Nitric oxide (NO) mediates vascular smooth muscle cell (SMC) relaxation, inhibits platelet and leukocyte adhesion, and prevents SMC proliferation. 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 ideal gene for this application is the inducible NO synthase (iNOS) isoform which produces high levels of NO independent 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 already established the adenovirus mediated iNOS gene deliver to animal models of vascular injury dramatically reduced intimal hyperplasia. With these encouraging preclinical results, iNOS gene therapy is ready to be evaluated in human disease. An attractive clinical model in which to evaluate this therapy is in arteriovenous (AV) grafts placed in hemodialysis (HD) patients. The venous anastomoses of AV grafts are extremely prone to an aggressive form of intimal hyperplasia that far exceeds the incidence or extent seen in angioplasty or bypass surgery. AV graft failure secondary to intimal hyperplasia is a financial burden and is also a source of morbidity among patients on HD. 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 adenoviral vector of iNOS administration.
AIM II : To determine the efficacy of iNOS gene transfer for the inhibition of intimal hyperplasia in AV grafts placed for HD as measured by graft function and patency in a Phase II clinical trial. Non-invasive 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, 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 intimal hyperplasia such as following angioplasty and peripheral and coronary bypass.
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