Targeting the Extracellular Matrix to Inhibit Saphenous Vein Graft (SVG) Failure

靶向细胞外基质抑制隐静脉移植物 (SVG) 失败

• 批准号: 8318591
• 负责人: Thomas N Wight
• 金额: $ 33.4万
• 依托单位: MATREXA, LLC
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-15 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8318591
• 关键词: Acute; Animal Disease Models; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Arterial Fatty Streak; Arteries; Atherosclerosis; Biochemical; Biological Assay; Blood Vessels; Bypass; Cardiovascular Diseases; Cells; Chondroitin Sulfates; Country; Data; Deposition; Development; Effectiveness; Elastic Fiber; Event; Excision; Exons; Extracellular Matrix; Failure; Gene Delivery; Goals; Growth; Healthcare; Human; Hyperplasia; In Vitro; Intervention; Laboratories; Lesion; Lipids; Mechanics; Methods; Nature; Operative Surgical Procedures; Organ Culture Techniques; Peptides; Prevention; Property; Proteins; Proteoglycan; RNA Splicing; Recombinants; Safety; Saphenous Vein; Smooth Muscle; Structure; Testing; Therapeutic; Therapeutic Agents; Therapeutic Uses; Time; Variant; Vascular Diseases; Veins; Western World; base; design; graft failure; improved; in vitro Assay; in vitro testing; macrophage; overexpression; prevent; success; therapeutic gene; treatment effect; versican

DESCRIPTION (provided by applicant): The goal of this proposal is for Matrexa to develop a protein product that will prevent intimal hyperplasia in human saphenous vein grafts (SVG) with the objective of reducing the exceedingly high failure rate of these surgical procedures. The strategy involves acute pre-treatment of saphenous veins at the time of surgery with proprietary agents, developed by Matrexa. The target for intervention is the large vascular matrix proteoglycan, versican, which is central to smooth muscle growth and hyperplasia, accumulation of atherogenic lipids, and macrophage ingress into developing lesions. We have successfully targeted versican and prevented these events in animal models of atherosclerosis through over expression of the small variant versican V3 (V3) and through over expression of versican antisense sequences. We have also discovered an additional and unexpected benefit of these approaches in that V3 promotes the synthesis and formation of elastic fibers and markedly improves the mechanical properties and stability of treated vessels. Once formed, the elastic fibers will maintain the structural integrity, anti-hyperplastic and anti-inflammatory nature of the vascular wall. We have further discovered, through deletion studies, that exon 3 of V3 contains this elastogenic activity. We recognize, however, that gene delivery and overexpression of V3 is therapeutically problematic for safety and other reasons and we therefore propose to develop and use rV3 protein and small peptides as therapeutic agents. In preliminary studies we have been successful in producing rV3 which possesses elastogenic activity. The Aims of the project are 1) to prepare rV3 protein in enough quantity and purity to test its bioactivity in biochemical and in vitro cell-based assays and 2) to demonstrate the efficacy of rV3 to prevent intimal hyperplasia and promote elastogenesis in ex vivo cultures of human saphenous vein.

描述（由申请人提供）：该提案的目的是使Matrexa开发一种蛋白质产品，该蛋白质产品将防止人类大隐静脉移植物（SVG）中的内膜增生，目的是降低这些手术程序的极高失败率。该策略涉及由Matrexa开发的专有剂在手术时急性预处理静脉。干预的目标是大型血管基质蛋白聚糖，versican，它是平滑肌生长和增生的核心，动脉粥样硬化脂质的积累以及巨噬细胞向发育的病变中的巨噬细胞。我们已经成功地针对versican，并通过过度表达versican V3（V3）和通过过度表达versican反义序列来阻止动脉粥样硬化动物模型中的这些事件。我们还发现了这些方法的额外和意外的好处，因为V3促进了弹性纤维的合成和形成，并显着提高了处理的血管的机械性能和稳定性。一旦形成，弹性纤维将保持血管壁的结构完整性，抗增生和抗炎的性质。我们通过缺失研究进一步发现，V3的外显子3包含这种弹性活性。但是，由于安全性和其他原因，我们认识到V3的基因递送和过表达在治疗上是有问题的，因此我们建议开发和使用RV3蛋白和小肽作为治疗剂。在初步研究中，我们成功地生产具有弹性活性的RV3。该项目的目的是1）以足够数量和纯度制备RV3蛋白，以测试其在生物化学和基于体外细胞的测定中的生物活性和2）2）证明RV3的功效可以防止内膜增生并促进人类毒素的体外培养物中的弹性生成。