Gene Therapy for Reconstructing Periodontal Tissues

描述（由申请人提供）：牙槽骨缺损重建的主要挑战是同时修复牙槽骨、牙骨质和功能性牙周韧带（PDL）。到目前为止，主要的限制存在于可预测性和再生程度可实现再生牙周治疗。基因治疗在靶向、传递和提高生长促进因子（如bmp和PDGFs）的生物利用度以刺激牙周缺损的再工程方面已显示出强大的潜力。这种竞争性更新的目标是开发新的组合基因传递策略，并将其应用于口腔和牙周病重建模式的相关模型。利用合适的载体传递系统和载体构建优化促生长分子的基因转移，修复相关的牙槽骨（牙支撑）缺陷。具体目的1：确定组合基因传递策略在实验性大鼠牙周病模型中组织工程牙周结构的能力，并测量基因治疗载体在体内的全身生物分布。具体目标2：应用传统和基于图像的支架组合基因传递策略，用于比格犬实验性牙支撑骨缺损的再生医学应用。这些研究的结果将有助于更好地理解持续生长因子和基因传递在牙周伤口修复中的作用。该项目的长期目标是优化和验证临床前基因治疗方法，为考虑将其应用于人类临床条件下修复大面积牙周、口腔和颅面骨缺损提供足够的证据。

DESCRIPTION (provided by applicant): A major challenge in the reconstruction of tooth-supporting alveolar bone defects is the simultaneous restoration of alveolar bone, cementum and a functional periodontal ligament (PDL). To date, major limitations exist with the predictability and extent of regeneration achievable via available regenerative periodontal therapies. Gene therapy has demonstrated strong potential to target, deliver, and improve bioavailability of growth-promoting factors (such as BMPs and PDGFs) to stimulate the re-engineering of periodontal defects. The goal of this competitive renewal is to exploit novel combinatorial gene delivery strategies and apply them to relevant models of oral and periodontal disease reconstructive modalities. Approaches will be employed to optimize gene transfer of growth promoting molecules using appropriate carrier delivery systems and vector constructs to repair relevant alveolar bone (tooth-supporting) defects. The specific aims of this proposal are: Specific Aim 1: To determine the ability of combinatorial gene delivery strategies to tissue engineer periodontal structures in an experimental periodontal disease model in rats as well as measure systemic biodistribution of gene therapy vectors in vivo. Specific Aim 2: To apply combinatorial gene delivery strategies using conventional and image-based scaffolding for regenerative medicine applications in experimental tooth- supporting bone defects in beagle dogs. Results from these studies will aid in the better understanding of sustained growth factor and gene delivery on periodontal wound repair. The long-term goal of this project will optimize and validate preclinical gene therapeutic approaches to provide sufficient evidence to consider application to human clinical conditions to repair large periodontal and oral and craniofacial bone defects.