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 最新的人口普查显示，美国有超过 5000 万成年人患有某种形式的关节炎，到 2030 年， 据估计，18 岁以上的美国人预计将有 6700 万被诊断患有关节炎。骨关节炎 (OA) 是最常见的关节炎形式，也是老年人口发病的主要原因 但对此的医疗治疗有限，也没有疾病缓解药物。虽然有效的疾病- 修饰 OA 药物 (DMOAD) 是迫切需要的，但尚未成功应用于临床。邮政- 创伤性 OA (PTOA) 是关节损伤后发生的 OA 的一种形式，其中损伤的性质和时间 创伤是众所周知的。大约 12% 的 OA 总负担可归因于关节创伤。真的 鉴于受伤和 PTOA 之间的较长时间间隔（10-15 年），PTOA 的患病率可能更高。 PTOA 影响美国 560 万人。发生膝关节 PTOA 的预计终生风险 50-70% 的人遭受前十字韧带 (ACL) 断裂或半月板损伤。 PTOA 占所有关节置换术的20%。退伍军人健康相关性：在服务人群中 成员们，与 28% 的士兵相比，PTOA 的所有原因都会导致某种程度的永久性残疾 12% 的平民遭受关节创伤。此外，来自以下国家的退伍军人患关节炎的频率也很高： 美国正在进行的军事行动估计为 11.8%。战斗相关关节炎的诊断 损伤会加速，并且往往伴随着不良后果，需要在较年轻的年龄进行关节置换 退伍军人人口与普通人口的比较。因此，任何改变曲线的干预措施 降低 PTOA 发生的风险将使普通大众以及军队的患者受益 服役人员和退伍军人。 研究记录了关节损伤后立即出现的强烈炎症反应（即关节损伤）。 持续数月至数年，尽管水平较低。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损伤 PTOA 的特征是软骨退变。我们认为这种早期炎症的调节限制了 急性软骨损伤，同时提供促进软骨修复/稳态的合成代谢因子 进一步延迟或阻止最终的 PTOA 发展。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 和信使 (m)RNA] 和 允许使用相同的细胞穿透肽同时靶向多个途径，而无需 需要对主干或末端件进行改造。我们展示了基于肽的关节内（IA）递送 纳米颗粒敲低 NFKB 的表达可减轻早期建立的 PTOA 在不稳定中的作用 手术引起的 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，WNT16 是维持 软骨稳态，进一步减轻了 DMM 模型中早期建立的 PTOA。去探索独特的 我们建议确定我们的自组装肽-核纳米平台的潜力以确定长期结果 DMM 模型中联合抗炎和合成代谢纳米疗法的研究。我们相信这些努力可能会 为 PTOA 开发一种改善疾病的纳米治疗方法。从这些研究中获得的见解可能是 适用于一般OA治疗。