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 的主要发病机制是异常的软骨基质重塑过程，导致软骨细胞和基质的损失，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，并且似乎更容易逆转。然而，尚未寻求针对该过程的治疗方法。在初步研究中，我们已确定氨基己糖苷酶是软骨中主要的糖胺聚糖降解酶，并开发了 OPT-66，一种该酶的新型有效且特异性的抑制剂。 OPT-66 完全防止培养软骨中糖胺聚糖的损失。 基于这些发现和初步体内数据，我们提出这样的假设：氨基己糖苷酶抑制剂代表了一种新的软骨保护方法。 具体目标是： 1. 制备 OPT-66 缓释制剂并测定关节内保留时间。 2. 与未治疗、注射盐水和乙酰透明质酸治疗的动物相比，评估 OPT-66 制剂的功效。 OPT-66 的功效定义为显着降低： (i) 组织学评分至少提高 2 级； (ii) 病变表面至少减少 30%； (iii)番红O染色损失至少20%； (iv) 软骨退化的生化标记。