Targeted nanotherapy for the prevention of post-traumatic osteoarthritis

预防创伤后骨关节炎的靶向纳米疗法

• 批准号: 10246574
• 负责人: Christine T. Pham
• 金额: --
• 依托单位: ST. LOUIS VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10246574
• 关键词: Acute; Adult; Affect; Age; American; Anti-Inflammatory Agents; Antiinflammatory Effect; Arthritis; Arthroscopy; Biological Factors; Cartilage; Cartilage Matrix; Cells; Censuses; Cessation of life; Chondrocytes; Clinic; Complex; Data; Degenerative polyarthritis; Development; Diagnosis; Disease; Etiology; Event; Failure; Fibroblast Growth Factor; Frequencies; Gait; General Population; Health; Homeostasis; Impairment; Individual; Inflammation; Inflammatory; Inflammatory Response; Injury; Intervention; Knee; Knee Osteoarthritis; Maintenance; Medial meniscus structure; Medical; Meniscus structure of joint; Messenger RNA; Modeling; Morbidity - disease rate; Motion; NF-kappa B; Nature; Nucleic Acids; Operative Surgical Procedures; Outcome; Pathogenesis; Pathway interactions; Patients; Peptide Nucleic Acids; Peptides; Pharmaceutical Preparations; Phase; Population; Prevalence; Prevention; Production; RNA; Replacement Arthroplasty; Research; Risk; Signal Pathway; Signal Transduction; Small Interfering RNA; Soldier; Structure; Syndrome; Time; Trauma; Treatment Protocols; Up-Regulation; Ursidae Family; Vertebral column; Veterans; WNT Signaling Pathway; aging population; anterior cruciate ligament reconstruction; anterior cruciate ligament rupture; base; beta catenin; cartilage degradation; cartilage repair; combat injury; combat veteran; cost; disability; effective therapy; fibroblast growth factor 18; improved; insight; joint function; joint injury; knock-down; lifetime risk; mRNA delivery; military operation; military service; military veteran; mouse model; nanoparticle; nanotechnology platform; nanotherapeutic; nanotherapy; overexpression; p65; pain behavior; preservation; prevent; primary outcome; repaired; reparative process; response; service member

ABSTRACT The latest census indicates that 50+ million adults in the US bear some form of arthritis and by 2030, an estimated 67 million Americans ages > 18 years are projected to have the diagnosis of arthritis. Osteoarthritis (OA) represents the most common form of arthritis and is a major cause of morbidity in the aging population but for which there are limited medical treatments and no disease modifying drugs. Although effective disease- modifying OA drugs (DMOADs) are critically needed, none has successfully emerged in the clinic. Post- traumatic OA (PTOA) is a form of OA that develops after a joint injury and in which the nature and time of trauma is generally known. Approximately 12% of the overall OA burden can be traced to joint trauma. True prevalence for PTOA may be higher, given the long delay between injury and PTOA (10-15 years). PTOA affects 5.6 million individuals in the US. The projected lifetime risk of developing PTOA of the knee in individuals who sustain anterior cruciate ligament (ACL) rupture or meniscal damage is 50-70%. PTOA accounts for 20% of all joint replacements. Veteran Health Relevance: Among the population of service members, all causes of PTOA result in some degree of permanent disability in 28% of soldiers compared to 12% of civilians who sustain joint trauma. In addition, the frequency of arthritis among combat veterans from ongoing US military operations is estimated at 11.8%. The diagnosis of arthritis resulting from combat-related injury is accelerated and often accompanied by poor outcomes, requiring joint replacement at a younger age in the veteran population compared to the general population. Thus, any intervention that shifts the curve and decreases the risk of PTOA development will benefit the patients in the general population as well as military service members and veterans. Studies have documented a robust inflammatory response in the immediate aftermath of joint injury (i.e. during the first week up to 2-3 months) that persists for months to years, albeit at a lower level. This inflammatory response likely contributes to chondrocyte death, impaired cartilage repair and the subsequent cartilage degeneration that characterizes PTOA. We posit that modulation of this early inflammation limits acute cartilage damage while delivery of an anabolic factor that promotes cartilage repair/homeostasis will further delay or prevent eventual PTOA development. We employed a peptide-based self-assembling nanocomplex, delivering a wide range of nucleic acids [small interfering (si)RNA and messenger (m)RNA] and allowing for the simultaneous targeting of multiple pathways using the same cell-penetrating peptide, with no need for backbone or end-piece alterations. We show that intra-articular (IA) delivery of our peptide-based nanoparticle to knock down expression of NFKB mitigates early established PTOA in the Destabilization of the Medial Meniscus (DMM) model of surgery-induced PTOA. We also demonstrate that simultaneous delivery of NFKB siRNA and mRNA that overexpresses WNT16, a signaling pathway important for the maintenance of cartilage homeostasis, further mitigates early established PTOA in the DMM model. To explore the unique potential of our self-assembling peptide-nucleic nanoplatform we propose to determine the long-term outcomes of combined anti-inflammatory and anabolic nanotherapy in the DMM model. We believe these efforts will likely produce a disease-modifying nanotherapeutic approach for PTOA. Insight gained from these studies may be applicable to OA treatment in general.

