HYALURONAN SYNTHASE GENE TRANSFER TO PREVENT RESTENOSIS

透明质酸合酶基因转移预防再狭窄

• 批准号: 6298666
• 负责人: WEILIAM CHEN
• 金额: $ 9.99万
• 依托单位: CLEAR SOLUTIONS BIOTECH, INC.
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-06-01 至 2003-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6298666
• 关键词: biomaterial development /preparation; biomaterial evaluation; blood vessel prosthesis; gel; gene delivery system; glucuronosyltransferase; restenosis; surface coating; swine; tissue /cell culture; transfection

DESCRIPTION (Verbatim From Applicant's Abstract): Stent implantation markedly reduces the observed frequency of restenosis (a phenomenon of cell proliferation after coronary angioplasty). However, in-stent restenosis is more difficult to treat than post angioplasty restenosis. No systemic pharmacological treatment has hitherto been shown to convincingly reduce the restenosis incidence in patients. It has been observed in animal studies that saturation of RHAMM and CD44 receptors by hyaluronan significantly reduces neointimal formation without cellular destruction. The applicant proposes to investigate the feasibility of using a biodegradable, biocompatible and nonthrombogenic hyaluronic acid hydrogel (HA)(crosslinked and rendered insoluble), as a metallic stent coating, for sustained transfer of plasmid DNA encoding a hyaluronan synthase gene (HASyn). This HA hydrogei will be gradually hydrolyzed, releasing HA and thus the therapeutic gene into the surrounding environment. Steady transfer of the HASyn gene to the arterial wall and the subsequent expression will theoretically sustain the high localized HA concentration. In this Phase I program, we will initially optimize the in vitro DNA release characteristics of the HA stent coating and study the longevity of its gene transfer in A10 (aortic smooth muscle cell) culture. The program will be concluded by a pilot scale efficacy study in a porcine coronary model to assess the efficiency of gene transfer and the potential for inhibition of neointimal formation following stent implantation. PROPOSED COMMERCIAL APPLICATION: In-stent restenosis have significant socioeconomic impact. Almost all the gene delivery stents currently under investigation target the destruction of proliferating smooth muscle cells. This Phase I application is to demonstrate the feasibility of using a biodegradable hydrogel metallic stent coating as a new sustained delivery therapeutic modality for delivering a therapeutic gene NOT targeting the destruction of proliferating cells (a distinct contrast to other gene delivery stents under investigation). Promising results obtained will expand this study into Phase II and thereafter clinical trial. This could result in a gene therapy stent with a unique and nondestruction mode of action.

描述（逐字化来自申请人的摘要）：支架植入明显 降低了观察到的再狭窄频率（细胞现象 冠状动脉成形术后的增殖）。但是，内部再狭窄更多 比血管成形术后再狭窄很难治疗。没有系统 迄今已证明药理学治疗可令人信服地减少 患者的再狭窄发病率。在动物研究中已经观察到 透明质酸对RHAMM和CD44受体的饱和度显着降低 新的形成而没有细胞破坏。申请人建议 研究使用可生物降解，生物相容性和 非组织性透明质酸水凝胶（HA）（交联并渲染 不溶性），作为金属支架涂层，用于替代质粒DNA的持续转移 编码透明质酸合酶基因（Hasyn）。此HA Hydrogei将逐渐 水解，释放HA，从而将治疗基因释放到周围 环境。将hasyn基因稳定转移到动脉壁和 从理论上讲，随后的表达将维持较高的本地化HA 专注。 在此阶段I计划中，我们最初将优化体外DNA释放 HA支架涂层的特征并研究其基因的寿命 在A10（主动脉平滑肌细胞）培养中转移。该程序将是 在猪冠状动脉模型中以试验量表效力研究结束于评估 基因转移的效率和抑制新内膜的潜力 支架植入后的形成。 拟议的商业应用： 内部再狭窄具有重大的社会经济影响。 几乎所有基因输送支架 目前正在研究的目标是破坏增殖的平滑肌细胞。 这 第一阶段的应用是证明使用可生物降解水凝胶金属的可行性 支架涂层是一种新的持续交付治疗方式，用于提供治疗 基因不针对增殖细胞的破坏（与其他基因形成鲜明对比 送货支架正在调查中）。 获得的有希望的结果将把这项研究扩展到 第二阶段以及此后的临床试验。 这可能会导致具有独特的基因疗法支架 和非毁灭行为方式。