Gene-eluting Stents: Adenovirus-mediated Delivery of eNOS to the Blood Vessel Wall Accelerates Re-endothelialization and Inhibits Restenosis

Sharif, Faisal; Hynes, Seán O.; Cooney, Ronan; Howard, Linda; McMahon, Jill; Daly, Kieran; Crowley, James J.; Barry, Frank; O’Brien, Timothy

doi:10.1038/mt.2008.165

Cited by 79 publications

(104 citation statements)

References 28 publications

Supporting

Mentioning

101

Contrasting

Order By: Relevance

“…We have shown that adenoviral delivery of eNOS accelerated re-endothelisation and inhibition of SMC proliferation in atheroclerotic rabbits [9,12]. We and others have also shown that eNOS can be delivered to arterial wall vessels by non-viral means using liposomes with efficacy in the form of endothelium regeneration [10,24] and inhibition of restenosis [10].…”

Section: Adenoviral Delivery Of Nos Genes To the Vasculature Have Shomentioning

confidence: 87%

“…We and others have shown the efficacy of eNOS derived nitric oxide in inhibiting SMC proliferation [11,21] as well as in preventing in-stent restenosis [9]. During vascular remodelling after injury, eNOS is known to have a dual role of simultaneously stimulating re-endothelisation of the denuded vessel wall, whilst inhibiting the proliferation of SMCs, and hence neointimal re-growth [9,10]. For this reason eNOS is of major therapeutic interest for reasons of promoting vascular repair and prevention of in-stent restenosis after surgical intervention in atherosclerotic patients.…”

Section: Accepted Manuscriptmentioning

confidence: 97%

“…Consequently, NOS gene therapy has been a promising therapeutic approach to vascular repair [7]. We and others have shown in rabbits that extraneous overexpression of eNOS by gene delivery to the vascular wall reverses thickening of the intimal layer by inhibiting SMC proliferation [8][9][10]. This phenomenon can be effectively mimicked in vitro by adenoviral delivery of an eNOS transgene into human arterial SMCs [11,12].…”

Section: Introductionmentioning

confidence: 98%

See 2 more Smart Citations

Endothelial nitric oxide synthase induces heat shock protein HSPA6 (HSP70B′) in human arterial smooth muscle cells

2016

View full text Add to dashboard Cite

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

show abstract

Section: Adenoviral Delivery Of Nos Genes To the Vasculature Have Shomentioning

confidence: 87%

Section: Accepted Manuscriptmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 98%

See 1 more Smart Citation

Endothelial nitric oxide synthase induces heat shock protein HSPA6 (HSP70B′) in human arterial smooth muscle cells

2016

View full text Add to dashboard Cite

show abstract

“…It is produced by nitric oxide synthase isoforms, and in particular, we have previously utilized endothelial nitric oxide synthase (eNOS) expression in the vasculature to increase NO production. [11][12][13] We have previously reported on successful transduction of rabbit iliac arteries with therapeutic eNOS gene using adenovirus-mediated gene-eluting stents, resulting in enhanced re-endothelialization with a reduction in intimal hyperplasia at 4 weeks post-gene delivery. 12 However, adenoviral-mediated gene delivery to the blood vessel wall has been associated with inflammation, which may impede progress of this potential therapy to the clinics.…”

Section: Introductionmentioning

confidence: 99%

“…[11][12][13] We have previously reported on successful transduction of rabbit iliac arteries with therapeutic eNOS gene using adenovirus-mediated gene-eluting stents, resulting in enhanced re-endothelialization with a reduction in intimal hyperplasia at 4 weeks post-gene delivery. 12 However, adenoviral-mediated gene delivery to the blood vessel wall has been associated with inflammation, which may impede progress of this potential therapy to the clinics. 14 Non-viral and, in particular, liposome-mediated gene delivery represents an interesting alternative to viral gene delivery as they can deliver a large insert size, and are less immunogenic and have fewer bio-safety concerns.…”

