Gene Transfer Treatment of Articular Cartilage Damage

描述（由申请人提供）：生长因子基因转移到关节软骨细胞可能能够增加关节软骨修复的细胞基础方法。目前可用的数据不足以使其转化为临床应用。这一建议的目的是帮助缩小目前的机械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。目的1：通过确定选定的生长因子之间的相互作用如何调节关节软骨细胞的功能，定义一组潜在的治疗关节软骨修复的生长因子基因。假设1：当igf - 1、FGF-2、BMP-2和BMP-7用于关节软骨细胞基因转移时，它们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：确定基因和组织工程方法在应用于关节软骨细胞时是否相互依赖。假设2：化学上不同的生物材料，包括海藻酸盐、胶原蛋白和透明质酸凝胶，对生长因子基因转移的影响有不同的调节作用。目的3：确定一组优化的生长因子基因与优化的生物材料的转移是否可以在大型软骨损伤动物模型中产生持久的修复。假设3：关节软骨病变的最佳修复需要调节细胞增殖和基质合成。通过生长因子组合基因转移处理的关节软骨细胞，并在选定的水凝胶中递送，差异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了关节软骨细胞的修复，这将有助于深入了解调节细胞疗法的机制，并为将这些疗法转化为人类关节软骨疾病提供关键的一步。

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. PUBLIC HEALTH RELEVANCE: Articular cartilage damage is the cause of pain and disability from acute joint trauma and chronic joint arthritis, and remains an unsolved problem in modern orthopaedics. Current therapies can help the symptoms that result from cartilage loss, but treatments are lacking that can correct the cartilage loss itself. This is a translational research project that will combine gene therapy and tissue engineering methods in a pre-clinical model to test a potential new treatment approach to articular cartilage repair.