Targeted therapy for osteoarthritis

骨关节炎的靶向治疗

• 批准号: 8634986
• 负责人: KAREN A. HASTY
• 金额: --
• 依托单位: MEMPHIS VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8634986
• 关键词: Accounting; Age-Years; Anterior Cruciate Ligament; Antibodies; Arthritis; Binding; Biological Assay; Cartilage; Cartilage Matrix; Cells; Chondrocytes; Clinical Trials; Collagen; Collagen Type II; Collagen Type X; Complex; Coupled; Degenerative polyarthritis; Development; Diagnostic; Disease; Dose; Drug Delivery Systems; Elements; Encapsulated; Enzyme-Linked Immunosorbent Assay; Enzymes; Fibrosis; Gene Targeting; General Population; Goals; Histological Techniques; Histopathology; Human Resources; Hypoxia Inducible Factor; IkappaB kinase; Image; Immunohistochemistry; Incidence; Indium; Inhibition of Matrix Metalloproteinases Pathway; Interruption; Joint Instability; Joints; Knee; Knee joint; Link; Luciferases; Macrophage Activation; Matrix Metalloproteinase Inhibitor; Matrix Metalloproteinases; Measures; Mechanical Stress; Medial meniscus structure; Mediator of activation protein; Methods; Military Personnel; Modeling; Monoclonal Antibodies; Mus; Musculoskeletal Pain; NF-kappa B; Occupational; Operative Surgical Procedures; Outcome; Patellar Dislocation; Pathology; Patients; Peptides; Pharmaceutical Preparations; Phase; Polymers; Population; Prevalence; Prevention; Production; Proteins; Quality of life; RNA; Regimen; Replacement Arthroplasty; Reporter; Rheumatoid Arthritis; Risk; Role; Services; Severities; Shoulder Dislocation; Signal Pathway; Signal Transduction; Site; Small Interfering RNA; System; Tendinitis; Testing; Therapeutic Agents; Time; Tissues; Transgenes; Up-Regulation; Vascular Endothelial Growth Factors; Veterans; Work; articular cartilage; bHLH-PAS factor HLF; cell type; collagenase; collagenase 3; disability; enzyme activity; gene discovery; high risk; improved; in vivo; in vivo imaging; inhibitor/antagonist; innovation; joint injury; ligament injury; macrophage; mouse model; nanomedicine; nanoparticle; novel; novel strategies; palliative; prevent; promoter; public health relevance; receptor; research study; targeted delivery

Osteoarthritis (OA) is a major cause of disability in the general population and is increased in Veterans. There are currently no effective pharmacologic agents capable of preventing or altering the course of disease. This project will use a novel interventional nanomedicine approach for preventing OA. Specifically, we will use targeted inhibitors to block activation of nuclear factor kappa B (NF¿B) and expression of the downstream signaling elements that result in expression of matrix metalloproteinase-13 (MMP-13), a collagenase responsible for degradation of type II collagen in articular cartilage. Our hypothesis is that interruption of the signaling pathway initiated by NF¿B and propagated by hypoxia inducible factor-2 alpha (HIF-2¿) will prove extremely effective in early OA. By reducing MMP-13 we will prevent the irreversible loss of type II collagen responsible for much of the pathology. To test our hypothesis, we will use a mouse model of OA induced by destabilization of the medial meniscus (DMM). To prevent disease we will use a cell-permeable peptide (NBD) that has proven effective in experimental inflammatory arthritis. The severity and progression of OA induced by DMM in the treated mice will be quantitated by in vivo imaging using diagnostic near-infrared fluorescent (NIF) monoclonal antibody to type II collagen (MabCII) and confirmed by histopathology of the joints. Efficacy of the NBD peptide to inhibit NF¿B activation in vivo will be evaluated in mice with a transgene containing NF¿B responsive elements in the promoter upstream from a luciferase reporter. Hypoxia-inducible factor (HIF- 2¿, encoded by EPAS1) has been shown to be responsible for expression of MMP-13 and OA in the DMM model. We will examine the hypothesis that NF¿B activation is a critical early point for induction of OA in joint instability and that prevention of its activation will block the downstream induction of expression of HIF-2¿ and ultimately expression of its target genes such as matrix metalloproteinase MMP-13. Microarray analyses on RNA from the DMM mouse knee will be used to discover genes that are linked to NF¿B activation. To establish the feasibility and efficacy of using a targeted delivery system to suppress arthritis we will employ antibody- targeted nanosome encapsulation to deliver the therapeutic agent to specific local sites. Nanosomes will be targeted using a monoclonal antibody to type II collagen (MabCII) for localization to damaged cartilage or antibody to Lyc6 for localization to activated macrophages. Synthetic inhibitors of MMPs have proven problematic in clinical trials due to musculoskeletal pain, fibrosis and tendonitis. We will overcome that problem by selectively blocking only locally produced MMP-13 with an inhibitor packaged within a pH-responsive, endosomolytic smart polymer nanoparticle (SPN). The nanoparticle is unique in that it localizes to specific sites but remains packaged until it is released by MMP-13 proteolytic activity (proximity activated targeting; PAT) due to the incorporation of an MMP-13 peptide in the outer shell. Methods for fully evaluating the development of disease and expression of the mediators involved are proposed. These experiments provide a novel approach to managing what has heretofore been an intractable problem.

