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Cardiovascular Research 1997 33(1):181-187; doi:10.1016/S0008-6363(96)00188-5
© 1997 by European Society of Cardiology
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Copyright © 1997, European Society of Cardiology

The DispatchTM catheter as a delivery tool for arterial gene transfer

Ouafae Tahlila, Marc Bramia, Laurent J Feldmana, Didier Branellecb and Ph.Gabriel Stega,*

aUnité ‘Physiopathologie du Coeur et des Artères’, Laboratoire de Pathologie Expérimentale, Faculté Xavier Bichat, Paris, France
bRhône-Poulenc Rorer GenCell, Courbevoie, France

Received 12 March 1996; accepted 30 July 1996


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
Objective: Most currently available percutaneous delivery methods for arterial gene therapy are limited by the need for a long incubation period, which may lead to unacceptable tissue ischemia, especially in the coronary vasculature. Conversely, shorter incubation times may result in inefficient gene transfer, especially in atheromatous arteries. A new local delivery autoperfusion multichamber catheter is now available which permits local delivery in the coronary arterial system without inducing myocardial ischemia. The present study aimed at evaluating the performance of this catheter for achieving arterial gene transfer using replication-defective adenoviral vectors in normal and atheromatous arteries. Methods: A replication-defective adenoviral vector carrying a nuclear-targeted β-galactosidase reporter gene (Ad-RSVβgal, 5.10[9] plaque-forming units [pfu]) was delivered to the iliac arteries of normal (n = 7) and atheromatous (1% cholesterol diet + arterial abrasion) (n = 6) rabbits, via a multichamber autoperfusion balloon catheter (DispatchTM, SciMed). Duration of gene delivery was 60 min. Results: Three days later, marked expression of the reporter gene was detected by histochemistry in the endothelium at the delivery site (percentage of transfected cells: 16 ± 8% /artery (range 11–25%). There was a low transduction rate in medial smooth muscle cells 0.7 ± 0.4% /artery (range 0.3–1.1%). In atheromatous arteries, transduction was consistently achieved in the superficial layers of the neointima but was lower (1.1 ± 0.5% /artery, range 0.3–1.7%). Transgene expression was detected by histochemistry in the liver of 3/13 animals, suggesting that there is a substantial risk of systemic dissemination of the viral vectors. Conclusion: Efficient arterial gene delivery to endothelial and superficial smooth muscle cells is feasible using local delivery of adenoviral vectors via the DispatchTM autoperfusion catheter, in both normal and atheromatous arteries. This perfusion catheter may be a useful tool for coronary artery gene transfer.

KEYWORDS Gene therapy; Gene transfer; Rabbit; Restenosis; Gene expression


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
Arterial gene therapy requires efficient local gene delivery to the cells of the arterial wall [1] especially if the transduced gene encodes for a non-secreted protein. Various vectors can be used, among which recombinant replication-defective adenoviral vectors [2] and Sendai virus protein-coated liposomes [3] appear the most efficient. These vectors can be delivered percutaneously using a host of delivery devices, such as double balloon catheters [4–6], hydrogel-coated balloon catheters [5, 7], porous balloon catheters [8], and ‘channeled’ balloon catheters [9]. One of the technical problems, however, is that when adenoviral vectors are used, transduction efficiency falls markedly with decreasing exposure times [10]. Using passive diffusion delivery devices with adenoviral vectors, an exposure of at least 30 min is necessary to achieve substantial transduction [5–7]. In the coronary vasculature, such protracted balloon inflations will generate unacceptable myocardial ischemia. In addition, transduction efficiency falls markedly when adenovirus-mediated gene delivery is performed in atheromatous arteries as opposed to normal arteries [9]. Therefore, before gene therapy can be applied clinically in the coronary vasculature (e.g., in the prevention of restenosis after angioplasty of atherosclerotic coronary arteries), delivery systems must be designed to achieve efficient gene transfer to the arterial wall while maintaining coronary perfusion to the distal arterial bed.

