RIBOZYMES FOR THE PREVENTION OF RESTENOSIS AFTER PTCA

用于预防 PTCA 术后再狭窄的核酶

• 批准号: 2678095
• 负责人: JACK R BARBER
• 金额: $ 10万
• 依托单位: ITHERX PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-01 至 1999-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2678095
• 关键词: cardiovascular disorder prevention; cell proliferation; chemoprevention; dosage; dosage forms; drug delivery systems; drug screening /evaluation; growth inhibitors; injection /infusion; intraluminal angioplasty; laboratory mouse; postoperative complications; proliferating cell nuclear antigen; restenosis; ribozymes; swine; vascular smooth muscle

DESCRIPTION (Adapted from applicant's abstract): This is a "fast track" application. In Phase I, the applicants state that percutaneous transluminal coronary angioplasty (PTCA) is a commonly used treatment for severe coronary artery disease. However, restenosis caused by vascular smooth muscle cell proliferation, is often a complication following PTCA within six months of treatment. Inhibition of vascular smooth muscle cell proliferation would be a major advancement in the treatment of coronary artery disease. Immusol currently has chimeric ribozyme-based therapeutic that has been effective in inhibiting vascular smooth muscle cell proliferation in in-vitro cell culture assays and in rat and porcine stenosis models. Optimization of the binding arm lengths and base modifications of the chimeric ribozyme as well as optimization of the delivery formulation could increase the efficacy of this treatment even further. The optimized chimeric ribozyme drug therapy will be tested for efficacy in porcine stenosis models. Successful inhibition of restenosis in this study would constitute a preclinical foundation for efficacy testing of the ribozyme formulation in a clinical trial. In Phase II, the applicants state that chimeric ribozyme-based therapeutics targeting proliferating cell nuclear antigen (PCNA) have been identified and shown to prevent vascular smooth muscle cell proliferation that is a major contributing factor in restenosis. Preclinical studies in rat and porcine stenosis models show dramatic, statistically significant, angiographic and histomorphological evidence in reduction in the experimental stenosis rate in treated vs control arteries. Successful inhibition of vascular smooth muscle cell proliferation following PTCA in stent placement would constitute a major advance in the treatment of coronary artery disease. At the completion of the Phase I portion of this application, Immusol will have optimized both the chimeric ribozyme structure and the stability of its prototype PCNA targeted ribozyme and evaluated its effect on restenosis by direct delivery of the drug via an available, FDA approved infusion device prior to deployment of the stent during PTCA in the porcine stenosis model. This portion of the study will examine the dose effect of this drug and establish this toxicologic safety in porcine and mouse models and, pending a successful outcome, proceed to a Phase I clinical trial of safety and restenosis following PTCA. PROPOSED COMMERCIAL APPLICATION: NOT AVAILABLE

描述（改编自申请人的摘要）：这是一条“快速通道” 应用。 在第一阶段，申请人表示经皮 腔内冠状动脉成形术（PTCA）是一种常用的治疗方法 严重的冠状动脉疾病。 然而，血管再狭窄 平滑肌细胞增殖，通常是 PTCA 术后的并发症 治疗六个月内。 抑制血管平滑肌细胞 增殖将是冠状动脉治疗的重大进步 动脉疾病。 Immusol 目前拥有基于嵌合核酶的治疗药物 有效抑制血管平滑肌细胞 体外细胞培养测定以及大鼠和猪中的增殖 狭窄模型。 绑定臂长度和底座的优化 嵌合核酶的修饰以及优化 递送配方甚至可以提高这种治疗的功效 更远。 优化的嵌合核酶药物疗法将进行测试 在猪狭窄模型中的功效。 成功抑制再狭窄 这项研究将为疗效奠定临床前基础 在临床试验中测试核酶制剂。 在第二阶段，申请人指出基于嵌合核酶的 靶向增殖细胞核抗原（PCNA）的治疗方法 已鉴定并显​​示可防止血管平滑肌细胞增殖 这是再狭窄的一个主要影响因素。 临床前研究 大鼠和猪的狭窄模型显示出显着的、具有统计学意义的、 血管造影和组织形态学证据表明 治疗动脉与对照动脉的实验性狭窄率。 成功的 PTCA后血管平滑肌细胞增殖的抑制 支架置入术将是治疗的重大进步 冠状动脉疾病。 在第一阶段部分完成时 应用程序中，Immusol 将优化嵌合核酶 PCNA靶向核酶原型的结构及其稳定性 通过直接给药评估其对再狭窄的影响 在部署支架之前可使用经 FDA 批准的输注装置 在猪狭窄模型中进行 PTCA 期间。这部分研究将 检查该药物的剂量效应并确定毒理学安全性 在猪和小鼠模型中，在获得成功结果之前，继续 PTCA 后安全性和再狭窄的 I 期临床试验。 拟议的商业应用：不可用