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Experimental Physiology 90.3 pp 307-313
DOI: 10.1113/expphysiol.2005.030403
© The Physiological Society 2005
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Cardiovascular Genomics

Does gene therapy become pharmacotherapy?

Ryuichi Morishita1, Motokuni Aoki2 and Toshio Ogihara2

1 Division of Clinical Gene Therapy2 Department of Geriatric Medicine, Graduate School of Medicine, Osaka University, Suita 565-0871, Japan


   Abstract
Top
 Abstract
Introduction
 References
 
Recent progress in molecular and cellular biology has led to the development of numerous effective cardiovascular drugs. However, there are still a number of diseases for which no known effective therapy exists, such as peripheral arterial disease, ischaemic heart disease, restenosis after angioplasty, and vascular bypass graft occlusion. Currently, gene therapy is emerging as a potential strategy for the treatment of cardiovascular disease despite its limitations. The first human trial in gene therapy for cardiovascular disease was started at 1994 to treat peripheral vascular disease using vascular endothelial growth factor (VEGF). Then, many different potent angiogenic growth factors were tested in clinical trials to treat peripheral arterial disease and ischaemic heart disease. Improvement of clinical symptoms in peripheral arterial disease and ischaemic heart disease has been reported. This review focuses on the future potential of gene therapy for the treatment of cardiovascular disease. In the future, gene therapy might become a real pharmacotherapy to treat cardiovascular disease.

(Received 3 March 2005; accepted after revision 9 March 2005; first published online 18 March 2005)
Corresponding author R. Morishita: Division of Clinical Gene Therapy, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita 565-0871, Japan. Email: morishit{at}cgt.med.osaka-u.ac.jp


   Introduction
Top
 Abstract
 Introduction
References
 
Currently, gene therapy is emerging as a potential strategy for the treatment of cardiovascular disease to treat peripheral arterial disease, ischaemic heart disease, vascular bypass graft occlusion and transplant coronary vasculopathy for which no known effective therapy exists. Although current in vivo methods for cardiovascular gene transfer are still limited by the lack of efficiency and potential toxicity, recent advances in in vivo gene transfer may provide the opportunity to treat cardiovascular diseases such as peripheral arterial disease by manipulating angiogenic growth factor genes. The present promising gene therapy is mainly locally administered agents, while most pharmacotherapy is based on oral drugs. To consider the advantage of gene therapy, one might compare the recombinant therapy, as both concepts are relatively closed. What are the advantages of gene therapy? First, it has the potential to maintain an optimally high and local concentration over time. This issue may be critical in the case of arterial gene therapy. However, in the case of therapeutic angiogenesis as discussed later, it may be preferable to deliver a lower dose over a period of several days or more from an actively expressed transgene in the iliac artery, rather than a single or multiple bolus doses of recombinant protein, to avoid side effects. In addition, the feasibility of a clinical trial of recombinant protein is currently limited by the lack of approved or available quantities of human quality of recombinant protein, due in large part to the nearly prohibitive cost of scaling up from research grade to human quality recombinant protein. Indeed, the report to compare the effectiveness of fibroblast growth factor-2 (FGF-2) as protein and as naked plasmid DNA in a porcine model of chronic myocardial ischaemia demonstrated that intramyocardial injection of FGF-2 plasmid was more effective than of FGF-2 protein in improving regional perfusion and contractility compared to untreated ischaemia (Heilmann et al. 2002). In contrast, gene therapy also has disadvantages such as safety aspects, and local and limited effects. After overcoming these disadvantages, gene therapy might become a real pharmacotherapy.