The DispatchTM catheter (Scimed Life Systems, Inc.) is an autoperfusion balloon catheter, designed for local drug delivery, which has been used clinically for intracoronary delivery of thrombolytic agents [11]. The aim of this study was to determine the results of arterial gene transfer in normal and atheromatous arteries achieved after local delivery of replication-defective adenoviral vectors via the DispatchTM catheter.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Conclusion
 References
 
2.1. The DispatchTM catheter
The device is an over-the-wire, nondilatation catheter that consists of a 4.4F shaft with a 20 mm POC (polyolefin copolymer) spiral inflation coil wrapped around a non-porous urethane sheath on its distal tip (Fig. GR1 A). When the spiral coil is inflated (Fig. GR1 B), it forms both an internal lumen that allows for distal coronary perfusion through the inner sheath (Fig. GR1 C) and a series of isolated chambers between the catheter coils, the urethane sheath, and the arterial wall [11]. The solution to be delivered is administered through a separate infusion port and is delivered locally through slits in the coils (Fig. GR1 A). The arterial wall segments limited by these coils stay in contact with the adenoviral solution and are isolated from blood flow through the inner urethane sheath. The catheter coil is inflated with a standard inflator and reaches nominal size at 8 atm (Fig. GR1 B). When the balloon is inflated in a 2.5 mm vessel, the total volume of the solution in the chambers approximates 100 µl.


Figure 1
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  		Fig. GR1 (A) Schematic diagram of the multichamber DispatchTM catheter. The polyurethane sheath defines an internal cylinder, through which blood can cross the occluded area and perfuse the distal bed (black arrow). The coils isolate 5 separate chambers, each of which is accessible via a separate port located on the eccentric shaft. (B) X-ray showing the coil catheter inflated in a rabbit iliac artery. (C) X-ray showing the DispatchTM catheter inside an iliac artery (black arrowheads), during aortography, in which the distal arterial bed is fully opacified via the Dispatch catheter (white arrows).

 
2.2. Adenoviral vector
A replication-defective recombinant adenoviral vector based on human adenovirus 5 serotype and carrying the nlslacZ gene was produced as previously described [12, 13]. This vector (Ad-RSVβgal) contains the Escherichia coli β-galactosidase gene and the SV40 early region nuclear localisation sequence (nls) under the control of the Rous sarcoma virus (RSV) promoter. The use of nuclear-targeted β-galactosidase allows separation of transduced cells which exhibit dark-blue staining of the nucleus after Xgal reagent staining [14], whereas endogenous β-galactosidase activity, such as seen in macrophages or after arterial injury [15], has an exclusively cytoplasmic location. To avoid variability of in vivo efficiency between viral stocks, all experiments were performed using the same viral stock.

2.3. Gene delivery
All animal procedures were performed in accordance with institutional guidelines, as well as with the Guide for Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH publication No. 85-23, revised 1985). Thirteen male NZW rabbits weighing 3.0 kg were used. Seven were kept on a standard diet, while 6 were put on 1% cholesterol-enriched diet. In the latter animals, balloon abrasion of the endothelium of the iliac artery was performed 26 days after the onset of a cholesterol-enriched diet, by 5 passes of an inflated latex balloon 4F Fogarty catheter (Baxter).

Local gene delivery was attempted either in rabbits with normal arteries or 24 days after arterial abrasion in hypercholesterolemic rabbits. After premedication with acepromazine (0.7 mg/kg i.m.), heparin (100 IU/kg i.v.) was injected and anesthesia was induced with pentobarbital (10 mg/kg i.v.). A 2.5 mm DispatchTM catheter was introduced into the right femoral artery retrogradely up to the iliac artery. The balloon was then inflated at 8 atm. Three hundred microliters of saline containing 5.109 pfu of Ad-RSVβgal were injected and left standing in contact with the vessel wall for 60 min. The solution was then withdrawn, the balloon deflated and the catheter retrieved. The right femoral artery was ligated, the skin closed and the animals were allowed to recover. In an attempt to mimic the clinical application of catheter-based gene transfer, these procedures were performed in strict percutaneous fashion, without surgical ligation or cross-clamping of side-branches. The left iliac artery was always used as a control: there were 13 control arteries with no instrumentation (from 7 normal and 6 atheromatous transfected rabbits) and 2 additional arteries from 2 normal untransfected animals who underwent sham delivery of 300 µl of saline with the DispatchTM catheter.

