Gene Therapy for Reconstructing Periodontal Tissues

描述(申请人提供)：支持牙齿的牙槽骨缺损重建的一个主要挑战是同时修复骨、牙骨质和功能性牙周膜(PDL)。到目前为止，通过目前的再生牙周疗法实现的修复的可预测性和程度存在显著的局限性。我们已经通过NIDCR的支持证明了基因治疗具有很强的靶向和传递生长促进因子(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的能力。此外，通过在基于图像的支架设计中使用新兴技术来解决牙周缺陷的复杂地形，我们建议使用定制的仿生支架策略来修复牙周伤口。这一竞争性更新的目标是加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。这项建议的具体目标是：具体目标1：发展基于载体和图像的混合支架结构，以使用体外和体内模型修复牙齿支持结构。假设：利用计算机设计的在牙齿-骨界面上具有纤维导向通道的混合支架来控制生长因子基因的输送将刺激和引导骨、韧带和牙骨质的形成。使用直接聚合物涂层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，以修复牙周缺陷。我们将使用生物结合过程使生物材料功能化，以将PDGF和BMPs等生长因子输送到组织工程牙周组织。具体目的2：通过基于成像的支架设计，将局部基因传递方法应用于犬实验性牙周病。假设。基于图像的支架的开发，能够适应牙齿-骨骼界面，并提高牙周伤口处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，我们将使用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。这些研究的结果将使我们能够很好地将这项技术应用于人类临床试验环境，并提交人类临床试验计划拨款，进行第一次人类研究。

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.