Achieving Sustained Control of Inflammation to Prevent Post-Traumatic Osteoarthritis (PTOA)

实现炎症的持续控制以预防创伤后骨关节炎 (PTOA)

• 批准号: 10641225
• 负责人: Carla Rose Scanzello
• 金额: --
• 依托单位: PHILADELPHIA VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10641225
• 关键词: Acceleration; Accounting; Acute; Adrenal Cortex Hormones; Animal Model; Animals; Anti-Inflammatory Agents; Antibodies; Arthritis; Bilateral; Biological Markers; Biological Sciences; Blocking Antibodies; CD14 Antigen; CD14 gene; Cartilage; Chronic; Clinical; Clinical Trials; Contralateral; Coupled; Cumulative Trauma Disorders; Data; Degenerative polyarthritis; Development; Devices; Disease; Disease Progression; Dose; Drug Delivery Systems; Emulsions; Encapsulated; Enzyme-Linked Immunosorbent Assay; Euthanasia; Family suidae; Functional disorder; Funding; Future; General Population; Genetic; Histopathology; Human; Image; Imaging Techniques; In Vitro; Incidence; Infection; Inflammation; Inflammatory Response; Injections; Injury; Innate Immune Response; Joints; Knee; Knee Injuries; Knee Osteoarthritis; Knee joint; Laboratories; Limb structure; Linear Regressions; Link; Liquid Chromatography; Magnetic Resonance Imaging; Measures; Mechanics; Medial meniscus structure; Mediating; Medical; Methods; Microcapsules drug delivery system; Microfluidics; Military Personnel; Miniature Swine; Modeling; Modification; Molecular; Monoclonal Antibodies; Mus; Operative Surgical Procedures; Outcome; Pain; Participant; Pathology; Pathway interactions; Patient Selection; Patients; Pattern recognition receptor; Performance; Pharmaceutical Preparations; Physical Function; Physical activity; Placebos; Prediction of Response to Therapy; Prevalence; Process; Protocols documentation; Quality of life; Receptor Activation; Recovery of Function; Regression Analysis; Rehabilitation therapy; Replacement Arthroplasty; Risk; Sampling; Serum; Severities; Severity of illness; Side; Standardization; Synovial Fluid; Synovitis; Technology; Testing; Therapeutic; Time; Tissues; Toll-Like Receptor Pathway; Toll-like receptors; Traumatic Arthropathy; Veterans; Work; active duty; anakinra; attenuation; biomarker validation; career; chronic pain; clinical care; clinical development; clinical predictors; clinically relevant; cofactor; cost; disability; economic impact; efficacy testing; functional decline; functional outcomes; immunoregulation; improved; in vivo imaging system; innovation; joint destruction; joint function; joint inflammation; joint injury; military service; motion sensor; mouse model; multiplex assay; novel; novel strategies; novel therapeutics; osteoarthritis pain; participant enrollment; patient stratification; pharmacologic; prevent; receptor; residence; response; service member; side effect; socioeconomics; symptom treatment; synergism; tandem mass spectrometry; therapeutic development; tissue injury; treatment effect; treatment response

Knee Osteoarthritis (KOA) is highly prevalent in U.S. military service members and Veterans due to the impact of joint trauma and overuse injury. Its socioeconomic impact is estimated at $60 billion per year, and no disease-modifying treatments exist. Joint inflammation is linked to severity and progression of disease 4, but current anti-inflammatory medications do not protect against progression, and have substantial side effects. The purpose of this project is to develop and employ a novel method to modulate the local inflammatory response in the joint after an injury in a sustained manner, to prevent post-traumatic osteoarthritis (PTOA). Specifically, we hypothesize that modulation of Toll-like receptor (TLR) activation, via blockade of the TLR co-receptor CD14, will reduce development of PTOA pathology and functional decline after knee injury. We were the first to discover high levels of CD14 in OA patients and show that it augmented TLR- mediated inflammatory responses. We have now demonstrated that genetic deficiency of CD14 reduces signs of disability and prevents progression of cartilage damage in a murine model of PTOA; Our preliminary data in this same model shows that pharmacologic blockade for therapeutic purposes is possible. We propose to establish blockade of TLR co-receptor CD14 as an effective strategy to prevent PTOA pathology and functional decline, using a large-animal (mini-pig) model of knee OA developed by our team. We will optimize intra- articular (IA) delivery of a clinically developed CD14 blocking antibody to achieve sustained release during the post-injury period, by encapsulating the antibody in innovative Mechanically Activated Microcapsules (MAMCs). Finally, we will test whether TLR activation markers in Veterans with KOA can predict clinical response to an existing anti-inflammatory therapeutic, with a focus on functional recovery, in order to optimize patient stratification for future clinical trials of TLR-targeted anti-inflammatory therapies. In Aim 1, Yucatan mini-pigs will undergo bilateral arthroscopic destabilization of the medial meniscus (DMM) surgery of both hind limbs. Starting one week after surgery, a neutralizing anti-CD14 monoclonal antibody (Implicit Biosciences) will be delivered IA to one knee; the contra-lateral side will receive isotype-matched antibody control. Functional outcomes will include activity and knee joint flexion angles measured every two weeks using a wearable motion-sensor device. Synovial fluid (SF) and serum will be collected prior to DMM and at endpoints for molecular/cellular analysis of effects of treatment. Groups of animals will be euthanized at endpoints up to six months after surgery, and PTOA pathology evaluated using novel MR imaging techniques allowing clinically-relevant early cartilage molecular changes to be detected, and imaging data will be validated using standardized histopathology. In Aim 2 we will optimize encapsulation of anti-CD14 in MAMCs using microfluidic double emulsion technology, and confirm sustained delivery of active drug after encapsulation using in vitro and ex vivo analyses. Encapsulated anti-CD14 will then be delivered IA to one hind knee joint of DMM-operated mini-pigs, and encapsulated control antibody to the contra-lateral side. A single dose will be given one week after DMM. The effects of encapsulated anti-CD14 vs. unencapsulated anti-CD14 on pathology and functional outcomes will be compared. Retention and distribution of MAMCs in the joint will be assessed by IVIS imaging. Finally, in Aim 3, we will leverage the availability of SF samples from participants in a VA-funded clinical trial (MOVE-OK study) testing the efficacy of IA corticosteroids in Veterans with knee OA. Biomarkers related to TLR activity (including sCD14, sTLR4, LBP) will be measured in SF collected and stored as part of the MOVE-OK protocol, using ELISA/multiplex assays. Associations between biomarker levels, and change in activity levels and disability scores with therapy will be tested using linear regression analysis. Pursuit of this project will result in the development of an innovative method to control joint inflammation after injury, and inform patient selection for future clinical trials of TLR-targeted immunomodulatory approaches.

