RIBOZYMES FOR THE PREVENTION OF RESTENOSIS AFTER PTCA

用于预防 PTCA 术后再狭窄的核酶

• 批准号: 6184488
• 负责人: JACK R BARBER
• 金额: $ 22.63万
• 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 2001-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6184488
• 关键词: cardiovascular disorder prevention; chemoprevention; dosage; drug delivery systems; drug screening /evaluation; histology; intraluminal angioplasty; laboratory mouse; laboratory rat; postoperative complications; proliferating cell nuclear antigen; protein purification; restenosis; ribozymes; swine; vascular smooth muscle

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 of reduction in the experimental stenosis rate in treated versus control arteries. Successful inhibition of vascular smooth muscle cell proliferation following percutaneous transluminaI coronary angioplasty (PTCA) and 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 has optimized both the chimeric ribozyme structure, and the stability of its prototype PCNA targeted ribozyme, and has shown effective inhibition of stenosis in the porcine stent model by direct delivery of the drug via an available, FDA-approved infusion device prior to PTCA. This portion of the study will establish the reproducibility of the drug manufacturing process, examine the dose effect of this drug, and establish its safety in porcine and rat models in preparation for a clinical trial of safety and efficacy in patients. PROPOSED COMMERCIAL APPLICATIONS: Immusol, Inc. plans to develop PCNA targeted ribozymes for use in the prevention of restenosis following PTCA.

靶向增殖细胞核抗原（PCNA）的基于嵌合核酶的治疗剂已被鉴定并显示出可预防血管平滑肌细胞增殖，血管平滑肌细胞增殖是再狭窄的主要促成因素。 大鼠和猪狭窄模型的临床前研究显示，与对照动脉相比，治疗动脉的实验狭窄率降低，血管造影和组织形态学证据显着、统计学显着。经皮冠状动脉腔内成形术（PTCA）和支架置入术成功抑制血管平滑肌细胞增殖将是冠心病治疗的一个重大进展。 在完成本申请的I期部分时，Immusol已经优化了嵌合核酶结构及其原型PCNA靶向核酶的稳定性，并且已经通过在PTCA之前经由可用的FDA批准的输注装置直接递送药物来显示对猪支架模型中的狭窄的有效抑制。 本研究的这一部分将确定药物生产工艺的重现性，检查该药物的剂量效应，并确定其在猪和大鼠模型中的安全性，为患者的安全性和有效性临床试验做准备。拟议商业应用：Immusol，Inc.计划开发PCNA靶向核酶用于预防PTCA后再狭窄。