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）是一般人群残疾的主要原因，在退伍军人中增加。那里 目前还没有能够预防或改变疾病进程的有效药物。这 该项目将使用一种新的介入纳米医学方法来预防OA。具体来说，我们将使用 靶向抑制剂阻断核因子κ B（NF B）的活化和下游转录因子的表达， 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型胶原的降解。我们的假设是， 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。 造成了很多病理学上的问题为了验证我们的假设，我们将使用由以下物质诱导的OA小鼠模型： 内侧半月板不稳定（DMM）。为了预防疾病，我们将使用细胞渗透肽（NBD） 已经证明对实验性炎症性关节炎有效。OA的严重程度和进展 将使用诊断性近红外荧光（NIF）通过体内成像定量给药小鼠中的DMM。 II型胶原蛋白的单克隆抗体（MabCII），并通过关节的组织病理学证实。疗效 将在具有含有NF B的转基因的小鼠中评价NBD肽在体内抑制NF B活化 启动子中荧光素酶报告基因上游的应答元件。缺氧诱导因子 由EPAS 1编码）已被证明负责DMM中MMP-13和OA的表达 模型我们将检验NF B激活是关节OA诱导的关键早期点的假设 不稳定性和阻止其活化将阻断下游诱导HIF-2表达， 最终表达其靶基因，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功效，我们将使用抗体- 靶向纳米体包封以将治疗剂递送至特定的局部位点。纳米体将是 使用针对II型胶原的单克隆抗体（MabCII）靶向定位至受损软骨，或 Lyc 6抗体用于定位于活化的巨噬细胞。MMPs的合成抑制剂已经证明 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。我们会克服这个问题的 通过用包装在pH响应性载体中的抑制剂选择性地仅阻断局部产生的MMP-13， 内体溶解智能聚合物纳米颗粒（SPN）。这种纳米粒子的独特之处在于它定位于特定的位点 但保持包装状态，直到通过MMP-13蛋白水解活性释放（邻近激活靶向; PAT） 这是由于在外壳中掺入了MMP-13肽。全面评价发展的方法 的疾病和表达的介质所涉及的建议。这些实验提供了一种新的 解决迄今为止一直是一个棘手问题的方法。