Gene Transfer Treatment of Articular Cartilage Damage

描述(申请人提供)：将生长因子基因转移到关节软骨细胞可能能够增强基于细胞的关节软骨修复方法。目前可用的数据不足以将其转化为临床使用。这项建议的目的是帮助弥合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，确定一组具有潜在治疗性的关节软骨修复生长因子基因。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，以不同的方式调节影响软骨细胞修复功能的基因的表达。目的2：确定基因工程和组织工程方法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相结合的转移是否能够在大型动物软骨丢失模型中产生持久的修复。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。关节软骨细胞通过基因转移与选定的生长因子组合处理，并在选定的水凝胶中输送，以不同的方式促进马膝关节软骨内关节软骨缺陷的修复。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，这一证明将有助于深入了解基于细胞的疗法的调节机制，并为将这些疗法转化为人类关节软骨疾病提供关键步骤。 公共卫生相关性：关节软骨损伤是急性关节创伤和慢性关节关节炎引起的疼痛和残疾的原因，在现代骨科中仍然是一个悬而未决的问题。目前的治疗方法可以帮助缓解软骨丢失引起的症状，但缺乏能够纠正软骨丢失本身的治疗方法。这是一个转化研究项目，将在临床前模型中结合基因治疗和组织工程方法，以测试一种潜在的关节软骨修复的新治疗方法。

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.