Heart and Metabolism

Gene therapy for ischemic heart disease: how far are we from clinical application?

F.C. Visser
Department of Cardiology, Vrije Universiteit Medical Center, Amsterdam, The Netherlands Correspondence: Professor F.C. Visser, Department of Cardiology, Vrije Universiteit Medical Center, De Boelelaan 117, 1081 HV Amsterdam, The Netherlands.
Tel: +31 20 4440123, fax: +31 20 4442446, e-mail: fc.visser@vumc.nl

Despite primary and secondary prevention, and advances in pharmacological and revascularization therapy, coronary artery disease remains the leading cause of cardiac morbidity and mortality. The widespread use of revascularization strategies such as percutaneous coronary interventions and bypass surgery has resulted in an improvement in anginal symptoms, left ventricular function, and prognosis in the majority of patients. However, despite these advances (or sometimes as a result of them), a large proportion of patients are not (or no longer) eligible for revascularization and consequently have a poor quality of life (see also Heart and Metabolism 2002, number 16, which focused on refractory angina).
During the last decade a tremendous amount of research has been devoted to the potential use of gene therapy to promote the development of blood vessels to enhance blood flow to ischemic myocardium. This process is called angiogenesis. In this issue, Schaper et al stress that angiogenesis should be distinguished from arteriogenesis: angiogenesis describes the sprouting of capillaries from pre-existing capillaries, whilst arteriogenesis is the process of developing new arteries from the pre-existing arteriolar network. This makes particular sense in the clinical situation since angiogenesis alone (increase in the number of capillaries) may not increase blood flow through ischemic tissue without also increasing collateral circulation (arteriogenesis).
The formation of blood vessels is a very complex process involving a number of steps: dissolution of the matrix underlying the endothelium; migration, adhesion, and proliferation of endothelial cells; and formation of new vessels for blood transport. A number of factors trigger the formation of new vessels and these can be divided into three categories: mechanical factors, chemical factors, and molecular factors (for an extensive review see [1]).
Mechanical factors include increased blood flow, shear stress, and mechanical stretch. The chemical factors that initiate angiogenesis are deprivation of oxygen and nutrients. Molecular influences include inflammatory cells, angiogenic factors such as fibroblast and vascular endothelial growth factors, the growth factor receptors on endothelial cells, and the downregulation of angiogenic inhibitors. Although all these factors stimulate angiogenesis, studies suggest that administration of growth factors alone may be sufficient to increase blood flow to ischemic tissue. Therefore, the potential clinical application of growth factors has been the focus of greatest interest.
There are two ways in which growth factors can be delivered to ischemic tissue: (1) by local administration of the growth factor itself, and (2) through transfer of the genetic material encoding for the growth factor. Systemic administration of native factors has potential general side effects, among them retinopathy, neoplastic growth, hypotension, edema, and telangiectases. Local drug delivery has its own limitations, such as multiple procedures and the precise site of delivery to the ischemic tissue. Gene transfer into the cells of the target organ may prove to be a successful alternative. The general side effects from systemic administration can be overcome and the exposure of the ischemic tissue to growth factors can be prolonged. In general, there are two different approaches to gene transfer: viral and nonviral. The most commonly used viral transporters (vectors) are the adenovirus and the retrovirus. The nonviral approach includes the local introduction of so-called naked DNA and the use of liposomes. Numerous animal and some patient studies have evaluated the safety and success of this gene therapy in ischemic tissue.
It is clear that gene therapy is not yet ready for routine clinical use. Many questions surrounding its safety/toxicity in humans, dosing, frequency of delivery, design of the vector, outcome measurements, and patient selection must first be addressed. All these questions are currently being investigated, and phase I and II clinical trials have produced encouraging results in terms of improvement in perfusion and clinical and functional status of the patients.
Because of these important new therapeutic developments the editorial board decided to produce an update in this field. Professor Schaper’s article provides an insight into the mechanisms of development of the collateral circulation. In the main clinical article, Vale and Losordo discuss the preclinical results and clinical trials in peripheral vascular and coronary disease.
The methods of gene transfer are summarized by Mercadier and Logeart, and Baker describes future developments in gene therapy. Because Heart and Metabolism is devoted to metabolism, inherited metabolic diseases and potential treatment with gene therapy are discussed by Spoor and Dyck.
In this respect an interesting case report is presented by Kampmann et al, who describe patients with an inherited error of lipid metabolism and their successful treatment with enzyme replacement therapy. Finally, the use of metabolic agents in combination with conventional hemodynamic agents for the treatment of myocardial ischemia is discussed by Holban and Hénane. We hope you enjoy this issue.

REFERENCE

1: Eur Heart J. 2001 Jun;22(11):903-18.