RIBOZYMES FOR THE PREVENTION OF RESTENOSIS AFTER PTCA

以增殖细胞核抗原（PCNA）为靶点的嵌合核酶为基础的治疗方法已经被确定并显示可以阻止血管平滑肌细胞增殖，而这是再狭窄的一个主要因素。在大鼠和猪狭窄模型中进行的临床前研究显示，与对照组相比，治疗组的血管造影和组织形态学证据显著降低了实验性狭窄率。经皮冠状动脉成形术（PTCA）和支架置入术后血管平滑肌细胞增殖的成功抑制将是冠状动脉疾病治疗的重大进展。在该申请的I期部分完成时，Immusol优化了嵌合核酶结构和其原型PCNA靶向核酶的稳定性，并在PTCA之前通过可用的fda批准的输注装置直接给药，有效抑制了猪支架模型中的狭窄。研究的这一部分将建立药物生产过程的可重复性，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。拟议的商业应用：Immusol公司计划开发PCNA靶向核酶，用于预防PTCA后的再狭窄。

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.