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Targeted therapy for osteoarthritis

骨关节炎的靶向治疗

基本信息

批准号：
9280825
负责人：
KAREN A. HASTY
金额：
--
依托单位：
MEMPHIS VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
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/9280825
关键词：
Age-Years Alpha Cell 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 I Kappa B-Alpha IkappaB kinase Immunohistochemistry Incidence Inflammatory Arthritis Inhibition of Matrix Metalloproteinases Pathway Interruption Intervention Intravenous 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 Microarray Analysis Military Personnel Modeling Monoclonal Antibodies Mus Musculoskeletal Pain NF-kappa B Occupational Operative Surgical Procedures Outcome Patellar Dislocation Pathology Patients Peptides Permeability Pharmaceutical Preparations Pharmacology Phase Polymers Population Prevalence Prevention Production Proteins Quality of life RNA Regimen Replacement Arthroplasty Reporter 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 cartilage degradation cell type collagenase collagenase 3 disability enzyme activity experimental study gene discovery high risk improved in vivo in vivo imaging in vivo imaging system inhibitor/antagonist innovation joint injury ligament injury macrophage mouse model nanomedicine nanoparticle novel novel strategies palliative prevent promoter public health relevance receptor targeted delivery targeted treatment

项目摘要

DESCRIPTION (provided by applicant): 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 b 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.

描述（由申请人提供）：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。目前还没有能够预防或改变疾病进程的有效药物。该项目将使用一种新的介入纳米医学方法来预防OA。具体而言，我们将使用靶向抑制剂来阻断核因子κ B（NF？B）和导致基质金属蛋白酶-13（MMP-13）表达的下游信号传导元件的表达，基质金属蛋白酶-13是一种负责关节软骨中II型胶原降解的胶原酶。我们的假设是，由NF启动的信号通路中断？B并通过缺氧诱导因子-2 α（HIF-2 β）增殖将被证明在早期OA中非常有效。通过减少MMP-13，我们将防止导致大部分病理的II型胶原蛋白的不可逆损失。为了验证我们的假设，我们将使用内侧半月板（DMM）不稳定诱导的OA小鼠模型。为了预防疾病，我们将使用一种细胞渗透肽（NBD），该肽已被证明在实验性炎症性关节炎中有效。将通过使用II型胶原蛋白（MabCII）的诊断性近红外荧光（NIF）单克隆抗体进行体内成像，并通过关节的组织病理学确认治疗小鼠中DMM诱导的OA的严重程度和进展。NBD肽抑制NF？B激活在体内将b评估在小鼠与转基因含有NF？荧光素酶报告基因上游的启动子中的B应答元件。缺氧诱导因子（HIF- 2 β，由EPAS 1编码）已被证明是负责表达MMP-13和OA在DMM模型。我们将研究的假设，NF？B激活是关节不稳定中诱导OA关键早期点，且阻止其激活将阻断下游表达诱导 HIF-2的表达，并最终表达其靶基因，如基质金属蛋白酶MMP-13。微阵列分析RNA从DMM小鼠膝盖将被用来发现基因与NF？B激活。为了建立使用靶向递送系统来抑制关节炎的可行性和功效，我们将采用抗体靶向纳米体包封来将治疗剂递送到特定的局部位点。将使用针对II型胶原的单克隆抗体（MabCII）靶向纳米体以定位于受损的软骨或针对Lyc 6的抗体以定位于活化的巨噬细胞。由于肌肉骨骼疼痛、纤维化和肌腱炎，MMPs的合成抑制剂在临床试验中已被证明存在问题。我们将通过用包装在pH响应性、内体溶解性智能聚合物纳米颗粒（SPN）中的抑制剂选择性地仅阻断局部产生的MMP-13来克服该问题。纳米颗粒的独特之处在于，它定位于特定位点，但保持包装，直到由于在外壳中掺入MMP-13肽而通过MMP-13蛋白水解活性（邻近激活靶向; PAT）释放。提出了充分评估疾病发展和相关介质表达的方法。这些实验提供了一种新的方法来管理迄今为止一直是一个棘手的问题。