Despite impressive evidence-based developments in pharmacotherapy, invasive management and device therapy over the last few decades, cardiovascular disease remains the largest killer in the developed world and new treatments are urgently needed. Ever since the first demonstration of gene transfer into the vascular wall over 20 years ago[1], gene therapy has been heralded as an imminent addition to the Cardiologist’s arsenal. However, despite a huge amount of basic science research, promising animal studies, and numerous clinical trials, to-date no gene therapy application has demonstrated unequivocal benefit in the clinical setting. Will gene therapy really become a clinical reality in the near future or is all the hype and research expenditure unwarranted?

Part of the reason that progress has been slow, as compared to traditional pharmacotherapy, is the complexity of gene therapy which requires several inter-related components. Firstly a vector is needed to deliver the DNA for a gene (which in turn will produce a therapeutic protein) into the cell nucleus - this is usually a virus or a plasmid.

Viruses have evolved exquisite mechanisms over millions of years to enter cells but this means that targeting is difficult and ectopic gene expression in non-target tissue is a problem. Another drawback is that immune responses to viral proteins can result in rapid elimination of the vector -overexuberant host immune responses have also resulted in trial patient deaths. Oncogenesis is an additional risk with viruses which integrate into the host genome.

Plasmids on the other hand are relatively simple circular strands of DNA which are safer than viruses and elicit a minimal immune response. However, as they lack dedicated cell entry mechanisms, gene transfer efficiency is orders of magnitude lower than with viral vectors.

Intense research effort has focussed on modification of both viruses and plasmids to improve safety, specificity and efficacy. As a result, modern vectors used in clinical studies bear little resemblance to their original forms.

The second aspect of a gene therapy application is the method of delivery – for cardiovascular applications intracoronary, intramuscular and intramyocardial injection remain the most common methods and coating stents with vector (“gene-eluting stents”) has shown promise in animal studies.

The choice of gene (and hence therapeutic protein) contained within the vector represents the final major consideration with dozens having undergone investigation. Most experience in clinical studies has been with the proangiogenic growth factors vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF).

So where does the field of cardiovascular gene therapy find itself today? Therapeutic angiogenesis for coronary and peripheral arterial disease and improving cardiomyocyte function for heart failure are currently the most promising potential applications and several phase III trials are now underway.

The AGENT series of clinical trials is the largest to date of cardiovascular gene therapy and involved intracoronary administration (to all three coronary arteries) of a virus (adenovirus) encoding FGF for patients with angina refractory to conventional therapy[2]. These phase II studies revealed an apparent gender-specific effect, with a significant benefit in women at 12 months, but no effect in men. The phase III AWARE trial, which is enrolling only women, should tell us whether this unusual finding is genuine (http://clinicaltrials.gov/ct2/show/NCT00438867).

End-stage peripheral arterial disease is a common target for gene therapy trials and most studies have used intramuscular injections of plasmid. The phase II TALISMAN study showed a decreased amputation rate using a plasmid encoding for FGF[3] and this is being investigated further in the phase III TAMARIS trial which should give preliminary results this year (http://clinicaltrials.gov/ct2/show/NCT00566657). The phase II HGF-STAT trial showed that a plasmid encoding for hepatocyte growth factor increased limb perfusion at 6 months[4]. A phase III trial of this therapy is also planned. Finally the WALK study of intramuscular adenovirus encoding hypoxia inducible factor-1α is due to present in 2010 (http://clinicaltrials.gov/ct2/show/NCT00117650).

Finally the first trials of gene therapy for heart failure have commenced investigating intracoronary delivery (using adeno-associated virus) of the SERCA2a gene, which encodes for the sarcoplasmic reticulum calcium pump. This protein has been shown to be deficient in patients with heart failure and restoration with gene therapy has improved left ventricular function in animal models. The CUPID study is investigating intracoronary virus infusion in patients with severe heart failure and has finished recruitment[5]; preliminary results are expected later this year. A second study in the UK is investigating intracoronary administration of a similar vector in patients with end-stage heart failure who have already undergone LVAD implantation. This study has received approval and is due to commence recruitment early this year (http://clinicaltrials.gov/ct2/show/NCT00534703).

How the field of cardiovascular gene therapy develops depends to a large extent on the results of the above trials. Positive results should refuel interest and ensure continued research funding. If these trials are negative the future of cardiovascular gene therapy, at least in the short-term, will be less certain. The fact that numerous animal studies have demonstrated that cardiovascular gene therapy can provide meaningful benefits suggests that gene therapy will ultimately have a role in humans. However this will only happen once the optimal vector, delivery method and gene have been identified for the specific clinical application, which may take many more years of preclinical research.

 

1.            Nabel, E.G., et al., Recombinant gene expression in vivo within endothelial cells of the arterial wall. Science, 1989. 244(4910): p. 1342-4.

2.            Henry, T.D., et al., Effects of Ad5FGF-4 in patients with angina: an analysis of pooled data from the AGENT-3 and AGENT-4 trials. J Am Coll Cardiol, 2007. 50(11): p. 1038-46.

3.            Nikol, S., et al., Therapeutic angiogenesis with intramuscular NV1FGF improves amputation-free survival in patients with critical limb ischemia. Mol Ther, 2008. 16(5): p. 972-8.

4.            Powell, R.J., et al., Results of a double-blind, placebo-controlled study to assess the safety of intramuscular injection of hepatocyte growth factor plasmid to improve limb perfusion in patients with critical limb ischemia. Circulation, 2008. 118(1): p. 58-65.

5.            Hajjar, R.J., et al., Design of a phase 1/2 trial of intracoronary administration of AAV1/SERCA2a in patients with heart failure. J Card Fail, 2008. 14(5): p. 355-67.