Early Detection and Quantification of OA

描述（由申请人提供）：治疗最常见的关节炎，骨关节炎（OA），目前主要是姑息性的，直到关节完全功能失调和需要假体置换。发展有效的OA治疗有许多障碍。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，并在通常用于治疗试验的小动物模型中监测其进展。组织病理学评估是OA的传统评估方法，但这需要牺牲动物，使用繁琐的主观标准，可能包含抽样误差，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，并定量评估其体内进展。早期骨关节炎的识别将允许在疾病的早期阶段进行介入治疗，此时病理可能更易于干预。我们建议使用结合受损软骨的天然II型胶原（CII）的单克隆抗体（Mab）来识别OA的早期亚临床病变和定量疾病进展。如果成功，这将提供一种廉价且可重复的方法，可用于诊断和监测治疗在相对短至中期期间对OA进展的影响。我们将使用OA动物模型来验证我们方法的有效性；一种具有良好特征的小鼠内侧半月板（DMM）手术破坏模型，以及Dunkin-Hartley豚鼠和Str/Ort小鼠的两种自发性骨关节炎模型，它们具有人类OA的许多特征。我们将使用并比较两种定位受损软骨的靶向荧光探针的方法；用近红外荧光（NIF）染料标记MabCII，并将MabCII靶向纳米体包裹NIF，静脉注射到这些动物体内。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合作研究确定的传统关节组织病理学指标相关联。我们的假设得到了初步数据的支持，即荧光标记抗体（NIF-MabCII）将选择性地定位于关节软骨表面被侵蚀和CII暴露的关节。我们期望这项技术将非常敏感，并识别最小的软骨损伤，更大和更晚期的病变将结合更多的NIF-MabCII。我们还将测试将这种方法用于mabcii靶向纳米体的定量测量的可行性，这些纳米体装载了99mTc锝，可用于使用现有临床方案和可用设备对患者进行评估。

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.