Section: Introductionmentioning

confidence: 99%

Gene-eluting stents: non-viral, liposome-based gene delivery of eNOS to the blood vessel wall in vivo results in enhanced endothelialization but does not reduce restenosis in a hypercholesterolemic model

et al. 2011

View full text Add to dashboard Cite

Although successful, drug-eluting stents require significant periods of dual anti-platelet therapy with a persistent risk of late stent thrombosis due to inhibition of re-endothelialization. Endothelial regeneration is desirable to protect against in-stent thrombosis. Gene-eluting stents may be an alternative allowing inhibition of neointima and regenerating endothelium. We have shown that adenoviral endothelial nitric oxide synthase (eNOS) delivery can result in significantly decreased neointimal formation and enhanced re-endothelialization. Here, we examined non-viral reporter and therapeutic gene delivery from a stent. We coated lipoplexes directly onto the surface of stents. These lipostents were then deployed in the injured external iliac artery of either normal or hypercholesterolemic New Zealand White rabbits and recovered after 28 days. Lipoplexes composed of lipofectin and a reporter lacZ gene or therapeutic eNOS gene were used. We demonstrated efficient gene delivery at 28 days post-deployment in the media (21.3 ± 7.5%) and neointima (26.8 ± 11.2%). Liposomal delivery resulted in expression in macrophages between the stent struts. This resulted in improved re-endothelialization as detected by two independent measures compared with vector and stent controls (Po0.05 for both). However, in contrast to viral delivery of eNOS, liposomal eNOS does not reduce restenosis rates. The differing cell populations targeted by lipoplexes compared with adenoviral vectors may explain their ability to enhance re-endothelialization without affecting restenosis. Liposome-mediated gene delivery can result in prolonged and localized transgene expression in the blood vessel wall in vivo. Furthermore, lipoeNOS delivery to the blood vessel wall results in accelerated re-endothelialization; however, it does not reduce neointimal formation. Gene Therapy (2012) 19, 321-328; doi:10.1038/gt.2011.92; published online 30 June 2011Keywords: endothelialization; coronary artery stents; restenosis; late stent thrombosis; liposome INTRODUCTION Drug-eluting stents (DES) are now routinely used for occlusive atherosclerotic coronary lesions to reduce the problem of restenosis. However, DES have been associated with a higher frequency of very late stenosis and re-infarction (more than 1 year) compared with bare metal stents, 1.9% versus 0.6% per year, respectively. 1,2 In addition, animal studies have shown that DES can cause local toxicity to the vessel wall in the form of medial necrosis, intimal proliferation, chronic inflammation and delayed re-endothelialization of the stents. 1-3 Thus, although DES reduce the risk of restenosis, they are associated with delayed re-endothelialization. 4,5 An optimal therapeutic approach would involve a strategy, which inhibits intimal hyperplasia while promoting re-endothelialization and suppressing stent-or vector-related inflammatory side effects.Gene-eluting stents have the potential to provide an alternative treatment strategy for the prevention of restenosis. The safety and feasibility of viral-medi...

show abstract

In vitro and In vivo studies of local arterial gene delivery and transfection using lipopolyplexes‐embedded stents

Brito

Chandrasekhar

Little

et al. 2009

J Biomedical Materials Res

View full text Add to dashboard Cite

Gene-eluting stents can have profound impact in the treatment of coronary restenosis, especially when the encoded protein can re-endothelialize the arterial lumen. In this study, we have examined gene delivery in vitro and in vivo using poly(beta-amino ester) (PbAE) precondensed plasmid DNA-containing cationic liposomes or lipopolyplexes (LPP) immobilized on stainless steel meshes and stents using gelatin coatings. In vitro studies using LPP-immobilized on 50 mm round meshes using type A and B gelatin coatings showed that LPP were efficiently internalized in human aortic smooth muscle cells (SMC) over time, leading to green fluorescent protein (GFP) expression. Type B gelatin coating was found to be more effective in intracellular delivery and transgene expression efficiency and, as such, was used for stent coating. In vivo studies, carried out in iliac artery restenosis model in New Zealand white rabbits, also showed GFP expression in arterial tissues after 24 h of implantation. Based on these encouraging preliminary results, LPP-based formulations can serve as a safe and effective nonviral gene delivery system for effective treatment of coronary restenosis.

show abstract

Gene-eluting Stents: Adenovirus-mediated Delivery of eNOS to the Blood Vessel Wall Accelerates Re-endothelialization and Inhibits Restenosis

Cited by 79 publications

References 28 publications

Endothelial nitric oxide synthase induces heat shock protein HSPA6 (HSP70B′) in human arterial smooth muscle cells

Endothelial nitric oxide synthase induces heat shock protein HSPA6 (HSP70B′) in human arterial smooth muscle cells

Gene-eluting stents: non-viral, liposome-based gene delivery of eNOS to the blood vessel wall in vivo results in enhanced endothelialization but does not reduce restenosis in a hypercholesterolemic model

In vitro and In vivo studies of local arterial gene delivery and transfection using lipopolyplexes‐embedded stents

Contact Info

Product

Resources

About