RIBOZYMES FOR THE PREVENTION OF RESTENOSIS AFTER PTCA

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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