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

利用小鼠种植体模型进行无菌性松动基因治疗的研究

• 批准号: 7620406
• 负责人: SHANG-YOU YANG
• 金额: $ 6.32万
• 依托单位: VIA CHRISTI REGIONAL MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-15 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7620406
• 关键词: Adverse effects; Adverse reactions; Age; Air; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Biomechanics; Bone Resorption; Bone Tissue; Canis familiaris; Cells; Characteristics; Clinical assessments; Code; Complication; Data; Dependovirus; Effectiveness; Engineering; Enzyme-Linked Immunosorbent Assay; Evaluation; Failure; Fibroblasts; Finite Element Analysis; Foundations; Future; Gene Delivery; Gene Transfer; Gene Transfer Techniques; Genes; Goals; Half-Life; Head; Histologic; Histology; Human; Implant; Incidence; Inflammation; Inflammatory; Investigation; Joint Prosthesis; Joints; Knee joint; Lead; Literature; Longevity; Mediating; Modeling; Molecular; Molecular Biology Techniques; Monitor; Mus; Operative Surgical Procedures; Oryctolagus cuniculus; Osteolysis; Osteolytic; Outcome Study; Particulate; Pathology; Patients; Principal Investigator; Process; Production; Property; Prosthesis; Prosthesis Failure; Publishing; Replacement Arthroplasty; Reporting; Safety; Scanning; Screening procedure; Shear Strength; Sheep; Site; Testing; Therapeutic; Therapeutic Agents; Therapeutic Effect; Therapeutic Intervention; Time; Tissues; Titanium; Transgenes; Treatment Protocols; Tumor necrosis factor receptor 11b; Virus; Weight-Bearing state; Work; Yang; adeno-associated viral vector; anakinra; bone; cellular engineering; combination gene therapy; compare effectiveness; cytokine; gene therapy; in vivo; infancy; innovation; migration; mouse model; novel; osteoclastogenesis; particle; prevent; programs; response; selective expression; stem; targeted delivery; therapeutic protein; therapeutic transgene; tibia; tool; trafficking; transgene expression; tumorigenesis; ultra-high molecular weight polyethylene; vector

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.

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，其发生率高达34%。我们的长期目标是开发治疗方法来预防或延缓人工关节无菌性松动的过程。我们的假设是磨损碎屑相关的炎症和骨质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质溶解治疗来抑制无菌性松动。将通常半衰期短的治疗剂递送到松动的假体关节是非常成问题的。基因治疗虽然仍处于起步阶段，但为治疗性蛋白质的靶向递送和持续表达提供了有吸引力的途径。本提案的目的是验证由于磨损碎屑刺激导致的人工关节失效的小鼠长期模型，以评估联合基因治疗对炎症和骨质溶解的影响。这将通过追求以下具体目标来实现：（1）表征碎片相关骨吸收和关节假体失效的长期小鼠模型的生物力学和病理学方面;（2）评价抗炎和抗溶骨性基因治疗组合在预防或治疗碎片相关植入物松动中的功效;以及（3）检查细胞-基因（离体）治疗的影响和细胞运输，并将其与体内基因转移在转基因表达和传播、长期有效性和潜在副作用方面进行比较。该研究的成功结果将为无菌性松动的研究提供一个有用的工具，并为病毒介导的治疗性蛋白质的基因递送奠定重要基础，特别是OPG与促炎细胞因子阻断剂的组合，作为一种有前途的治疗方案，用于碎片相关的假体松动。

项目成果

Effects of Ti, PMMA, UHMWPE, and Co-Cr wear particles on differentiation and functions of bone marrow stromal cells.

• DOI: 10.1002/jbm.a.34595
• 发表时间: 2013-10
• 期刊: JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART A
• 影响因子: 4.9
• 作者: Jiang, Yunpeng;Jia, Tanghong;Gong, Weiming;Wooley, Paul H.;Yang, Shang-You
• 通讯作者: Yang, Shang-You

Titanium particle-challenged osteoblasts promote osteoclastogenesis and osteolysis in a murine model of periprosthestic osteolysis.

• DOI: 10.1016/j.actbio.2013.03.010
• 发表时间: 2013-07
• 期刊: ACTA BIOMATERIALIA
• 影响因子: 9.7
• 作者: Jiang, Yunpeng;Jia, Tanghong;Gong, Weiming;Wooley, Paul H.;Yang, Shang-You
• 通讯作者: Yang, Shang-You

Cell-based osteoprotegerin therapy for debris-induced aseptic prosthetic loosening on a murine model.

• DOI: 10.1038/gt.2010.64
• 发表时间: 2010-10
• 期刊: Gene therapy
• 影响因子: 5.1

Current research in the pathogenesis of aseptic implant loosening associated with particulate wear debris.

• 发表时间: 2013-02
• 期刊: Acta orthopaedica Belgica
• 影响因子: 0.4
• 作者: Yunpeng Jiang;T. Jia;P. Wooley;Shang-You Yang

The effect of osteoprotegerin gene modification on wear debris-induced osteolysis in a murine model of knee prosthesis failure.

在膝关节假体衰竭的鼠模型中，骨蛋白蛋白蛋白基因的基因修饰对磨损碎屑诱导的溶解度的影响。

• DOI: 10.1016/j.biomaterials.2009.07.032
• 发表时间: 2009-10
• 期刊: BIOMATERIALS
• 影响因子: 14
• 作者: Zhang, Tao;Yu, Haiying;Gong, Weiming;Zhang, Laibo;Jia, Tanghong;Wooley, Paul H.;Yang, Shang-You
• 通讯作者: Yang, Shang-You