抽象的 最新的人口普查表明，美国有50多百万以上的成年人患有某种形式的关节炎，到2030年， 估计有6700万> 18岁的美国人预计将诊断为关节炎。骨关节炎 （OA）是关节炎的最常见形式，是衰老人口发病率的主要原因 但是，对医疗治疗有限，没有修改药物的疾病。虽然有效疾病 - 迫切需要修改OA药物（DMOADS），在诊所中没有成功出现。邮政- 创伤性OA（PTOA）是一种OA的形式，在联合受伤后发展，并且性质和时间的性质和时间 创伤通常是已知的。大约12％的OA负担可以追溯到关节创伤。真的 鉴于受伤和PTOA之间的延迟（10 - 15年），PTOA的患病率可能更高。 PTOA 在美国影响560万个人。预计的终身风险是在 维持前交叉韧带（ACL）破裂或半月板损害的个体为50-70％。 PTOA 占所有关节替代品的20％。资深健康相关性：服务人口 成员，PTOA的所有原因导致28％的士兵的某种程度的永久残疾 维持联合创伤的平民中有12％。另外，战斗退伍军人之间关节炎的频率 持续的美国军事行动估计为11.8％。与战斗有关的关节炎诊断 受伤是加速的，经常伴随着较差的结果，需要在年轻的年龄较小的时候更换关节 与普通人群相比，退伍军人人口。因此，任何改变曲线和的干预措施 降低PTOA开发的风险将使普通人群和军事中的患者受益 服务成员和退伍军人。 研究已经记录了在关节损伤后立即发生的强大炎症反应（即 在第一个星期至2-3个月内）持续数月至数年，尽管处于较低水平。这 炎症反应可能导致软骨细胞死亡，软骨修复受损以及随后的 特征PTOA的软骨变性。我们认为对这种早期炎症限制的调节 促进软骨修复/稳态的合成代谢因素的急性软骨损害将 进一步延迟或防止最终的PTOA开发。我们采用了基于肽的自组装 纳米复合物，提供多种核酸[小干扰（SI）RNA和Messenger（M）RNA]，并且 允许使用相同的细胞穿透肽同时靶向多个途径，没有 需要骨干或末端更改。我们表明，基于肽的关节内（IA）递送 纳米颗粒敲低NFKB的表达，早期建立了PTOA在不稳定的情况下建立的PTOA 手术诱导的PTOA的内侧半月板（DMM）模型。我们还证明了同时交付 过表达WNT16的NFKB siRNA和mRNA，这是一种对维持很重要的信号通路 软骨稳态进一步减轻了DMM模型中早期建立的PTOA。探索独特 我们提出的自我组装的肽核纳米平台的潜力，我们建议确定长期结局 DMM模型中的抗炎和合成代谢纳米疗法的组合。我们相信这些努力可能会 为PTOA产生一种调整疾病的纳米治疗方法。从这些研究中获得的洞察力可能是 通常适用于OA治疗。