Gene therapy to treat peripheral arterial disease using therapeutic angiogenesis

Critical limb ischaemia that is estimated to develop in 500–1000 individuals per million per year is considered one of the most suitable diseases for gene therapy. Recently, the efficacy of therapeutic angiogenesis using vascular endothelial growth factor (VEGF) gene transfer has been reported in human patients with critical limb ischaemia (Isner et al. 1996a, 1998; Baumgartner et al. 1998, 2000). An initial trial was performed using a hydrogel catheter with naked VEGF165 plasmid in 1994 by Professor Isner. Although this procedure seems to be effective to stimulate collateral formation in patients with peripheral arterial disease (Isner et al. 1996a, HREF="#B17"> 1998; Baumgartner et al. 1998, 2000), it is not ideal to treat many patients, as most patients lack an appropriate target vascular lesion for catheter delivery. Thus, intramuscular injection of naked plasmid encoding VEGF165 gene was used (Fig. 1). This clinical trial demonstrated clinical efficacy for treatment of peripheral arterial disease (Isner et al. 1996a, 1998; Baumgartner et al. 1998, HREF="#B5"> 2000). Since then, numerous angiogenic growth factors such as VEGF121, VEGF-2 and bFGF (fibrolast growth factor) have been tested in clinical trials (Makinen et al. 2002; Comerota et al. 2002). In addition to intramuscular injection of naked plasmid DNA, adenoviral delivery, liposomal delivery of angiogenic growth factors was also utilized in these trials (Isner et al. 1996a, 1998; Baumgartner et al. 1998, 2000; Rajagopalan et al. 2001; Makinen et al. 2002; Comerota et al. 2002; Rajagopalan et al. 2003), despite an unfortunate accident at the University of Pennsylvania (Morishita et al. 1999). A study using adenovirus encoding VEGF121 demonstrated the improvement of endothelial dysfunction in response to acetylcholine or nitroglycerine (Rajagopalan et al. 2001). In addition to the intramuscular injection of VEGF165 and VEGF2 plasmid DNA, a trial of local catheter-mediated VEGF165 gene therapy in ischaemic lower-limb arteries after percutaneous transluminal angioplasty (PTA) was also reported (Comerota et al. 2002). However, the high level of incidence of oedema as a side effect has been reported in a VEGF trial. In the case of Fontaine II as intermittent claudication, the recent result from the Regional Angiogenesis with Vascular Endothelial growth factor (RAVE) trial as the randomized study of adenoviral vascular endothelial growth factor VEGF121 gene transfer was not successful (Rajagopalan et al. 2003). The selection of the agent (VEGF121versusVEGF165), patient population (intermittent claudication versus critical limb ischaemia) and outcome measures (peak walking time versus ulcer size) should be considered in the quest for optimal angiogenic strategies that result in the growth of functional blood vessels and improvement in clinical symptoms.



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  		Figure 1.  Concept of therapeutic angiogenesis using DNA of angiogenic growth factors

 
The safety and efficacy of increasing single and repeated doses of intramuscular naked plasmid DNA encoding for FGF type 1 administered to patients with unreconstructible end-stage peripheral arterial disease (PAD) was also reported (Makinen et al. 2002). A significant reduction in pain and aggregate ulcer size was detected after FGF gene transfer associated with an increased transcutaneous oxygen pressure and ankle pressure index (ABI) as compared with baseline pretreatment values (Makinen et al. 2002). We and others also identified hepatocyte growth factor (HGF) as a novel candidate for therapeutic angiogenesis (Nakamura et al. 1996; Belle et al. 1998; Morishita et al. 1999; Hayashi et al. 1999; Taniyama et al. 2001a, b; Morishita et al. 2002; Hiraoka et al. 2003; Koike et al. 2003). Based upon these findings, we planned a human clinical trial using intramuscular injection of naked human HGF plasmid (0.5 mg x 4 or 8 sites) twice every month. Currently, HGF gene transfer has been performed in 22 patients with PAD or Buerger disease of Fontaine grade IIb, III or IV who had failed conventional therapy. Preliminary results demonstrated the significant reduction in pain and increase in ABI (Morishita et al. 2004). Of importance, the serum level of human HGF protein did not change during gene therapy. It is noteworthy that there was no evidence of oedema in the patients transfected with the human HGF gene, in marked contrast to the VEGF trial in which 60% of patients developed moderate or severe oedema in a phase I/IIa trial. Currently, a phase III trial in Japan and phase II in the USA to treat PAD are underway.

Gene therapy to treat myocardial ischaemic disease using therapeutic angiogenesis

Professor Isner and colleagues have applied a similar idea to treat coronary artery disease using VEGF165 gene (Losordo et al. 1998; Vale et al. 2000). An initial trial was performed with intramuscular injection of naked plasmid encoding VEGF gene into ischaemic myocardium through mini-operation. They reported that the transfection of VEGF gene resulted in a marked increase in blood flow and improved clinical symptoms without apparent toxicity (Losordo et al. 1998; Vale et al. 2000). These data revealed that phVEGF165 (human VEGF165 plasmid DNA) gene therapy may successfully rescue foci of hibernating myocardium. In addition, a phase 1 clinical trial of direct myocardial gene transfer of naked DNA-encoding VEGF165, as sole therapy for refractory angina, was reported in 30 patients with class 3 or 4 angina (Lathi et al. 2001; Fortuin et al. 2003). Similarly, gene therapy using VEGF121 gene was performed by intramuscular injection of adenoviral vector (Rosengart et al. 1999b). Currently, no evidence of systemic or cardiac-related adverse events related to vector administration was observed up to 6 months after therapy (Rosengart et al. 1999a). Intracoronary gene transfer of VEGF165 resulted in a significant increase in myocardial perfusion, although no differences in clinical restenosis rate or minimal lumen diameter were present after the 6-month follow-up (Hedman et al. 2003). More recently, intracoronary infusion of adenovirus encoding FGF gene was performed in a multicentre trial as phase I/IIa. The report documented that intracoronary infusion of FGF gene improved cardiac dysfunction without severe toxicity (Grines et al. 2003). In addition, the report of the treatment of 52 patients with stable angina and reversible ischaemia documented that FGF-4 adenoviral injection resulted in a significant reduction of ischaemic defect size (Grines et al. 2003). However, a more recent report documented the failure of this trial (Adis International, 2002).

