Stent angioplasty over the last decade has made a major impact on improved therapeutic outcomes for coronary disease. Our group has pioneered the concept that an even greater therapeutic benefit than possible with current bare metal stents (BMS) or drug eluting stents (DES) could be achieved with stent-mediated gene therapy from the bare metal surfaces of stents. This proposal will address the following questions: 1) Can a high enough dose of a gene vector be loaded onto a stent? 2) Can transgene expression be sustained long enough to achieve a therapeutic benefit? The first question is now addressed through our investigations of a three component synthetic complex that includes a synthetic amplifier construct (AC) thereby enabling higher dosing. Prolonged expression will be addressed through our use of Helper Dependent Adenoviruses (HD-Ad) that can demonstrate transgene expression in vivo for several years.
Aim 1. To investigate the syntheses of novel Amplifier Constructs (AC) for attaching higher levels of HD-Ad to the bare metal surfaces of stents. The overall complex consists of: 1) A water soluble bisphosphonate (PABT) with irreversible binding to stent surfaces;2) A hydrolysable linker (HL) that can be reacted with Ad (via sulfyhydryl chemistry) for tethering Ad to stents;and 3) An amplifier construct (AC).
This Aim will focus on novel AC synthetic constructs to increase HD-Ad doses.
Aim 2. To investigate and model in cell culture, local delivery of HD-Ad from steel surfaces, in order to assess the site specific efficiency and therapeutic potential of novel synthetic ACs. We will create HD- Ad vectors: For reporter HD-Ad cell culture studies, we will create a green fluorescent protein (GFP) vector under the control of the cytomegalovirus promoter (CMV). We will also create a HD-Ad luciferease (LUC) construct with a CMV promoter to be evaluated in vitro and also used in the Aim 3 in vivo studies for optical imaging studies. Our therapeutic vector will include rat inducible nitric oxide synthase (iNOS) with the rat arterial smooth muscle cell specific SM22alpha promoter, to both target smooth muscle cells and to minimize the effects of immune factors on both the efficacy and duration of therapeutic transgene activity.
Aim 3. To investigate in vivo the efficiency and efficacy of AC enhanced local delivery of HD-Ad from stent surfaces. These investigations will study the dose ranging and therapeutic dose response capabilities of our three component complex approach to gene delivery from stent surfaces. Reporter studies delivering LUCHD-Ad will investigate transgene activity over time using in vivo LUC optical imaging of stent delivery. Once the lead AC formulation with the greatest in vivo delivery capacity of reporter HD-Ad (re. the upper limits of the dose range) has been characterized, therapeutic studies will be carried out investigating sustained transgene expression and anti-instent restenosis efficacy over time with iNOSHD-Ad delivery using our 3 component complex with maximal AC HD-Ad delivery capacity.
The use of stents for treating coronary artery disease had been associated with both therapeutic benefit and significant complications, including reobstruction post-stenting, termed instent restenosis. Drug eluting stents have been shown to ameliorate instent restenosis, but with significant risks. This proposal will investigate gene delivery stents as a novel approach for regenerating diseased blood vessels.
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