Ultrasound-mediated endothelial-specific gene therapy for therapeutic revascularization

Peripheral arterial disease (PAD), which affects roughly 15% of Americans over the age of 60, is a condition in which patients develop atherosclerotic blockages of the peripheral arteries. These plaques can result in critical limb ischemia. Our lab uses a mouse model of femoral artery ligation (FAL) to recapitulate the PAD symptoms of limb ischemia and microvascular remodeling. We have identified epigenetic regulators of arteriogenesis that exhibit altered expression patterns in endothelial cells following FAL surgery, including a mechanosensitive microRNA called miR-199a that has been shown to downregulate a number of pro-arteriogenic and pro-angiogenic proteins. We are working on developing a novel therapeutic revascularization method in which we use ultrasound to target delivery of plasmids that inhibit miR-199a (and other negative regulators of arteriogenesis) to the endothelia of ischemic tissue. We will target delivery using endothelial-specific promoters within the plasmids and tailored ultrasound pulsing protocols that preferentially transfect endothelia. We hope to observe increased arteriogenesis, angiogenesis, and reperfusion of the affected tissue with minimal off-target effects thanks to the targeted nature of the ultrasound-mediated delivery. The results of these studies will be used to further develop potential therapies for PAD.

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