Cardiovascular gene delivery: The good road is awaiting

Abstract

Atherosclerotic cardiovascular disease is a leading cause of death worldwide. Despite recent improvements in medical, operative, and endovascular treatments, the number of interventions performed annually continues to increase. Unfortunately, the durability of these interventions is limited acutely by thrombotic complications and later by myointimal hyperplasia followed by progression of atherosclerotic disease over time. Despite improving medical management of patients with atherosclerotic disease, these complications appear to be persisting. Cardiovascular gene therapy has the potential to make significant clinical inroads to limit these complications. This article will review the technical aspects of cardiovascular gene therapy; its application for promoting a functional endothelium, smooth muscle cell growth inhibition, therapeutic angiogenesis, tissue engineered vascular conduits, and discuss the current status of various applicable clinical trials.

Fig. 1

(A) Angiogram illustrating a stenosis in an in situ femoro-popliteal vein bypass graft (left). Corresponding histology demonstrates the robust myointimal growth (right). Arrow denotes IH and near occlusion. (B) Table shows a table summary of the four waves of SMC response in a rat balloon angioplasty model [36].

Fig. 2

This is a line diagram of the most common complications after vascular interventions.

Fig. 3

The vascular wall. (A) Graphic representation of the cross section of a small muscular artery (e.g., renal or coronary artery). (B) Photomicrograph of histologic section containing a portion of an artery (A) and adjacent vein (V). Elastic membranes are stained black (internal elastic membrane of artery highlighted by arrow). Because it is exposed to higher pressures, the artery has a thicker wall that maintains an open, round lumen, even when blood is absent. Moreover, the elastin of the artery is more organized than in the corresponding vein. In contrast, the vein has a larger, but collapsed, lumen, and the elastin in its wall is diffusely distributed. (B, Courtesy of Mark Flomenbaum, M.D., Ph.D., Office of the Chief Medical Examiner, New York City) [18]. Reprinted with permission from Kumar [18].

Fig. 4

This is a plot demonstrating an increase in SMC proliferation with sparsely populated overlying ECs that decreases with increased percent re-endothelialization in vivo using a canine carotid artery balloon angioplasty model [93]. Reprinted from [93], with permission from the Society for Vascular Surgery.

Fig. 5

Exogenous delivery of FGF-1 promotes endothelialization of prosthetic graft (expanded polytetrafluoroethylene [ePTFE]). Untreated graft is on the left (x117), and FGF-1 treated graft is on the right (x486). Note the capillary in-growth, cellular coverage, and the central mitotic figure [98]. Reprinted from [98], with permission from the Society for Vascular Surgery.

Fig. 6

The structure of FAK is on top and its C-terminal homologue, FRNK, is on the bottom. Moving from N-terminus to C-terminus in FAK (but not FRNK) are the FERM (protein 4.1, ezrin, radixin and moesin homology) domain, which houses the autophsophorylation sites and src binding sites, and the kinase domain. The rest of FAK is remarkably similar to FRNK, and it is currently unknown if FRNK’s C-terminal region has phosphorylation sites that are activated by growth factor stimulation like FAK. (PR: proline-rich regions; FAT: focal adhesion targeting sequence.)

Fig. 7

Fluorescent images of three-dimensional SMC invasion. This figure illustrates the successful infection of vascular smooth muscle cells (500 moi, 7d) through an in vitro 3-D co-culture model of SMC hyperplasia. Here, Adv-GFP-FRNK infected SMCs (left) invasion can be compared to an adenovirus control group (adv-GFP infected SMCs) (right) to quantify SMC invasion into the matrix under clinically relevant situations (i.e., various ECM proteins or growth factors) [156].