Gene Transfer Treatment of Articular Cartilage Damage

描述（由申请人提供）：将生长因子基因转移至关节软骨细胞可能能够增强关节软骨修复的基于细胞的方法。目前可用的数据不足以转化为临床应用。本建议的目的是帮助缩小目前的机制知识和治疗应用之间的差距。我们将重点关注三个相关的具体目标。目标1：通过确定所选生长因子之间的相互作用如何调节关节软骨细胞功能，确定一组用于关节软骨修复的潜在治疗性生长因子基因。 假设1：当用于关节软骨细胞基因转移时，IGF-I、FGF-2、BMP-2和BMP-7相互作用以差异调节影响软骨细胞修复功能的基因的表达。目的2：确定遗传和组织工程方法，当应用于关节软骨细胞，是相互依赖的。假设二：化学上不同的生物材料，包括藻酸盐，胶原蛋白和透明质酸为基础的凝胶，差异调节生长因子基因转移的影响。目标3：确定在软骨损失的大型动物模型中，转移一组优化的生长因子基因与优化的生物材料结合是否可以产生持久的修复。 假设3：关节软骨损伤的最佳修复需要细胞增殖和基质合成的调节。通过基因转移与选择的生长因子组合处理的关节软骨细胞，并在选择的水凝胶中递送，差异性地促进马膝关节软骨内关节软骨缺损的修复。这些基因工程和组织工程技术之间的相互作用促进关节软骨细胞修复的证明将有助于深入了解调节基于细胞的疗法的机制，并为将这些疗法转化为人类关节软骨疾病提供关键一步。

DESCRIPTION (provided by applicant): Growth factor gene transfer to articular chondrocytes may be capable of augmenting cell-based approaches to articular cartilage repair. Currently available data is insufficient to enable translation into clinical use. The purpose of this proposal is to help close the gap between present mechanistic knowledge and therapeutic application. We will focus on three related specific aims. Aim 1: Define a potentially therapeutic set of growth factor genes for articular cartilage repair by determining how interactions among selected growth factors regulate articular chondrocyte function. Hypothesis 1: IGF-I, FGF-2, BMP-2, and BMP-7, when employed for articular chondrcyte gene transfer, interact to differentially regulate the expression of genes that influence chondrocyte reparative functions. Aim 2: Determine whether genetic and tissue engineering methods, when applied to articular chondrocytes, are interdependent. Hypothesis 2: Chemically distinct biomaterials, including alginate, collagen, and hyaluronic acid-based gels, differentially modulate the effects of growth factor gene transfer. Aim 3: Determine whether transfer of an optimized set of growth factor genes coupled with an optimized biomaterial can generate durable repair in a large animal model of cartilage loss. Hypothesis 3: Optimal repair of articular cartilage lesions requires a modulation of cell proliferation and matrix synthesis. Articular chondrocytes treated by gene transfer with selected combinations of growth factors and delivered in a selected hydrogel differentially promote repair of intrachondral articular cartilage defects in the equine knee. The demonstration that interactions between these genetic engineering and tissue engineering technologies promote repair by articular chondrocytes would lend insight into the mechanisms that regulate cell-based therapies and provide a key step in the translation of these therapies to human articular cartilage diseases.