Gene Therapy for Reconstructing Periodontal Tissues

描述（由申请人提供）：重建支持牙齿的牙槽骨缺损的一个主要挑战是同时修复骨、牙骨质和功能性牙周韧带（PDL）。迄今为止，通过目前的再生牙周治疗，修复的可预测性和程度存在显著的局限性。通过NIDCR的支持，我们已经证明基因治疗具有很强的潜力，可以靶向并传递生长促进因子（如血小板衍生生长因子、骨形态发生蛋白和LIM结构域矿化蛋白）来刺激牙周缺损的再工程。此外，通过利用基于图像的支架设计中的新兴技术来解决牙周缺陷的复杂地形，我们建议采用定制的仿生支架策略来修复牙周伤口。这种竞争性更新的目标是增强新的基因传递再生医学策略，并将其应用于口腔和牙周病的相关模型。本提案的具体目标是：具体目标1：开发基于矢量和图像的混合支架结构，使用离体和体内模型修复牙齿支撑结构。假设：通过计算设计在牙-骨界面具有纤维导向通道的杂交支架来控制生长因子基因的递送，将刺激和引导骨、韧带和骨质的形成。使用直接和反应性聚合物涂层促进生长因子基因传递的比较将在体内评估修复牙周缺损。我们将采用一种生物偶联工艺来功能化生物材料，以将生长因子（如PDGF和bmp）输送到组织工程牙周病。特定目标2：通过基于图像的支架设计在实验性犬牙周病中使用区域基因传递方法。假设。基于图像的支架的开发，可以适应牙-骨界面，提高牙周伤口部位生长因子基因的生物利用度。我们将利用结扎诱导的牙周病模型来制造牙周骨缺损。然后，我们将采用SA #1的基因传递技术，使用基于图像的混合支架来促进牙周修复。这些调查的结果应该建立在我们小组在牙周组织工程领域取得的证据的基础上。这些调查的结果将使我们能够很好地将这项技术应用于人体临床试验环境，并为首次人体研究提交人体临床试验计划拨款。

DESCRIPTION (provided by applicant): A major challenge in the reconstruction of tooth-supporting alveolar bone defects is the simultaneous restoration of bone, cementum and a functional periodontal ligament (PDL). To date, significant limitations exist with the predictability and extent of repair achievable via current regenerative periodontal therapies. We have demonstrated through the support of the NIDCR that gene therapy has strong potential to target and deliver growth-promoting factors (such as platelet-derived growth factor, bone morphogenetic proteins and LIM domain mineralization protein) to stimulate the re-engineering of periodontal defects. Further, by employment of emerging technologies in image-based scaffold design to address the complex topography of periodontal defects, we propose to employ customized biomimetic scaffolding strategies to repair periodontal wounds. The goal of this competitive renewal is to enhance novel gene delivery regenerative medicine strategies and apply them to relevant models of oral and periodontal disease. The specific aims of this proposal are: Specific Aim 1: Development of vector and image-based hybrid scaffolding constructs to repair tooth- supporting structures using ex vivo and in vivo models. Hypothesis: The controlled delivery of growth factor genes using computational design of hybrid scaffolds with fiber-oriented channels at the tooth-bone interface will stimulate and guide bone, ligament and cementum formation. A comparison of using direct versus reactive polymer coatings to facilitate growth factor gene delivery will be evaluated in vivo to repair periodontal defects. We will employ a bioconjugation process to functionalize biomaterials for the delivery of growth factors such as PDGF and BMPs to tissue engineer periodontia. Specific Aim 2: To use regional gene delivery methods via imaged-based scaffold design in experimental periodontal disease in canines. Hypothesis. The development of image-based scaffolds that can adapt to the tooth-bone interface and improve the bioavailability of growth factor genes at periodontal wound sites. We will utilize a ligature-induced model of periodontal disease to create periodontal osseous defects. We will then employ gene delivery technologies from SA #1 to use image-based hybrid scaffolds to promote periodontal repair. The results of these investigations should build on the body of evidence that our group has achieved in the field on periodontal tissue engineering. The findings from these investigations will well position us to apply this technology to the human clinical trial setting and submit a human clinical trial planning grant for a first-in-human investigation.