Assessment of combinatorial gene therapy for the treatment of Osteoarthritis

组合基因疗法治疗骨关节炎的评估

• 批准号: 9284382
• 负责人: Adrianne Gouge Stone
• 金额: $ 4.4万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9284382
• 关键词: Acute; Address; Adverse event; Affect; Age; Age-Months; American; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Area; Arthralgia; Behavior Therapy; Bone Spur; Cartilage; Cartilage Matrix; Cells; Chondrocytes; Clinical; Complex; Data; Degenerative polyarthritis; Development; Disease; Disease Progression; Equilibrium; Etiology; Extracellular Matrix; Functional disorder; Gene Expression Profiling; Gene Transfer; Generations; Genetic Transcription; Goals; Harvest; Health Care Costs; Histologic; Hypertrophy; Hypoxia; Hypoxia Inducible Factor; Imaging Techniques; Individual; Inflammation; Inflammatory Response; Injectable; Injection of therapeutic agent; Injury; Interleukin-1; Joints; Lead; Ligaments; Lubrication; Mechanical Stress; Mediating; Medical; Medication Management; Modeling; Molecular; Mono-S; Mus; Nature; Operative Surgical Procedures; Optics; Pain management; Pathogenesis; Pathway interactions; Patients; Phase; Physical therapy; Population; Protein Isoforms; Proteoglycan; Publishing; Recombinants; Replacement Arthroplasty; Research; Signal Pathway; Signal Transduction; Staining method; Stains; Supplementation; Surface; Synovial Fluid; Testing; Therapeutic; Therapeutic Intervention; Transgenic Mice; Translational Repression; Up-Regulation; Viral Vector; Wild Type Mouse; Work; age related; anakinra; arthropathies; articular cartilage; base; combinatorial; curative treatments; cytokine; end stage disease; gene therapy; in vivo; joint destruction; joint stiffness; microCT; new therapeutic target; novel; overexpression; pre-clinical trial; prevent; programs; progressin; promoter; public health relevance; response; subchondral bone; targeted treatment; therapeutic target; vector

 DESCRIPTION (provided by applicant): Osteoarthritis (OA) is a progressively debilitating condition involving joint degeneration that causes substantial joint stiffness and pain, decreased mobility, and increased health care costs. Despite approximately 27 million Americans being afflicted with this disease, there are no medical treatments that significantly alter its progressin. Currently, an individual suffering from OA will only be proscribed pain management medication, physical therapy and lifestyle modification, and in end---stage disease a joint replacement surgery will be advised. Injections of cytokines and proteoglycans have shown some promise in clinical and pre---clinical trials, yet due to the rapid degradation and turnover of these compounds, repeated injections are necessary to obtain any long---lasting results, potentially leading to an increase in adverse events. Major obstacles to the development of new treatments for OA have include both the difficulty of identifying quantifiable endpoints for progression in animal models, and the complex cell autonomous and non---cell autonomous components of the pathophysiology of the joint. To overcome these obstacles, our lab developed a novel imaging technique combining staining, phase--- contrast optics, and microCT analysis of the joint, which allows the robust quantification of murine cartilage volume, surface area, and osteophyte formation. To address the issue of the complex etiology of OA development, our lab has identified secreted molecules as potential therapeutic targets - Proteoglycan 4 (PRG4) and the anti---inflammatory Interleukin 1 Receptor antagonist (IL1Ra). PRG4 is a major component of the cartilage extracellular matrix and mediates mechanical stress by providing lubrication. Inflammation has also been attributed to disease progression, and IL1Ra has been proven to function as an anti---inflammatory through the inhibition of Interleukin 1 (IL1). Both published work and preliminary data from our lab and others shows that individually each provides some protection from OA progression. We hypothesize that combinatorial therapy with both PRG4 and IL1Ra will provide increased protection from OA development and progression through addressing cartilage matrix loss and inflammation. We aim to test this by comparing the effects of combinatorial therapy to mono---therapy in a post---traumatic model and in an age---related model of OA development, as the balance of individual factors contributing to disease is different in each. Prior studies have also shown that PRG4 potentially mediates cartilage protection through inhibition of the hypoxic response via upregulation of the inhibitory hypoxia inducible factor 3a (Hif3a); therefore in the third aim of this project we will investigate this futher through the generation and characterization of a cartilage---specific Hif3a transgenic mouse, and determine whether it is also protected from OA development and progression. This research is important for establishing new treatment options and therapeutic targets for patients with osteoarthritis.

 描述（由申请人提供）：骨关节炎（OA）是一种渐进性衰弱性疾病，涉及关节退行性变，可导致严重的关节僵硬和疼痛、活动性降低和医疗保健费用增加。尽管大约有2700万美国人患有这种疾病，但没有任何药物治疗可以显着改变其进展。目前，患有OA的个体将仅被禁止使用疼痛管理药物，物理治疗和生活方式改变，并且在终末期疾病中，将建议进行关节置换手术。细胞因子和蛋白聚糖的注射在临床和临床前试验中显示出一定的前景，但由于这些化合物的快速降解和周转，需要重复注射才能获得任何持久的结果，这可能导致不良事件的增加。开发OA新治疗方法的主要障碍包括难以在动物模型中确定进展的可量化终点，以及关节病理生理学的复杂细胞自主和非细胞自主成分。为了克服这些障碍，我们的实验室开发了一种新的成像技术，结合染色，相衬光学和microCT分析的关节，它允许强大的量化小鼠软骨体积，表面积和骨赘形成。为了解决OA发展的复杂病因学问题，我们的实验室已经确定了分泌分子作为潜在的治疗靶点-蛋白聚糖4（PRG 4）和抗炎白细胞介素1受体拮抗剂（IL 1 Ra）。PRG 4是软骨细胞外基质的主要成分，并通过提供润滑来介导机械应力。炎症也被归因于疾病的进展，并且IL 1 Ra已被证明通过抑制白细胞介素1（IL 1）而起抗炎作用。已发表的工作和来自我们实验室和其他实验室的初步数据都表明，每一种单独提供了一些防止OA进展的保护。我们假设PRG 4和IL 1 Ra的联合治疗将通过解决软骨基质丢失和炎症提供对OA发展和进展的增加的保护。我们的目的是测试这一点，通过比较组合治疗的效果，单-治疗创伤后模型和年龄相关的模型的OA发展，作为平衡的个别因素，有助于疾病是不同的。先前的研究也表明PRG 4可能通过上调抑制性缺氧诱导因子3a（Hif 3a）抑制缺氧反应来介导软骨保护;因此，在本项目的第三个目标中，我们将通过软骨特异性Hif 3a转基因小鼠的产生和表征来进一步研究这一点，并确定它是否也可以防止OA的发展和进展。这项研究对于为骨关节炎患者建立新的治疗选择和治疗目标非常重要。