The study of gene therapy for aseptic loosening using a mouse implant model

描述(由申请人提供)： 无菌性松动已成为全关节置换术的主要并发症，发生率高达34%。我们的长期目标是开发治疗方法，以防止或延缓假体关节无菌性松动的过程。我们的假设是，磨屑相关的炎症和骨溶解是假体周围组织中独立但相关的机制，需要抗炎治疗和抗骨溶解治疗来抑制无菌性松动。将通常较短的半衰期治疗剂输送到松动的假体关节是非常有问题的。基因治疗虽然仍处于初级阶段，但为靶向传递和治疗性蛋白的持续表达提供了有吸引力的途径(S)。这项建议的目的是验证由于磨屑刺激而导致假体关节失败的小鼠长期模型，以评估抗炎和骨溶解的联合基因治疗。这将通过追求以下特定目标来实现：(1)表征长期的碎屑相关骨吸收和关节假体失败的小鼠模型的生物力学和病理学方面的特征；(2)评估联合抗炎和抗骨溶解基因治疗在预防或治疗碎屑相关种植体松动方面的有效性；以及(3)检测细胞-基因(体外)治疗的影响和细胞迁移，并在转基因表达和传播、长期有效性和潜在的不良反应方面与体内基因转移进行比较。这项研究的成功结果将验证无菌性松动研究的有用工具，并为病毒介导的治疗性蛋白的基因传递，特别是OPG与促炎细胞因子阻滞剂的联合应用，作为治疗碎片相关假体松动的一种有前景的治疗方案奠定重要基础。

DESCRIPTION (provided by applicant): Aseptic loosening has become the major complication of total joint replacement, with an incidence of as high of 34%. Our long-term goal is to develop therapeutic approaches to prevent or retard the process of aseptic loosening of prosthetic joint. Our hypothesis is that wear debris-associated inflammation and osteolysis are separate but related mechanisms in the periprosthetic tissue, and both anti-inflammatory therapy and antiosteolytic therapy are required to inhibit aseptic loosening. Delivery of the generally short half-life therapeutic agents to the loosening prosthetic joint is highly problematic. Gene therapy, though still in its infancy, provides attractive avenue for targeted delivery and sustained expression of therapeutic protein(s). The objective of this proposal is to validate a murine long-term model of a prosthetic joint failure due to wear debris stimulation for the evaluation of combination gene therapy against inflammation and osteolysis. This will be accomplished by pursuing the following specific aims: (1) to characterize the biomechanical and pathological aspects of a longterm mouse model of debris-associated bone resorption and joint prosthesis failure; (2) to evaluate the efficacy of combination anti-inflammatory and anti-osteolytic gene therapy in preventing or treating debris-associated implant loosening; and (3) to examine the influence and cell trafficking of a cell-gene (ex vivo) therapy, and compare it with in vivo gene transfer on the aspects of transgene expression and dissemination, long-term effectiveness, and potential adverse effects. The successful outcome of the study will validate a useful tool for the investigation of aseptic loosening, and lay important foundations for virus-mediated gene delivery of therapeutic proteins, especially OPG in combination with pro-inflammatory cytokine blockers, as a promising therapeutic regimen for debris-associated prosthetic loosening.