Intravascular Magnetic Resonance/Radiofrequency May Enhance Gene Therapy for Prevention of In-stent Neointimal Hyperplasia

doi:10.1016/j.acra.2005.12.017

Academic Radiology

Volume 13, Issue 4, April 2006, Pages 526-530

https://doi.org/10.1016/j.acra.2005.12.017 Get rights and content

Rationale and Objectives

We evaluated the potential of using intravascular magnetic resonance (MR)/radiofrequency (RF) to enhance vascular endothelial growth factor (VEGF) gene therapy of in-stent neointimal hyperplasia.

Materials and Methods

By using a catheter-based approach, VEGF/lentivirus was locally transferred into 10 (five paired) bilateral femoral-iliac arteries of five hypercholesterolemic pigs, whereas the right arteries were heated up to approximately 41°C by using an intravascular MR/RF system. Then, identical stents were placed immediately into the bilateral VEGF-targeted arteries to create in-stent neointimal hyperplasia. At day 60 after gene/stent interventions, the targeted arteries were harvested for histological correlation.

Results

X-Ray angiography–detectable in-stent stenoses were found in three of the arteries treated with VEGF genes only, whereas there were no in-stent stenoses in arteries treated by using MR/RF-heated VEGF genes. Correlative histological examination confirmed a 138% reduction in average thickness of neointimal hyperplasia in VEGF/RF-treated arteries compared with VEGF-only–treated arteries (P < .01).

Conclusion

We report a potential method of using an intravascular MR/RF heating technique to enhance gene therapy of in-stent restenosis.

Section snippets

Preparation of VEGF/Lentivirus

VEGF has been documented to inhibit neointimal hyperplasia in vivo (6, 7). Therefore, we chose to use this gene to show that MR-mediated RF heating would enhance expression of this gene in target vascular cells and, in doing so, effectively decrease the amount of neointimal hyperplasia associated with stent placement in a cholesterolemic animal. Lentivirus-based gene therapy was evaluated in phase I/IIa trials (12). Thus, we used a lentivirus vector to carry a therapeutic gene, VEGF (VEGF₁₆₅)

Results

Gene delivery and stenting procedures were primarily successful in all 10 arteries, and all animals survived the procedures with no complications. DSA performed 60 days after gene and stent interventions showed in-stent stenosis in three of five VEGF-only arteries, whereas all five of the VEGF/RF-treated arteries remained patent (Figure 2). Microscopic examination showed that the average neointimal hyperplasia was 138% thinner in VEGF/RF arteries than VEGF arteries (VEGF/RF and VEGF = 318.9 ±

Discussion

Endovascular stenting exerts its effect through purely mechanical means, providing lumen scaffolding that decreases recoil. However, in-stent restenosis is still a common problem after interventional therapies on atherosclerotic vessels, even with drug-eluting stents, and is particularly prominent in the small arteries, such as coronary arteries (15). Some studies showed that the VEGF gene not only promotes angiogenesis (5), but also inhibits in-stent restenosis through its properties as an

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Cited by (9)

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Citation Excerpt :
Besides, decreasing the activity of cell-cycle regulators proliferating-cell nuclear antigen and cyclin-dependent kinase-2 prevented SMCs proliferation and subsequent neointima formation in a rat carotid balloon-injury model [80]. Other approaches aim to inhibit SMCs proliferation, such as overexpression of light-type caldesmon [81] or SOCS-3 (suppressor of cytokine signaling-3) [61] can significantly inhibit the abnormal injury-induced SMCs growth and prevents neointima formation. Inhibition of matrix metalloprotease (MMP) activity by overexpression of tissue inhibitor of matrix metalloprotease (TIMP)-1 [82] and TIMP-3 [83] decreased the migratory properties of SMCs and inhibited their proliferation in models of in-stent restenosis.
Although vessels are directly exposed to the bloodstream, vascular gene transfer is rarely used as a tool for preclinical studies for several reasons: (i) viral and non-viral vectors show a low transduction efficiency in the vascular system; (ii) classical vascular gene therapy approaches such as treatment of peripheral or cardiac ischemia are focusing on non-vascular target cells; and (iii) vascular diseases are rarely monogenetic, thus gene replacement approaches are uncommon. Here, we provide an overview of recent approaches in developing novel vectors and modes of application for improved transduction efficiency of large and small vessels. Increased availability of such tools for vascular gene transfer has already facilitated preclinical studies addressing a broad variety of vascular diseases like transplant vasculopathy, atherosclerosis, and hereditary aortic diseases such as Marfan syndrome.
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2007, Progress in Nuclear Magnetic Resonance Spectroscopy
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2006, FEBS Letters
MRI has the ability to generate high-contrast and high-resolution images, to obtain multiple diagnostic evaluations of organ function and morphology, and to provide multiple image planes with no risk of ionizing radiation. Recent efforts have focused on using MR technology to monitor gene delivery, to enhance gene transfection/transduction, and to track gene expression. This review summarizes the current status of MRI-guided gene therapy.
iMRI for Clinical Gene Therapy
2022, Gene Delivery Systems: Development and Applications
Nanoparticle-based imaging in gene/drug therapy
2013, Nanotechnology in Modern Medical Imaging and Interventions

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¹: Supported by NIH grant no. R01 HL66187.

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Work in progressIntravascular Magnetic Resonance/Radiofrequency May Enhance Gene Therapy for Prevention of In-stent Neointimal Hyperplasia1

Rationale and Objectives

Materials and Methods

Results

Conclusion

Section snippets

Preparation of VEGF/Lentivirus

Results

Discussion

Am J Cardiol

Lancet

Biochem Biophys Acta

Ultrasound Med Biol

2003 Heart and Stroke Statistical Update

Drug-eluting stentsthe new gold standard for percutaneous coronary revascularisation

Eur Heart J

New approaches to preventing restenosis

BMJ

Gene transfer approaches for cardiovascular disease

Work in progress
Intravascular Magnetic Resonance/Radiofrequency May Enhance Gene Therapy for Prevention of In-stent Neointimal Hyperplasia1