2.4. Morphometric analysis and analysis of transgene expression
Three days following transfection, animals were anesthetized with acepromazine and pentobarbital. A 6F arterial sheath was surgically inserted into the abdominal aorta. Rabbits were killed by pentobarbital overdose. Transfected (n = 13), contralateral (n = 13) and sham-transfected (n = 2) iliac arteries were excised after fixation with 4% paraformaldehyde. The arteries were then rinsed in PBS-Mg2+. To assess nlslacZ gene expression, the arteries were stained with X-gal reagent (Sigma) for 2 hours at 37°C [5, 16]. Each iliac artery was cut into 6 segments, which were then sectioned into 3–6 5-µm-thick sections proportionally spaced along the arterial segment. Each 5-µm-thick section was counterstained for morphometric analysis with orcein or hematoxylin-eosin. Sections with processing artefacts were discarded from quantitative morphometry. Overall, 268 sections from 13 transfected iliac arteries were available for morphometric analysis, representing a total of approximately 536 000 cells. Transgene expression was considered positive only when dark-blue nuclear or perinuclear staining was observed. In atheromatous arteries, however, due to the massive staining of the superficial layers of the neointima, it was not possible to discriminate between the endothelial or smooth muscle nature of transfected cells; therefore, results in atheromatous arteries are expressed as total number of transduced cells in the neointima. The percentage of transduced endothelial as well as medial/neointimal smooth muscle cells was counted on each section. Comparisons and calculations were made using the artery as the experimental unit, therefore: n = 7 for normal and n = 6 for atheromatous arteries. To identify smooth muscle cells within the arterial wall, immunohistochemical staining of X-gal-stained arterial sections was performed, using a mouse monoclonal primary antibody specific for smooth muscle {alpha}-actin (HHF-35, Enzo Diagnostics) and a polyclonal peroxidase-labeled anti-mouse IgG secondary antibody (Signet Laboratories). Samples of brain, liver, lung, heart, testes, kidney and skeletal muscle (n = 13 for each) were taken for X-gal staining as previously described. For analysis of transgene expression at remote sites, sections were selected at random from each tissue sample and scanned for presence of nuclear β-gal staining. In addition, whenever tissue samples displayed evidence of staining on macroscopic examination, sections were also examined by light microscopy. The total number of cells submitted to light microscopic examination per organ sample ranged from 30.103 to 81.103, (mean ± s.d. = 36 805 ± 15 875 cells).


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Conclusion
 References
 
3.1. Histological and histochemical analyses of transfected arteries
In each transfected artery, 3 days following gene delivery, massive punctiform blue staining was found on the luminal aspect of the vessel, and was strictly localized to the site of balloon inflation (Fig. GR2 A,B). The stained cells were arranged according to diagonal stripes corresponding to the space delimited by the spiral coil of the catheter (Fig. GR2 B). There was no thrombus at the site of balloon inflation. Light microscopic examination of the vessels showed minimal abrasion of the endothelial layer by the balloon, and a preserved vessel architecture, with neither disruption of the internal elastic lamina nor medial necrosis. Macroscopic and light microscopic examination of the arterial segments transduced with the Dispatch catheter, as well as of the adjacent tissues did not reveal evidence of severe ischemia (such as inflammatory cell migration or tissue edema). Most importantly, in normal arteries trans-gene expression was present in a substantial percentage of endothelial cells (mean ± s.d.: 16 ± 8% / artery (range 11–25%) and 16 ± 11% / section (range 6–46%)). Conversely, only occasional transduced smooth muscle cells were found in the media 0.7 ± 0.4% /artery (range 0.3–1.1%) and 0.8 ± 0.8% / section (range 0–3.1%) (Fig. GR3 A). Although transduced cells tended to be found in the most superficial layers of the arterial wall (i.e., the endothelium and superficial smooth muscle cells), there were occasional instances in which transduction extended deep into the media (Fig. GR3 B). In transfected atheromatous arteries, transduced cells were found in the most superficial neointimal layers, 1.1 ± 0.5%/artery (range 0.3–1.7%) and 1.1 ± 0.7%/section (range 0–3.4%) (Fig. GR4 A,B). The transduced cells formed a nearly continuous layer in the superficial plaque close to the lumen. However, the depth of the plaque remained largely unaffected. In these atheromatous arteries, there were no X-gal-stained cells in the media. In both normal and atheromatous animals, there was no detectable nuclear X-gal staining in control arteries whether uninstrumented (Fig. GR2 C) or sham-transfected with saline (Fig. GR3 C), on both gross and light microscopic examination.


Figure 2
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  		Fig. GR2 (A) Macroscopic view ‘en face’ of the luminal aspect of the right iliac artery of a normal rabbit, 3 days after percutaneous delivery of Ad-RSVβgal via the DispatchTM catheter and after X-gal staining. Dark dots represent transduced cell. Cell transduction is visible on the area covered by the balloon, with sometimes massive staining in the location of the marks left by the catheter coils (x 6). (B) Same view of the luminal aspect of the right iliac artery of an atheromatous rabbit iliac artery (x 9). Note the evenly-spaced diagonal strips indicating the location of the coils (black arrows). Note the sharp delineation between the infected segment and the adjacent non infected segment (white arrows). (C) Same view of the terminal abdominal aorta and contralateral iliac artery showing the absence of cell staining in untransduced segments.

