Early Detection and Quantification of OA

描述（由申请人提供）：目前，最常见的关节炎（骨关节炎）的治疗主要是姑息性的，直到关节完全功能障碍，需要进行假体置换。开发有效的OA治疗存在许多障碍。一个是缺乏良好的诊断工具来有效地识别疾病的早期阶段，并在通常用于治疗测试的小动物模型中监测其进展。组织学评价是OA的传统评估，但这需要处死动物，使用繁琐的主观标准，可能包含抽样误差，并且不能用于单个动物的连续测量。我们的总体目标是建立一种创新的方法来识别OA的早期软骨损伤，并定量评估其在体内的进展。早期OA的识别将允许在疾病的最早阶段进行介入治疗，此时病理学可能更适合干预。我们建议使用单克隆抗体（单克隆抗体）的天然II型胶原蛋白（CII），结合受损的软骨，以确定早期亚临床病变和定量疾病进展的OA。如果成功，这将提供一种廉价且可重复的方法，可用于诊断和监测相对较短至中等时间段内治疗对OA进展的影响。我们将使用OA动物模型建立我们方法的有效性;一种充分表征的手术横断小鼠模型，用于使小鼠内侧半月板（DMM）不稳定，以及两种自发性骨关节炎模型，Dunkin-Hartley豚鼠和Str/Ort小鼠具有许多人类OA的特征。我们将使用和比较两种方法的本地化有针对性的荧光探针受损的软骨; MabCII标记的近红外发射荧光（NIF）染料和MabCII靶向nanosomes封装NIF静脉注射到这些动物。损伤程度将使用IVIS（R）成像技术进行量化，并与通过荧光标记和高分辨率MRI合作研究确定的关节的传统组织病理学指标相关联。我们的假设，初步数据的支持，是荧光标记的抗体（NIF-MabCII）将选择性地定位到关节软骨表面被侵蚀和CII暴露的关节。我们预计该技术将非常敏感，并确定最小的软骨损伤，更大和更先进的病变将结合更大量的NIF-MabCII。我们还将测试修改这种方法的可行性，以定量测量与MabCII靶向纳米体加载99 mTc锝，可用于评估患者使用现有的临床协议和可用的设备。 公共卫生相关性：骨关节炎是一种老化软骨的退行性疾病，通常始于一个小的病变，逐渐退化。我们将使用选择性单克隆抗体检测和测量不同动物模型中的早期OA，并将小荧光脂质体靶向受损软骨。

DESCRIPTION (provided by applicant): Treatments for the most prevalent form of arthritis, osteoarthritis (OA), currently are primarily palliative until joints become totally dysfunctional and prosthetic replacement is needed. There are numerous obstacles for developing effective OA therapy. One is the lack of good diagnostic tools for efficiently identifying early stages of the disease and monitoring its progression in small animal models typically used for therapeutic testing. Histopathological evaluation is the traditional assessment for OA, but this requires sacrifice of the animal, uses tedious subjective criteria, may contain sampling error and cannot be used for serial measurements in a single animal. Our overall goal is to establish an innovative method to identify early cartilage damage in OA and to quantitatively assess its progression in vivo. Identification of early OA would permit interventional therapy at the earliest stages of disease when the pathology may be more amenable to intervention. We propose to use monoclonal antibodies (Mab) to native type II collagen (CII) that bind damaged cartilage to identify early subclinical lesions and quantitate disease progression in OA. If successful, this will provide an inexpensive and reproducible method that can be used for diagnosis and to monitor the effects of therapy on OA progression over relatively short to intermediate time periods. We will establish the validity of our approach, using animal models of OA; a well characterized mouse model of surgical transection for destabilization of the medial meniscus (DMM) in mice, and two models of spontaneous osteoarthritis with Dunkin-Hartley guinea pigs and Str/Ort mice that share many features of human OA. We will use and compare two methods of localization of targeted fluorescent probes to damaged cartilage; MabCII labeled with near infrared emitting fluorescent (NIF) dyes and MabCII-targeted nanosomes encapsulating NIF intravenously injected into these animals. The degree of damage will be quantified using IVIS(R) imaging technology and correlated with traditional histopathological indices for the joints identified by fluorescently labeling and in collaborative studies for high resolution MRI. Our hypothesis, supported by preliminary data, is that the fluorescently labeled antibodies (NIF-MabCII) will selectively localize to joints in which the surface of articular cartilage is eroded and CII is exposed. We expect that the technique will be extremely sensitive and identify minimal cartilage damage and that larger and more advanced lesions will bind larger quantities of NIF-MabCII. We will also test the feasibility of modifying this approach for quantitative measurements with MabCII-targeted nanosomes loaded with 99mTc technetium which could be used for evaluation in patients using existing clinical protocols and available equipment. PUBLIC HEALTH RELEVANCE: Osteoarthritis is a degenerative disease of aging cartilage that typically begins as a small lesion that progressively worsens. We will use a selective monoclonal antibody to detect and measure early OA in different animal models and to target small fluorescent liposomes to damaged cartilage.