Gene therapy is often depicted as representing ‘just another drug delivery strategy’. However, there are a growing number of examples of a new and much more fundamental applicability: altering a cell phenotype or structure. In the latest example, published in Nature, Miake et al1 present exciting results that suggest a possible alternative to electronic pacemakers.

Most gene therapy trials are in essence examining a genetic means of administering drug therapy. This applies to a diverse range of therapeutic studies, including genetic treatments of cystic fibrosis and hemophilia and the delivering of cytotoxic agents to cancer cells. Gene therapy in these studies may provide more selective or more potent delivery techniques compared to standard drug delivery approaches, but basically the aim and the outcome are the same.

In contrast, the new Nature study1 is one of a growing number of attempts to use gene therapy in a way that is fundamentally different from drug-based therapies. The common aim of this new generation of studies is to actually alter a cell phenotype or structure. In the case of the Miake study, the aim was to create the ‘pacemaker’ phenotype, usually only present in a select few pacemaker cells, in normal heart cells.

Pacemaker cells are characterized by spontaneous cycles of depolarization and repolarization, which create an electrical impulse transmittable to adjoining heart cells. These cycles are mediated by the opening and closing of transmembrane ion channels in the cells. The authors of the new study hypothesized that one of the potassium channels that is intensely expressed in nonpacemaker heart cells represses pacemaker activity. To test this, they suppressed this potassium channel, encoded by the Kir 2 gene family, in target cells in guinea-pigs by transducing them with a modified, ‘dominant negative’ version of Kir2.1. Transduced heart cells thus lacked normal function of the potassium channel encoded by Kir2. This strategy worked as predicted, creating spontaneous ‘pacemaker’ activity in the transduced heart cells.

The structural modification of the target cell in the Nature study is a successful fulfillment, one of the true promises of gene therapy: ‘getting at’ intracellular signaling or structural machinery in a way that would be difficult or impossible with conventional drug treatments. Targeting the cellular phenotype in this way would appear to be a strategy uniquely applicable through gene therapy. Similarly, in recent times gene therapy has been used to modify structurally a diverse range of other cellular proteins including transcription factors, intracellular proteins, and membrane receptors.2,3,4

Realistically, there are many other factors that need to be considered before biological pacemakers can replace electronic ones. Given recent evidence that the Kir 2 potassium channel plays a role in Andersen syndrome (a rare inherited disorder associated with long QT and ventricular arrhythmias), it may not be the ideal protein to target for gene therapy. Other transmembrane channels could provide alternative targets through which this strategy could be successfully applied. Another question that would need to be considered is, would a biological pacemaker need to be located in a specific position in the heart to be effective? Conventional electronic pacemakers in use today need merely to be in contact with some aspect of the atrium/or the ventricle. If a certain position were a requirement, the therapeutic vector could easily be precisely delivered with standard electrophysiology catheter techniques. Finally, the sustainability of such pacemaker cells would need to be reasonably verified before individuals with life-threatening dependence on such pacemaker activity could reliably be treated by this gene therapy.

Despite these minor caveats, the therapeutic first described by Miake et al is an impressive accomplishment. Aside from its therapeutic applications, this work clearly demonstrates the latent presence of the ‘pacemaker phenotype’ in normal heart cells. It also highlights the importance of the Kir 2 potassium channel in determining pacemaker activity in cardiac tissue. Future studies with adenovirus and/or chronic expression vectors are needed to move toward the more effective and persistent effect we would need to create a biological pacemaker. Clinical trials would even be possible in the foreseeable future. In many endeavors, once the gate is cracked open, the floodwaters often pour through. Conceivably, this and similar breaches will provide such an opportunity for delivering the true promise of gene therapy.