In addition to these angiogenic growth factors, over-expression of HGF was also reported to stimulate angiogenesis and collateral formation in a rat and canine myocardial infarction model (Ueda et al. 1999; Aoki et al. 2000). Interestingly, an antifibrosis action of HGF has been identified, as HGF inhibited collagen synthesis through transforming growth factor (TGF-ß) and stimulated collagen degradation through up-regulation of matrix metalloprotease (MMP-1) and urokinase-type-plasminogen activator (uPA) (Taniyama et al. 2002a). Currently, a phase I study using HGF plasmid DNA to treat patients with severe stable angina is on-going in the USA. Overall, the treatment for coronary artery disease may be curable using therapeutic angiogenesis by gene therapy. Table 1 summarizes the present status of gene therapy trials.


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  		Table 1.  Clinical trial of angiogenesis gene therapy
 
Gene therapy for restenosis after angioplasty and graft failure

Another important disease potentially amenable to gene therapy in cardiovascular disease is restenosis after angioplasty. One of the attractive possibilities of treating restenosis is to inhibit target gene expression (Fig. 2). In particular, the application of DNA technology such as antisense strategy to regulate the transcription of disease-related genes in vivo has important therapeutic potential. Accordingly, inhibition of other proto-oncogenes such as c-myc by antisense oligodeoxynucleotidase (ODN) was also reported to inhibit neointimal formation in several animal models (Shi et al. 1994). Currently, a phase II trial using antisense c-myc to treat restenosis is underway. However, as this trial utilized intracoronary infusion of antisense c-myc ODN, several issues such as low transfection efficiency may limit the efficacy of this strategy. In addition, transfection of cis-element double stranded (ds) ODN (= decoy) has been reported as a powerful tool in a new class of antigene strategies for gene therapy (Morishita et al. 1998; Fig. 3). Transfection of ds ODN corresponding to the cis sequence will result in the attenuation of authentic cis–trans interaction, leading to the removal of trans-factors from the endogenous cis-element, with subsequent modulation of gene expression. Therefore, the decoy approach may also enable us to treat diseases by modulation of endogenous transcriptional regulation. Transfection of decoy ODN against E2F, a key transcription factor for cell cycle progression, into rat and porcine balloon-injured arteries resulted in the inhibition of neointimal formation after balloon injury (Morishita et al. 1995; Nakamura et al. 2002). Based on these results, we started a clinical trial using hydrogel catheter delivery of E2F decoy to treat restenosis after angioplasty in April 2000. We did not observe any side effects up to 6 months after delivery, although the clinical outcome has not yet been evaluated.



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  		Figure 2.  Target sites for antisense, ribozyme, RNAi and decoy strategies
Antisense, antisense ODN; ribozyme, ribozyme ON; decoy, decoy ODN; TF, transcription factor.

 


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  		Figure 3.  Scheme of 'decoy' strategy against transcription factor
A, in the basal state, transcription factor is not bound to the cis-element. B, after stimulation, transcription factor is bound to the cis-element, resulting in continuous activation of target gene expression. C, 'decoy' cis element ds ODN binds to transcription factor, resulting in prevention of transactivation of transcription factor-promoting target gene expression. TF, transcription factor.

 
In addition, clinical application of ‘decoy’ against E2F was also approved by the US Food and Drug Administration (FDA) to treat neointimal hyperplasia in vein bypass grafts, which results in failure in up to 50% of grafts within a period of 10 years. A proof-of-concept study, the Project in Ex-Vivo Vein Graft Engineering Via Transfection (PREVENT) I study, was the first clinical trial using genetic engineering techniques to inhibit cell-cycle activation in vein grafts (Mann et al. 1999). This prospective, randomized, controlled trial demonstrated the safety and biological efficacy of intra-operative transfection of human bypass vein grafts with E2F decoy oligonucleotides in a high-risk human patient population with peripheral arterial occlusion. More recently, similar results were obtained in PREVENT II, a randomized, double-blind, placebo-controlled trial investigating the safety and feasibility of E2F decoy oligonucleotides in preventing autologous vein graft failure after coronary artery bypass surgery (Dzau, 2003). Unfortunately, a recent report of a phase III trial to treat PAD patients documented no difference between E2F treatment and placebo (unpublished observation), although a phase III trial to treat ischaemic heart disease is still ongoing.

