RIBOZYMES FOR THE PREVENTION OF RESTENOSIS AFTER PTCA

针对增殖细胞核抗原(增殖细胞核抗原)的嵌合核酶治疗已经被发现并被证明可以防止血管平滑肌细胞的增殖，而血管平滑肌细胞增殖是导致再狭窄的主要因素。在大鼠和猪的狭窄模型上进行的临床前研究表明，与对照组相比，治疗组的实验性动脉狭窄率降低了，这是具有统计学意义的显著血管造影和组织形态证据。成功地抑制经皮冠状动脉腔内成形术(PTCA)和支架置入术后血管平滑肌细胞的增殖将是冠状动脉疾病治疗的重大进展。在完成这一应用的第一阶段时，Immusol优化了嵌合核酶结构及其原型的增殖细胞核抗原靶向核酶的稳定性，并在PTCA之前通过可用的FDA批准的输液设备直接输送药物，显示出有效地抑制猪支架模型中的狭窄。这部分研究将确定药物制造过程的重复性，检查该药物的剂量效应，并在猪和大鼠模型上建立其安全性，为患者的安全性和有效性临床试验做准备。建议的商业应用：Immusol公司计划开发针对增殖细胞核抗原的核酶，用于预防PTCA术后的再狭窄。

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.