为了在相关的效力分析中验证有效性，将开发与人类细胞共培养的3D模型，并在模拟关节环境和生物力学的独特生物反应器中进行测试。根据确定的细胞靶点，IA-HA将被一种免疫调节剂多肽修饰，该多肽将激活适应性免疫反应，负责骨关节炎的再生。SINPAIN的4种流水线产品将在相关的骨性关节炎模型中进行体内验证，采用SOA技术，将证明最后一种产品的炎症和疼痛减轻，以及软骨再生。利用项目期间获得的所有数据，将验证基于机器学习的决策工具，为患者提供个性化治疗。

According to the WHO Osteoarthritis (OA) is one major course of years lived with disability in the elderly and is considered a high-burden disease, which makes it a research priority in Europe. There is no cure for OA and SoA treatments need to be reconsidered. Current pharmacological interventions consist of analgesic, and anti-inflammatory drugs as well as intraarticular steroids and hyaluronic acid (IA-HA) with moderate efficacy and associated long-term side effects. New medications are thus needed both to alleviate pain and slow down disease progression. Taking advantage of the explosion of RNA technologies in the last years, SINPAIN aims to develop a pipeline of siRNA-based therapy built on the combination of current technologies (dynamic IA-HA and nanocarriers) that will be designed step-by-step in order to reach successful management of inflammation and innervation therapy for the treatment of early (grade 0-1) and later stages (grade 3-4) of knee osteoarthritis (OA). To do so, a nanoformulation composed of functional IA-HA that can be loaded with vectors, for the delivery of siRNA targeting IL1ß and NGF, and nanocarriers will be developed. In parallel, a large effort will focus on understanding the pathological mechanisms of OA. To validate efficacy in relevant potency assays, 3D coculture models will be developed with human cells and tested in unique bioreactors mimicking joint environments and biomechanics. With the identified cell targets, IA-HA will be modified with an immunomodulator peptide which will activate the adaptive immune response, responsible for OA regeneration. The 4 pipeline products of SINPAIN will be validated in vivo in a relevant OA model with SoA techniques that will demonstrate the reduced inflammation and pain, as well as the cartilage regeneration for the last product. Taking advantage of all the data obtained during the project, a decision-making tool based on machine learning will be validated to offer patients a personalized therapy.