TIMP Gene Transfer to Alter Course of Disc Degeneration

TIMP 基因转移改变椎间盘退变进程

• 批准号: 6900359
• 负责人: JAMES D KANG
• 金额: $ 16.58万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-06-04 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6900359
• 关键词: Adenoviridae; biosynthesis; biotechnology; biotransformation; disease /disorder model; extracellular matrix; functional ability; gene delivery system; gene therapy; intervertebral disk; laboratory rabbit; magnetic resonance imaging; nonhuman therapy evaluation; pathologic process; spine disorder; tissue inhibitor of metalloproteinases; transfection /expression vector

DESCRIPTION (provided by applicant): The prevalence of musculoskeletal impairments of the spine in the U.S. is estimated to be greater than 18 million--many of which are the direct or indirect result of intervertebral disc degeneration (IDD). The limited available technology for the treatment of the pathologic and disabling conditions arising from IDD generally is highly invasive (e.g., surgical discectomy and fusion), manifesting a certain degree of complications and unsatisfactory clinical outcomes. To date, little effort has been made to directly treat the underlying problem of disc degeneration--a chronic process characterized in part by progressive loss of proteoglycans leading to disc dehydration, alterations in disc structure, and impaired disc function. Recent advancements in molecular biology have made it possible to contemplate treating the intervertebral disc itself at a molecular level to prevent or delay the progression of IDD. We hypothesize that imbalance in the synthesis and catabolism of certain critical extracellular matrix (ECM) components (a final common pathway in IDD) can be mitigated by the transfer of genes to intervertebral disc cells encoding factors that modulate synthesis and catabolism of these ECM components--thereby improving disc composition, structure, and ultimately function. The proposed study will test the efficacy of adenovirus-mediated delivery of tissue inhibitor of matrix metalloproteinases-1 (TIMP-1) genes in interrupting the degenerative cascade in a novel rabbit model of disc degeneration, using functional outcomes and MRI to assess preservation of disc composition, structure, and function. The significance of this study includes an improved basic science understanding of the pathogenesis and pathophysiology of IDD, as well as the identification of novel therapeutic approaches to the clinical treatment of IDD.

描述（由申请人提供）：在美国，脊柱肌肉骨骼损伤的患病率估计超过 1800 万，其中许多是椎间盘退变 (IDD) 的直接或间接结果。用于治疗 IDD 引起的病理和致残病症的现有技术有限，通常具有高度侵入性（例如手术椎间盘切除术和融合术），表现出一定程度的并发症和不令人满意的临床结果。迄今为止，几乎没有做出任何努力来直接治疗椎间盘退变的根本问题，椎间盘退变是一种慢性过程，其部分特征是蛋白聚糖逐渐丧失，导致椎间盘脱水、椎间盘结构改变和椎间盘功能受损。 分子生物学的最新进展使得考虑在分子水平上治疗椎间盘本身以预防或延缓 IDD 的进展成为可能。我们假设，某些关键细胞外基质 (ECM) 成分（IDD 的最终共同途径）合成和分解代谢的不平衡可以通过将基因转移到编码调节这些 ECM 成分合成和分解代谢的因子的椎间盘细胞来缓解。 -从而改善椎间盘的组成、结构和最终功能。 拟议的研究将测试腺病毒介导的基质金属蛋白酶组织抑制剂 - 1 (TIMP-1) 基因的传递在新型兔椎间盘退变模型中中断退行性级联的功效，使用功能结果和 MRI 来评估椎间盘的保存组成、结构和功能。 这项研究的意义包括提高对 IDD 发病机制和病理生理学的基础科学认识，以及确定 IDD 临床治疗的新治疗方法。