iNOS Gene Therapy to Prevent AV Graft Intimal Hyperplasia

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Nitric oxide (NO) mediates vascular smooth muscle cell (SMC) relaxation, inhibits platelet and leukocyte adhesion, and prevents SMC proliferation. Delivery of NO to sites of vascular injury prevents intimal hyperplasia (IH). Systemic NO administration may be associated with adverse effects such as hypotension. We propose that local NO delivery through the use of adenoviral gene therapy techniques will locally augment NO production and avoid systemic toxicity. The gene of choice for this application is the inducible NO synthase (iNOS) isoform which produces high levels of NO independent of calcium fluxes. The greater enzymatic activity of iNOS as compared with the other isoforms may yield greater clinical efficacy with lower gene transfer efficiency. We have established that adenovirus mediated iNOS gene delivery to rodent and porcine models of vascular injury dramatically reduced IH. The safety of local vascular delivery of an adenoviral vector carrying iNOS (AdiNOS) has been demonstrated in pigs as well as following systemic delivery to rats. With these preclinical efficacy and safety data, iNOS therapy is ready to be evaluated in human disease. The clinical grade AdiNOS has been prepared and meets FDA requirements regarding RCA as well as residual cellular DNA content. We will evaluate the safety and efficacy of iNOS gene transfer to inhibit IH in arteriovenous (AV) grafts placed in hemodialysis (HD) patients. The venous anastomoses of AV grafts are prone to an aggressive form of IH that exceeds the incidence seen in angioplasty or bypass surgery. AV graft failure is a safe and feasible model in which to study iNOS gene therapy. AIM I: To assess the safety of adenovirus mediated iNOS gene transfer into patients undergoing AV graft placement for HD access in a Phase I clinical trial. We will perform dose escalation studies to determine the highest and safest dose of adenoviral vector to use in Aim II. Patients will be closely followed for evidence of adverse systemic or local reactions to adenviral vector or iNOS administration. AIM II: To determine the efficacy of iNOS gene transfer for the inhibition of IH in AV grafts placed for HD as measured by graft function and patency in a Phase II clinical trial. Noninvasive duplex imaging and venous resistance measurements made during routine HD will allow graft function to be monitored with no additional risk to the patient. The outcomes that will be assessed are primary graft patency, assisted primary patency, secondary patency, and number of graft revisions. The information from this clinical study will determine the efficacy of iNOS gene therapy. If beneficial, this therapy will be applied to other etiologies of IH such as following angioplasty and peripheral and coronary bypass.