On the other hand, the transcription factor NF(B also plays a pivotal role in the coordinated transactivation of cytokine and adhesion molecule genes whose activation has been postulated to be involved in numerous diseases. It is important to note that increased NF{kappa}B binding activity has been confirmed in balloon-injured blood vessels (Yoshimura et al. 2001). Our recent study provided the first evidence of the feasibility of a decoy strategy against NF{kappa}B in treating restenosis (Yoshimura et al. 2001). Transfection of NF{kappa}B decoy ODN into balloon-injured carotid artery or porcine coronary artery markedly reduced neointimal formation (Yoshimura et al. 2001; Yamasaki et al. 2003). Based upon the therapeutic efficacy of this strategy, we treated the patients after angioplasty as a phase I/IIa trial. Overall, the decoy approach is particularly attractive for several reasons: (1) the potential drug targets (transcription factors) are plentiful and readily identifiable; (2) the synthesis of sequence-specific decoys is relatively simple and can be targeted to specific tissues; (3) knowledge of the exact molecular structure of the targeted transcription factor is unnecessary; and decoy ODN may be more effective than antisense ODN in blocking constitutively expressed factors as well as multiple transcription factors that bind to the same cis element. Thus, the decoy strategy may be useful for treating a broad range of human diseases. In contrast, because an important concern regarding the decoy strategy revolves around the potential inhibition of normal physiological responses, the application of the decoy strategy as gene therapy may be limited to treatment of acute conditions, namely ‘transcription factor-driven diseases’.

In contrast, the trials using the transfection of foreign genes are few, although inhibition of the cell cycle using non-phosphorylated retinoblastoma gene or anti-oncogenes such as p53 and p21 has been reported in several animal models (Chang et al. 1995a,b; Yonemitsu et al. 1998; Taniyama et al. 2002b). Recently, over-expression of inducible nitric oxide synthase gene has been tested in human subjects, although the results are not yet published. Alternatively, it has been hypothesized that rapid regeneration of endothelial cells without replication of vascular smooth muscle cells may also modulate vascular growth, because multiple antiproliferative endothelium-derived substances (e.g. NO) are secreted from endothelial cells. This concept was first tested by over-expression of VEGF165 gene (Asahara et al. 1995). Based upon this finding, a human trial using VEGF165 gene by hydrogel catheter delivery of naked VEGF165 plasmid DNA has been started for restenosis after angioplasty in peripheral artery (Isner et al. 1996b). The preliminary results documented the successful inhibition of restenosis after angioplasty (Vale et al. 1998). A similar trial using VEGF165 gene has been started in Finland (Laitinen et al. 2000). Although gene transfer with VEGF using adenovirus during percutaneous transluminal coronary angioplasty (PTCA) and stenting shows that intracoronary gene transfer can be performed safely, no differences in clinical restenosis rate or minimal lumen diameter were present after the 6-month follow-up (Hedman et al. 2003). Further studies are necessary to prove the efficacy of re-endothelialization strategy to treat restenosis. Currently, the researchers have tried to develop gene- or decoy-eluting stents to treat restenosis.

Perspectives in gene therapy

Overall, now that gene therapy for cardiovascular disease appears to be not far from reality, it is time to take a hard look at practical issues that will determine the real clinical potential. These include: (1) further innovations in gene transfer methods (especially after the accidents using adenoviral and retroviral vectors); (2) well-defined disease targets; (3) cell-specific targeting strategies; and (4) effective and safe delivery systems. As gene therapy becomes a therapeutic reality, the following must be addressed: (1) safety; (2) persistence of gene expression and duration of treatment; and (3) regulation. In the future, gene transfer as a drug delivery system might overcome present limitations to identify suitable targets to treat unmet cardiovascular disease. Further modification of gene transfer methods would provide novel drug delivery system-based pharmacotherapy.


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   Acknowledgements
 
This work was partly supported by a Grant-in-Aid from the Organization for Pharmaceutical Safety and Research, a Grant-in-Aid from The Ministry of Public Health and Welfare, a Grant-in-Aid from Japan Promotion of Science and a Grant-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology, and the Japanese Government.





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