由于影响 关节创伤和过度使用伤害。它的社会经济影响估计为每年600亿美元，没有 存在疾病改良治疗。关节炎症与疾病的严重程度和进展有关4，但 当前的抗炎药不能防止进展，并且具有实质性的副作用。 该项目的目的是开发和采用一种新颖的方法来调节局部炎症 持续受伤后的关节反应，以防止创伤后骨关节炎（PTOA）。 具体而言，我们假设通过封锁的封锁来调节Toll样受体（TLR）激活 TLR共受体CD14将减少PTOA病理学的发展和膝盖功能下降 受伤。我们是第一个在OA患者中发现高水平CD14的人，并表明它增强了TLR- 介导的炎症反应。现在，我们已经证明CD14的遗传缺乏降低了体征 残疾和防止PTOA鼠模型中软骨损伤的进展；我们的初步数据 同一模型表明，出于治疗目的的药理阻滞是可能的。我们建议 建立对TLR共受体CD14的封锁，作为预防PTOA病理和功能的有效策略 下降，使用我们团队开发的膝盖OA的大动画模型。我们将优化内部 关节（IA）的临床开发的CD14阻断抗体的递送，以实现持续的释放 伤害后，通过将抗体封装在创新的机械激活的微胶囊中 （MAMCS）。最后，我们将测试KOA退伍军人的TLR激活标记是否可以预测临床 对现有的抗炎治疗的反应，重点是功能恢复，以优化 患者分层进行未来的TLR靶向抗炎疗法的临床试验。 在AIM 1中，Yucatan迷你猪将经历双侧关节镜的内侧弯月板（DMM）的稳定 两个后肢的手术。手术后一周开始中和抗CD14单克隆抗体 （隐式生物科学）将被交付给一个膝盖；相反的一方将获得同型匹配 抗体控制。功能结果将包括活动和膝关节屈曲角度每两个测量 使用可穿戴运动传感器设备数周。滑液（SF）和血清将在DMM之前收集 并在终点上进行分子/细胞分析治疗的作用。一群动物将被安乐死 手术后长达六个月的终点，并使用新型MR成像技术评估了PTOA病理学 允许检测到与临床相关的早期软骨分子变化，并将验证成像数据 使用标准化的组织病理学。在AIM 2中，我们将使用使用MAMC中对抗CD14的封装进行优化 微流体双重乳液技术，并确认封装后持续的活性药物递送 使用体外和体内分析。然后将封装的抗CD14送到一个后膝关节 DMM操作的迷你杆，并将对照抗体封装到相反的侧面。一个剂量将是 在DMM之后一个星期给予。封装的抗CD14与未包容的抗CD14对 将比较病理和功能结果。关节中MAMC的保留和分布将是 通过IVIS成像评估。最后，在AIM 3中，我们将利用参与者的SF样本的可用性 VA资助的临床试验（Move-OK研究）测试了IA皮质类固醇在膝关节OA的退伍军人中的功效。 将在收集并存储的SF中测量与TLR活性相关的生物标志物（包括SCD14，STLR4，LBP） 作为Move-OK协议的一部分，使用ELISA/多重测定。生物标志物水平和 通过线性回归分析，将测试活性水平和残疾评分的变化。 追求该项目将导致开发一种创新方法来控制关节炎症之后 伤害，并告知患者选择以将来的TLR靶向免疫调节方法的临床试验。