Predicting the future of human gene therapy for cardiovascular diseases: what will the management of coronary artery disease be like in 2005 and 2010?

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Abstract

Gene therapy is the use of gene delivery as a means to achieve high levels of the therapeutic gene product (ie, “drug” delivery) to treat acquired cardiovascular diseases. Human gene therapy for cardiovascular disease is expected to provide important advances in therapeutic angiogenesis, myocardial protection, myocardial regeneration and repair, restenosis, prevention of bypass graft failure, and risk-factor management. The data from ongoing phase 2 and future phase 3 studies will provide evidence to show whether therapeutic angiogenesis is effective, and these studies will identify the types of patients who may benefit. An important therapeutic target is the cell cycle. Data from the Project in Ex-Vivo Vein Graft Engineering via Transfection (PREVENT) I and II studies suggest that a synthetic DNA decoy can sequester the E2F family of transcription factors and arrest cells at the gap period (G1) checkpoint. This mechanism prevents intimal hyperplasia, which is associated with atherosclerosis and coronary graft failure. Administration of a myocardial protective gene (eg, heme oxygenase) via a recombinant adeno-associated virus vector reduces infarct size in animal models of ischemia and reperfusion. Other studies have shown that fractionated bone marrow stem cells promote myocardial repair and regeneration in myocardial infarction. If applied in humans, it will be possible to use a single administration of gene therapy to provide long-term prophylaxis against secondary coronary events and to promote myocardial repair in patients who have experienced an infarct, as well as in those at high risk of myocardial injury. In the future, new technology using stable gene integration may lead to the development of more effective and lifelong therapy for diabetes, familial homozygous hypercholesterolemia, and other acquired diseases.

Section snippets

Systemic risk factors

Probably the best-known example of gene therapy to treat inherited disease is in the treatment of familial homozygotic hypercholesterolemia (FHH). FHH is a monogenic genetic disease resulting from mutation of low-density lipoprotein (LDL) cholesterol receptors. Premature CAD mortality is a result of the rapidly ensuing atheroma precipitated by the presence of very high cholesterol levels that are unresponsive to conventional treatment with statins and other agents. Grossman et al2 reintroduced

Therapeutic angiogenesis

Gene therapy has an important application in enabling therapeutic concentrations of a gene product to be accumulated at the target site of action. It also offers the possibility of minimizing systemic side effects by avoiding high plasma levels of the gene product.

A number of small, mostly open-label phase 1 or 2 studies have been conducted with adenovirus- and plasmid-based vascular endothelial growth factor and fibroblast growth factor (FGF) gene constructs in CAD and peripheral vascular

Restenosis

Nitric oxide has a pleiotropic effect in that it causes vasodilatation, prevents proliferation and clotting, and acts as a scavenger of free radicals. Many animal models have demonstrated the therapeutic effect of this form of gene therapy,4 but it is difficult to apply these results to humans.

The use of endogenous or induced nitric oxide synthetase in rat carotid artery has produced promising results and, in a more recent study in pigs, induced nitric oxide synthetase administration via

Bypass graft failure

Arresting the cell cycle at the transition from the first gap period (G1) to the synthetic (S) phase provides an exciting opportunity for preventing graft failure. Quiescent (G0) cells enter G1, during which the factors necessary for DNA replication in the subsequent S phase are assembled. After DNA replication is completed, the cells enter another gap phase (G2) in preparation for mitosis (M).

The transition from G1 to S is a very important therapeutic target. This checkpoint is regulated by

Myocardial protection

Gene therapy is usually considered to be an acute intervention at the time of ischemia and/or reperfusion. However, problems lie in the delay in introducing the gene and the time for it to be transcribed, translated, and ultimately modified and released. Transfection efficiency also needs to be improved. Because of these difficulties, gene therapy for acute myocardial ischemia and/or reperfusion is unlikely to be a reality in the very near future.

Long-term use of gene therapy ahead of the event

Myocardial repair and regeneration

The goal of this form of therapy is to activate and mobilize cells for repair and reconstitution after an acute coronary event. Myocardial infarction (MI) leads to loss of tissue because of apoptotic and necrotic cell death. The remaining myocytes are unable to reconstitute the lost tissue, and the postinfarcted heart deteriorates functionally with time. Recent data suggest that progenitor cells originating from bone marrow can migrate to the site of damage and undergo differentiation, thereby

Conclusions

By 2005, it is likely that phase 3 studies in many of the areas discussed will be complete, but it is unlikely that these gene therapy applications will be used routinely in clinical practice because of the time taken for the regulatory process to be completed and for physicians to adopt the technologies in their daily practice.

However, we can predict that 5 years further on, in 2010, some of the studies will have resulted in products that are in regular clinical use. It is possible, for

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