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Validation of a novel imaging technique to detect early osteoarthritis using an antibody specific for post-translationally modified collagen type II

使用翻译后修饰 II 型胶原蛋白特异性抗体验证一种检测早期骨关节炎的新型成像技术

基本信息

批准号：
MR/J002747/1
负责人：
Ahuva Nissim
金额：
$ 32.94万
依托单位：
Queen Mary University of London
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2012
资助国家：
英国
起止时间：
2012 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FJ002747%2F1
关键词：
Validation novel imaging technique detect

项目摘要

As the age of the world's population increases, osteoarthritis (OA) is becoming by far the most common joint condition and is a major cause of chronic pain and disability. OA is a disease of the whole joint but one major characteristic is the breakdown of the articular cartilage, a smooth layer of tissue that protects the ends of bones and enables frictionless movement of the joint.Currently there are no treatments that prevent the breakdown of cartilage and patients must depend upon simple pain killers, physiotherapy and ultimately surgical joint replacement. In recent years new therapies for treating OA have been identified (such as inhibitors of the key enzymes that break down the tissue), but the introduction of such treatments, has been hampered by the lack of specific tests capable of detecting early disease (where treatment is most likely to be successful), and discerning modest changes in disease progression following treatment (in order to conduct clinical trials). The current gold standard of OA assessment is by plain X-ray which is insensitive, and MRI which is a more sensitive and specific radiographic tool but costly and harder to access. The bad news is that although large pharmaceutical companies have developed 'safe' and effective drugs to use in individuals with OA, they have chosen not to test these compounds in clinical trials at the current time. There is therefore an urgent unmet need to develop a simple and sensitive tool to detect cartilage damage in man.We have developed a human antibody that binds strongly and specifically to damaged cartilage and we believe that this antibody could be developed as an imaging marker for early OA. We have labelled our antibody with a fluorescent marker and shown that it homes to the joints of mice with inflammatory arthritis (where there is also cartilage damage). Our current proposal is to test this antibody in a mouse model of OA in which OA has been induced by surgically cutting the medial meniscus (leading to joint destabilisation). Two refinements will be made to improve the intensity of staining. Firstly we plan to use a near infra red (NIR) fluorescent probe, which has better tissue penetration and which also reduces background signal. Secondly, we will fuse two antibody fragments together which will improve binding of the antibody to the damaged cartilage and increase the amount of fluorescence that the antibody fragment will carry. If successful we will test this imaging technique in patients (in a subsequent application). The ability to translate this project to humans is tractable especially as the antibody was originally raised against modified human cartilage, and stains damaged tissues from human as well as murine arthritic joints. Translation of this project to the human is likely to have a significant impact on the development, validation and introduction of new treatments for OA.

随着世界人口年龄的增长，骨关节炎（OA）正在成为迄今为止最常见的关节疾病，是慢性疼痛和残疾的主要原因。骨性关节炎是一种整个关节的疾病，但一个主要特征是关节软骨的破坏，关节软骨是一层光滑的组织，保护骨头的末端，使关节无摩擦运动。目前还没有防止软骨破裂的治疗方法，患者必须依靠简单的止痛药、物理治疗和最终的手术关节置换术。近年来，已经确定了治疗OA的新疗法（例如分解组织的关键酶的抑制剂），但由于缺乏能够检测早期疾病（治疗最有可能成功）和识别治疗后疾病进展的适度变化（以便进行临床试验）的特定测试，这些疗法的引入一直受到阻碍。目前评估OA的金标准是通过不敏感的x线平片，而MRI是一种更敏感和特异性的放射成像工具，但价格昂贵且难以获得。坏消息是，尽管大型制药公司已经开发出用于OA患者的“安全”和有效的药物，但他们目前没有选择在临床试验中测试这些化合物。因此，迫切需要开发一种简单灵敏的工具来检测人体软骨损伤。我们已经开发出一种人类抗体，它能与受损软骨紧密结合，我们相信这种抗体可以作为早期OA的成像标记物。我们已经用荧光标记标记了我们的抗体，并表明它是患有炎症性关节炎的老鼠的关节（那里也有软骨损伤）的家。我们目前的建议是在OA小鼠模型中测试这种抗体，其中OA是通过手术切割内侧半月板（导致关节不稳定）诱导的。为了提高染色的强度，将进行两次改进。首先，我们计划使用近红外（NIR）荧光探针，它具有更好的组织穿透性，也可以减少背景信号。其次，我们将两个抗体片段融合在一起，这将改善抗体与受损软骨的结合，并增加抗体片段携带的荧光量。如果成功，我们将在患者身上测试这种成像技术（在随后的应用中）。将这个项目转化为人类的能力是容易处理的，特别是因为抗体最初是针对改良的人类软骨提出的，并且可以染色来自人类和小鼠关节炎关节的受损组织。将该项目转化为人类可能会对OA新疗法的开发、验证和引入产生重大影响。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Autoantibodies to posttranslational modifications in rheumatoid arthritis.

DOI：
10.1155/2014/492873
发表时间：
2014
期刊：
Mediators of inflammation
影响因子：
4.6
作者：
Burska AN;Hunt L;Boissinot M;Strollo R;Ryan BJ;Vital E;Nissim A;Winyard PG;Emery P;Ponchel F
通讯作者：
Ponchel F

Early Detection of Osteoarthritis in the Rat With an Antibody Specific to Type II Collagen Modified by Reactive Oxygen Species

使用活性氧修饰的 II 型胶原蛋白特异性抗体早期检测大鼠骨关节炎