Gene Transfer Treatment of Articular Cartilage Damage

描述(申请人提供)：关节软骨损伤仍然是 整形外科中尚未解决的问题。拟议研究的目的是 阐明自分泌/旁分泌机制在生长中的潜在作用 因子介导的关节软骨修复。这项研究将在体外进行 重组腺相关病毒(RAAV)介导的基因转移 检验以下假设：(1)局部生长因子生产可以 RAAV载体介导的牛关节软骨细胞基因转移 并将促进急性软骨创伤的软骨修复；(2)局部生长 通过rAAV载体介导的基因转移可以实现要素生产 人关节软骨细胞并将促进骨关节炎的修复 软骨；(3)局部生产一种以上的生长因子 通过rAAV载体介导的基因转移和表达的生长因子 相互作用在创伤和骨关节炎软骨修复中的调节 损伤；以及(4)局部生长因子的产生，加上表达 生长因子受体可通过rAAV介导的基因转移获得 并将加强创伤和骨性关节炎软骨损伤的修复。 这些假说将使用胰岛素样生长因子I(IGF-I)和 成纤维细胞生长因子-2、成纤维细胞生长因子-2和目标4中的I型IGF受体 (IGF-IR)。修复将使用生物合成、组织学、生化进行评估 和生物力学参数。这些研究表明，增长 因子介导的软骨修复可通过自分泌/旁分泌实现 机制不仅将使我们深入了解这些因素在 软骨的调节，但可能有助于促进未来的发展 潜在的基于基因转移的疗法。

DESCRIPTION (provided by applicant): Articular cartilage damage remains an unsolved problem in orthopaedics. The purpose of the proposed studies is to elucidate the potential role of autocrine/paracrine mechanisms in growth factor-mediated articular cartilage repair. The studies will employ in vitro recombinant adeno-associated virus (rAAV) mediated gene transfer methods to test the following hypotheses: (1) local growth factor production can be achieved by rAAV vector-mediated gene transfer to bovine articular chondrocytes and will augment cartilage repair in acute cartilage trauma; (2) local growth factor production can be achieved by rAAV vector-mediated gene transfer of human articular chondrocytes and will augment repair of osteoarthritic cartilage; (3) local production of more than one growth factor can be achieved by rAAV vector-mediated gene transfer and expressed growth factors will interact in the regulation of repair in traumatic and osteoarthritic cartilage damage; and (4) local growth factor production, coupled with expression of growth factor receptors can be achieved by rAAV-mediated gene transfer to chondrocytes and will augment repair in traumatic and OA cartilage damage. These hypotheses will be tested using insulin-like growth factor I (IGF-I) and fibroblast growth factor-2, (FGF-2) and, in Aim 4, the type I IGF receptor (IGF-IR). Repair will be assessed using biosynthetic, histological, biochemical and biomechanical parameters. The demonstration by these studies that growth factor-mediated cartilage repair can be achieved through autocrine/paracrine mechanisms would not only lend insight into the role of these factors in cartilage regulation, but may serve to facilitate the development of future potential gene transfer-based therapies.