Hexosaminidase, a novel target for chondroprotection

己糖胺酶，软骨保护的新靶点

• 批准号: 6880579
• 负责人: YOSHITAKA ICHIKAWA
• 金额: $ 10.7万
• 依托单位: OPTIMER PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-10 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6880579
• 关键词: antiarthritic agent; articular cartilage; beta N acetylhexosaminidase; cartilage metabolism; chondrocytes; collagen; cytoprotection; digital imaging; enzyme inhibitors; enzyme linked immunosorbent assay; enzyme therapy; high performance liquid chromatography; laboratory rabbit; mucopolysaccharides; nuclear magnetic resonance spectroscopy; osteoarthritis; protein degradation; tissue /cell culture

DESCRIPTION (provided by applicant): Osteoarthritis (OA) is the most common joint disease, currently affecting approximately 40 million Americans. The central pathogenetic mechanism in OA is an aberrant cartilage matrix remodeling process with loss of cartilage cells and matrix, resulting in biomechanical joint failure and inflammation. Loss of glycosaminoglycans precedes the degradation of cartilage matrix proteins and appears to be more readily reversible. However, therapeutic approaches targeting this process have not been pursued. In preliminary studies we have identified hexosaminidase as the major glycosaminoglycan degrading enzyme in cartilage and developed OPT-66, a novel potent and specific inhibitor of this enzyme. OPT-66 completely prevented loss of glycosaminoglycans in cultured cartilage. Based on these findings and preliminary in vivo data we propose the hypothesis that hexosaminidase inhibitors represent a novel approach to chondroprotection. The specific aims are: 1. Prepare sustained release formulations of OPT-66 and determine intraarticular retention time. 2. Assess efficacy of OPT-66 formulations in comparison to untreated, saline injected and hyaluronan-treated animals. Efficacy of OPT-66 is defined as significant reduction in: (i) histologic scores by at least 2 grades; (ii) lesion surface by at least 30%; (iii) loss of safranin O staining by at least 20%; (iv) biochemical markers of cartilage degradation.

描述（由申请人提供）：骨关节炎（OA）是最常见的关节疾病，目前影响约4000万美国人。 OA中的中心致病机制是一个异常的软骨基质重塑过程，损失了软骨细胞和基质，导致生物力学关节衰竭和炎症。糖胺聚糖的损失先于软骨基质蛋白的降解，并且似乎更容易可逆。但是，尚未采用针对此过程的治疗方法。在初步研究中，我们确定己糖胺酶是软骨中主要的糖胺聚糖降解酶，并开发了OPT-66，这是该酶的一种新型有效和特异性抑制剂。 OPT-66完全阻止了培养软骨中糖胺聚糖的损失。 基于这些发现和体内数据的初步数据，我们提出了以下假设：己糖胺酶抑制剂代表了一种新型的软骨保护方法。 具体目的是： 1。准备OPT-66的持续释放公式并确定关节内保留时间。 2。与未经处理的盐水注射和透明质酸处理的动物相比，评估OPT-66制剂的功效。 OPT-66的功效定义为：显着降低： （i）至少2年级的组织学评分； （ii）病变表面至少30％； （iii）safranin o染色的损失至少20％； （iv）软骨降解的生化标志物。