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(Circulation Research. 1999;84:1471-1472.)
© 1999 American Heart Association, Inc.

Editorials

Thinking Globally, Acting Locally

The Promise of Cardiovascular Gene Therapy

Toren Finkel

From the Cardiology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md.

Correspondence to Toren Finkel, MD, PhD, Cardiology Branch, NHLBI/NIH, Bldg 10, Room 7B15, 10 Center Dr, MSC 1650, Bethesda, MD 20892-1650. E-mail finkelt@gwgate.nhlbi.nih.gov

Key Words: gene therapy • adenovirus • endothelial nitric oxide synthase • tissue factor pathway inhibitor

Most diseases are local problems, whereas most treatments are systemic in nature. This simple, maddening imbalance remains one of the major causes of the ineffectiveness of our current pharmacological armamentarium. The notion of treating local disease with localized therapy has however emerged as one of the great promises of gene therapy. Two articles^{1 2} in this issue of Circulation Research eloquently demonstrate this point. Although the major rationale for early gene therapy efforts was to deliver functional copies of defective genes for a variety of inherited conditions, the emphasis has most recently shifted. As demonstrated in the two articles published in this issue, there is increasing interest in using gene therapy techniques to deliver therapeutic products to diseased tissues or organs for any of a number of acquired conditions. Underlying these efforts is the hope to express therapeutic molecules that have great local benefit but which have limiting systemic toxicities.

The study of Nishida and colleagues¹ applies this concept to a model of arterial thrombosis. To achieve their local objectives, they have constructed a recombinant adenovirus encoding tissue factor pathway inhibitor (TFPI). TFPI is a curious molecule whose biological activity was noted more than 40 years ago but was only cloned relatively recently.³ The molecule is composed of three tandem Kunitz-type proteinase domains that appear to be responsible for the interaction of TFPI with factor Xa.⁴ Indeed, TFPI is thought to form a quaternary complex composed of Xa, as well as factor VIIa and tissue factor.⁵ This complex results in reduced . . . [Full Text of this Article]

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