 

Figure 3
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  		Fig. GR3 (A) Light microscopic view of the artery shown in Fig. GR2 A after hematoxylin-eosin counterstaining. Dark nuclei indicate β-galactosidase activity. The endothelium is nearly intact and show massive transduction. In contrast, only two medial smooth muscle cells, located immediately below the internal elastic lamina, are transduced (white arrows). (B) Light microscopic view of a normal artery 3 days after transfection (hematoxylin-eosin), displaying evidence of β-galactosidase expression over nearly the entire thickness of the media. (C) Light microscopic view of a sham-transfected artery using saline after hematoxylin-eosin counter-staining. Note the absence of β-galactosidase activity in both endothelial cells (black arrowheads) and the media. The internal elastic lamina is indicated by the white arrows (x 200).

 

Figure 4
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  		Fig. GR4 Low (A) and high (B) light microscopic views of an X-gal-stained atheromatous rabbit iliac artery, 3 days after gene delivery, showing a nearly continuous layer of transduced cells (dark nuclei) in the superficial layers of the neo-intima. L = lumen, N = neointima, M = media. The internal elastic lamina is indicated by black arrowheads.

 
3.2. Detection of nlslacZ gene at remote sites
Macroscopic and light microscopic examination of all arteries never showed β-galactosidase expression in regions other than those in direct contact with the catheter. Specifically, the adjacent arterial segments were never transduced. In each animal, gross examination of X-gal-stained tissue samples from liver, brain, testes, heart, lungs, kidneys and skeletal muscle showed no X-gal staining except in the liver of one animal. On light microscopic examination, however, nuclear X-gal-staining was found in 3 out of 13 liver samples (representing 17 cells out of a total of approximately 659 x 103 cells in 19 sections): therefore, less than 1 in 106 cells expressed β-galactosidase (Fig. GR5). No nuclear X-gal staining was seen in other organs.


Figure 5
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  		Fig. GR5 Light microscopic view of a rabbit liver 3 days after Ad-RSVβgal delivery via the DispatchTM catheter and after X-gal staining (x 150). The blue dots represent two transduced liver cells, indicating dissemination of the viral vector during local arterial delivery (black arrows).

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Conclusion
 References
 
While the ultimate criterion for judging the interest of the DispatchTM catheter for gene transfer will be experiments using therapeutic genes delivered via this device, the present study demonstrates the feasibility of gene transfer to normal and atheromatous arteries using local delivery of adenoviral vectors via the DispatchTM catheter. With this device, it was possible to achieve percutaneous transduction of a substantial number of endothelial cells in normal arteries and endothelial as well as neointimal smooth muscle cells in atherosclerotic arteries, while maintaining distal perfusion and without resorting to surgical ligation, cross-clamping of side-branches or jet-producing catheters[2, 17, 18], the latter being associated with substantial tissue damage and occasionally resulting in perforation [19]. While transduction efficiency to smooth muscle cells may appear low, in both normal and atheromatous arteries (in the range of 1%), it must be pointed out that this figure was calculated over the whole thickness of the media, whereas efficiency approximated 100% in the most superficial layers of the arteries. In addition, in several instances, expression of the reporter gene could be found to extend to deep layers of the media (Fig. GR3 B). Finally, the percentage of transfected cells obtained with the DispatchTM catheter in normal and atheromatous arteries (0.7 and 1%, respectively), albeit low, compares favorably with results from previous studies using the same reporter gene with the double balloon catheter (0.18 ± 0.5% in normal arteries) [5] or the channeled balloon catheter (2 ± 1.3 and 0.2 ± 0.03% in normal and atheromatous arteries, respectively)[9]. Such transduction efficiencies in smooth muscle cells are compatible with a significant therapeutic effect in atherosclerotic vessels [20]. Likewise, using the β-galactosidase reporter gene, the Wolinsky catheter has achieved a transduction efficiency of 0.13% in the media of normal arteries [18].

In addition, contrary to other devices for local delivery (with the exception of the double balloon catheter and possibly the InfusaSleeveTM), the DispatchTM catheter preserves the endothelial layer and in fact results in a high transduction rate in the endothelium (16 ± 11%). Thus the DispatchTM catheter represents a device ideally suited to gene therapy strategies targeting the endothelium.