骨关节炎 (OA) 是普通人群残疾的主要原因，并且在退伍军人中发病率有所增加。那里 目前尚无能够预防或改变病程的有效药物。这 该项目将使用一种新型介入纳米医学方法来预防 OA。具体来说，我们将使用 靶向抑制剂可阻断核因子 kappa B (NF¿B) 的激活和下游表达 导致基质金属蛋白酶-13 (MMP-13)（一种胶原酶）表达的信号元件 负责关节软骨中 II 型胶原蛋白的降解。我们的假设是，中断 由 NF¿B 启动并由缺氧诱导因子 2 α (HIF-2¿) 传播的信号通路将证明 对早期 OA 非常有效。通过减少 MMP-13，我们将防止 II 型胶原蛋白的不可逆损失 造成大部分病理学变化的原因。为了验证我们的假设，我们将使用 OA 诱导的小鼠模型 内侧半月板（DMM）不稳定。为了预防疾病，我们将使用细胞渗透性肽 (NBD) 已被证明对实验性炎症关节炎有效。 OA 的严重程度和进展 将使用诊断性近红外荧光 (NIF) 通过体内成像对接受治疗的小鼠中的 DMM 进行定量 II 型胶原蛋白单克隆抗体 (MabCII) 并经关节组织病理学证实。功效 NBD 肽在体内抑制 NF¿B 激活的作用将在含有 NF?B 转基因的小鼠中进行评估 荧光素酶报告基因上游启动子中的响应元件。缺氧诱导因子（HIF- 2¿，由 EPAS1 编码）已被证明负责 DMM 中 MMP-13 和 OA 的表达 模型。我们将检验以下假设：NF¿B 激活是关节中诱导 OA 的关键早期点。 不稳定性，并且阻止其激活将阻止 HIF-2 表达的下游诱导，并且 最终表达其靶基因，例如基质金属蛋白酶MMP-13。微阵列分析 来自 DMM 小鼠膝盖的 RNA 将用于发现与 NF¿B 激活相关的基因。建立 使用靶向递送系统抑制关节炎的可行性和有效性，我们将采用抗体- 靶向纳米体封装将治疗剂递送到特定的局部位点。纳米体将是 使用 II 型胶原单克隆抗体 (MabCII) 定位受损软骨或 Lyc6 抗体用于定位到活化的巨噬细胞。 MMP 的合成抑制剂已被证明 由于肌肉骨骼疼痛、纤维化和肌腱炎，在临床试验中存在问题。我们将克服这个问题 通过使用包装在 pH 响应性容器内的抑制剂选择性地阻断局部产生的 MMP-13， 内体溶解智能聚合物纳米颗粒（SPN）。纳米颗粒的独特之处在于它定位于特定位点 但仍保持包装状态，直至通过 MMP-13 蛋白水解活性释放（邻近激活靶向；PAT） 由于外壳中掺入了 MMP-13 肽。全面评估发展的方法 提出了疾病的发生和相关介质的表达。这些实验提供了一种新颖的 解决迄今为止一直是一个棘手问题的方法。