Abstract

Neointima formation and vascular remodeling through vascular smooth muscle cell migration and proliferation can limit the long-term success of coronary interventions, for example, in coronary artery bypass grafting (CABG). Ex vivo gene therapy has the potential to reduce unnecessary cell proliferation and limit neointima formation in vascular pathologies. To date, the species C adenovirus serotype 5 has been commonly used for preclinical gene therapy; however, its suitability is potentially limited by relatively poor tropism for vascular cells and high levels of preexisting immunity in the population. To avoid these limitations, novel species of adenovirus are being tested; here we investigate the potential of adenovirus 49 (Ad49) for use in gene therapy. Transduction of primary human vascular cells by a range of adenovirus serotypes was assessed; Ad49 demonstrated highest transduction of both vascular smooth muscle and endothelial cells. Gene transfer with Ad49 in vascular smooth muscle and endothelial cells was possible following short exposure times (<1 hr) and with low MOI, which is clinically relevant. Ex vivo delivery to surplus CABG tissue showed efficient gene transfer with Ad49, consistent with the in vitro findings. Luminal infusion of Ad49GFP into intact CABG samples ex vivo resulted in efficient vessel transduction. In addition, no seroprevalence rates to Ad49 were observed in a Scottish cohort of patients from cardiovascular clinics, thus circumventing issues with preexisting immunity. Our results show that Ad49 has tropism for vascular cells in vitro and ex vivo and demonstrate that Ad49 may be an improved vector for local vascular gene therapy compared with current alternatives.

Highlights

  • Cardiovascular disease remains one of the leading causes of mortality worldwide.[1]

  • Efficient gene transfer to cardiomyocytes using adeno-associated virus (AAV) vectors has been shown in many preclinical models, and promising results have been reported in the phase 2 CUPID clinical trial overexpressing sarcoplasmic reticulum Ca2 + -ATPase (SERCA2a) via AAV-1 in patients with advanced heart failure.[3]

  • To initially evaluate vector tropism for vascular cells, the transduction efficiency of four serotypes of adenovirus was evaluated in primary vascular smooth muscle cell (VSMC) and endothelial cells (ECs), in comparison to the commonly used vector adenovirus serotype 5 (Ad5)

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Summary

Introduction

Cardiovascular disease remains one of the leading causes of mortality worldwide.[1] Use of gene therapy, targeting myocardium and vascular cells, remains a promising strategy for treatment of a variety of cardiovascular diseases. Efficient gene transfer to cardiomyocytes using adeno-associated virus (AAV) vectors has been shown in many preclinical models (reviewed in ref.2), and promising results have been reported in the phase 2 CUPID clinical trial overexpressing sarcoplasmic reticulum Ca2 + -ATPase (SERCA2a) via AAV-1 in patients with advanced heart failure.[3] Outside the myocardium, targeting vascular cells for gene therapy could be beneficial in reducing both cardiovascular diseases, for example, angiogenesis associated with ischemic disease and pathological vascular remodeling associated with vein graft failure. The vessel undergoes a period of remodeling to adapt to the increased blood flow and pressure in the arterial circulation. Excessive vascular smooth muscle cell (VSMC) migration and proliferation and damaged endothelium cause neointima formation and can limit the long-term success of the graft; studies report that > 25% of grafts have reduced patency after 4 years and up to 50% at 10 years.[4]

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