In order to use gene therapy for the prevention of restenosis, efficient gene transfer must be achieved in atheromatous coronary arteries. The most efficient vectors to date are replication-defective adenoviral vectors. In previous studies, adenoviral vectors were incubated for 30 min in order to achieve efficient gene transfer [5, 7]. In the coronary vasculature, such protracted exposure times are likely to result in severe ischemia. The DispatchTM catheter permits effective local drug delivery in the coronary arterial system [21]. It can be inflated in the coronary vasculature for periods as long as 16 h without inducing myocardial ischemia [11, 22, 23]. Ischemia, however, may stem from the possibility of side-branch occlusion by the coils. Therefore, at present, considering the need for protracted balloon inflations and the fact that no other local delivery catheter has the capability of maintaining distal coronary blood flow, the DispatchTM catheter appears to be the only catheter clinically applicable to percutaneous gene delivery to the coronary vasculature

While adenovirus-mediated gene delivery is substantial in normal arteries, there is evidence [9] that transduction efficiency is markedly reduced in atheromatous vessels, which represents a potential liability for clinical applications of adenovirus-based arterial gene therapy [24] especially if the therapeutic transduced gene encodes a non-secreted protein, in which case transduction efficiency must be high in order to achieve substantial biological effects. This is the case, for example, when cytostatic strategies are used to attempt prevention of restenosis[17, 25]. In our experiments, consistent transduction of the atheromatous lesions was achieved, most likely because of the protracted exposure made possible by the perfusion catheter. In normal arteries, while the number of transduced smooth muscle cells may appear low, it was superior to that achieved in our laboratory using similar methods with a double balloon catheter [5]. In addition, in atheromatous arteries, the transduced cells were located in the superficial layers of the atheromatous plaque, where migrating and proliferating smooth muscle cells are most likely to be recruited during generation of neointimal hyperplasia, although recent work by [26] suggests that in fact recruitment of cells from the adventitia may be important in the restenotic process. Finally, many gene therapy strategies involve genes which encode secreted proteins; therefore, transduction of only a fraction of the target cells may yield a substantial amount of protein likely to exert therapeutic biological effects [27]. Caution should be exercised, however, before extending the results of these experiments to human atheromatous coronary arteries, given the well-documented limitations of rabbit models of atherosclerosis and restenosis, and differences between peripheral and coronary arteries.

The main limitation of the DispatchTM catheter, which it shares with other delivery systems for arterial gene therapy[5], is the risk of viral dissemination at sites remote from the delivery site. In the case of the DispatchTM catheter, the viral dissemination observed resulted most likely from suboptimal isolation of transfection chambers by the eccentric shaft carrying the infusion ports. The zebra appearance of the artery after transduction of the β-galactosidase gene raises the concern that when the DispatchTM catheter is used for therapeutic purposes, there may be a continuing disease process (e.g., restenosis) between the coils. This, however, may be circumvented by using a therapeutic insert resulting in a substantial bystander effect, such as the thymidine kinase gene [17, 28, 29], in which transduced cells treated with ganciclovir generate a therapeutic effect in untransduced adjacent cells. While histochemical study of the liver may underestimate systemic vector spread (especially with comparison with PCR techniques), adenovirus affinity for liver tissue is well documented [30] and in previous similar studies [5] the liver was the only organ demonstrating histochemical transgene expression or PCR presence of the transgene. It must be pointed out, however, that nearly all local delivery catheters tested have been found to result in substantial systemic and specifically liver transduction [31, 32]. In addition, the risks related to leakage of adenoviral vectors may be circumvented by the use of tissue-specific promoters [33, 34]. Finally, the Dispatch catheter is not an angioplasty catheter [11], and therefore requires exchange over a wire with a conventional angioplasty balloon catheter. This, however, is a simple procedure, routinely performed in clinical practice, but immediately after balloon injury the distribution of virus and gene expression may be quite different from those observed 24 days later as in the present study.


   5. Conclusion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
References
 
Adenovirus-mediated gene delivery to the superficial layers of normal and atheromatous arteries is feasible using the DispatchTM catheter. Distal perfusion allows for prolonged infusion without ischemia. This delivery method achieves transduction of the endothelium and superficial layers of the neointima in atheromatous vessels, a pre-requisite for many arterial gene therapy strategies.


   Acknowledgements
 
This work was supported by the BIOAVENIR program financed by Rhône Poulenc, Ministère de la Recherche et de l'Espace and Ministère de l'Industrie et du Commerce Extérieur as well as by a joint grant from INSERM/Merck-Sharpe-Dohme. The authors are grateful to SciMed Life Systems Inc. for generously providing the catheters, and gratefully acknowledge Catherine Guettier, M.D., for her help with tissue processing.


   Notes
 
* Corresponding author. Service de Cardiologie A, Hôpital Bichat Claude-Bernard, 46 rue Henri Huchard, 75877 Paris Cedex 18, France. Tel. +33 1 40 25 86 69; Fax +33 1 40 25 88 65. Back


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 

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