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，膝骨关节炎 (KOA) 在美国军人和退伍军人中非常普遍 关节创伤和过度使用损伤。其社会经济影响估计每年达 600 亿美元，并且没有 存在缓解疾病的治疗方法。关节炎症与疾病 4 的严重程度和进展有关，但是 目前的抗炎药物不能防止病情进展，并且有很大的副作用。 该项目的目的是开发和采用一种新方法来调节局部炎症 损伤后关节的持续反应，以预防创伤后骨关节炎（PTOA）。 具体来说，我们假设通过阻断 Toll 样受体 (TLR) 的激活来调节 TLR 辅助受体 CD14，将减少膝关节术后 PTOA 病理学的发展和功能下降 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。我们现在已经证明 CD14 的遗传缺陷会减少症状 在 PTOA 小鼠模型中减少残疾并防止软骨损伤的进展；我们的初步数据在 该模型表明，用于治疗目的的药物阻断是可能的。我们建议 建立 TLR 辅助受体 CD14 阻断作为预防 PTOA 病理和功能的有效策略 使用我们团队开发的大型动物（小型猪）膝关节骨关节炎模型。我们将优化内部 关节（IA）递送临床开发的CD14阻断抗体以在治疗期间实现持续释放 损伤后时期，通过将抗体封装在创新的机械激活微胶囊中 （MAMC）。最后，我们将测试患有 KOA 的退伍军人中的 TLR 激活标记是否可以预测临床 对现有抗炎治疗的反应，重点是功能恢复，以优化 未来 TLR 靶向抗炎治疗临床试验的患者分层。 在目标 1 中，尤卡坦半岛小型猪将接受双侧关节镜下内侧半月板不稳定术 (DMM) 双后肢手术。手术后一周开始，中和抗 CD14 单克隆抗体 （Implicit Biosciences）将 IA 交付单膝；对侧将接受同型匹配 抗体对照。功能结果将包括每两次测量的活动和膝关节弯曲角度 使用可穿戴运动传感器设备几周。在 DMM 之前收集滑液 (SF) 和血清 以及治疗效果的分子/细胞分析的终点。成群的动物将被安乐死 术后六个月内的终点，并使用新型 MR 成像技术评估 PTOA 病理学 允许检测临床相关的早期软骨分子变化，并验证成像数据 使用标准化组织病理学。在目标 2 中，我们将使用 MAMC 优化抗 CD14 的封装 微流控双乳化技术，并确认封装后活性药物的持续递送 使用体外和离体分析。然后将封装的抗 CD14 递送至 IA 的一侧后膝关节 DMM 操作的小型猪，并将对照抗体封装到对侧。单剂量将是 DMM 后一周给予。封装的抗 CD14 与未封装的抗 CD14 的影响 将比较病理学和功能结果。 MAMC 在关节中的保留和分配将 通过 IVIS 成像进行评估。最后，在目标 3 中，我们将利用参与者提供的 SF 样本 一项由 VA 资助的临床试验（MOVE-OK 研究），测试 IA 皮质类固醇对患有膝骨关节炎的退伍军人的疗效。 与 TLR 活性相关的生物标志物（包括 sCD14、sTLR4、LBP）将在收集和存储的 SF 中进行测量 作为 MOVE-OK 方案的一部分，使用 ELISA/多重检测。生物标志物水平之间的关联，以及 将使用线性回归分析来测试治疗后活动水平和残疾评分的变化。 该项目的追求将导致开发出一种创新方法来控制关节炎症 损伤，并为未来 TLR 靶向免疫调节方法的临床试验的患者选择提供信息。