J Thorac Cardiovasc Surg 1999;118:34-35
© 1999 Mosby, Inc.
SURGERY FOR ACQUIRED CARDIOVASCULAR DISEASE |
Commentary
Andrew S. Wechsler, MD,
Philadelphia, Pa
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Introduction
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The tools of molecular biology have allowed us to understand physiologic processes at the level of chemical signals and mediators that alter fundamental cell function. Part of the molecular biology paradigm is a shift to experimental models that use manipulation of phenotype to produce changes in protein composition that affect cell behavior, even when the protein itself is difficult to measure or when its effect is so compartmentalized that measurement would provide little useful information.
However, for clinicians, the holy grail of molecular biology is gene therapy. That is, the ability to change cell phenotype so that a protein product is enhanced or diminished to achieve a desired physiologic effect.
The ability to alter cell phenotype by introducing genetic material has been demonstrated in almost every organ system. When genetic material is introduced into rapidly dividing cells or stem cells, there is hope that the genetic material may become incorporated into the genome of subsequent cells and be permanently carried forward. Introducing genetic material into mature and frequently nonreplicating cells is a much more difficult task. In contrast to disease states in which a single enzyme is missing (for example, adenosine deaminase), some pathologic conditions require repeated rather than sustained therapy. Introduction of genetic material into cells would be a far more effective strategy if the altered phenotype could be controlled with an "off-on" switch. Lee and his colleagues have admirably demonstrated this technique in this issue of the Journal. It is interesting that the protein produced in response to stimulation of the promoter region of the gene is in such small quantities that it cannot yet be measured. However, the effects of the up-regulated protein are easily measurable in the form of a platelet count. These studies address one of the important issues in gene therapy—control of the gene product expressed.
1 In experimental animals, many genes and gene products of interest to cardiac biologists and pulmonary biologists have been manipulated. These include the genes responsible for the defect in cystic fibrosis (CFTR), angiogenesis (VEGF), the beta receptor (ß-AR), genes regulating the expression of myocardial protective factors such as heat shock protein (HSP), genes that influence the inflammatory process in endothelial cells (NFKB), and genes that may prolong transplant graft survival (TGF-ß1). 2
These laboratory experiments have come to fruition in clinical trials experimenting both with the protein products that govern angiogenesis and with gene strategies to up-regulate angiogenic growth factors. However, a number of problems remain. In mature cells, it appears inexorable that the vector genome (synonymous with the genetic material producing the designed alteration in phenotype) diminishes. Mechanisms for gene destruction may be inflammatory, the normal process of degradation and turnover of nuclear proteins and bases, gene products that are recognized as "foreign" with time, and the attachment of the transfected material to chromosomal locations where the effect is blunted. There is inadequate understanding of factors controlling long-term expression of gene actions determined by complex interactions between promoters and enhancers within the cell, some of which may be located at sites distant from the genetic material. 3
Lee and his colleagues have not offered a solution to the problem of gene therapy, and the use of gene enhancers has been successfully demonstrated in other organ systems. Ultimately, the coming together of an entire science facilitating control of gene expression will perhaps make gene therapy in mature cells a reality. For the time being, let us regard this contribution as another "baby step" toward this ultimate goal.
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References
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Blau HM, Springer ML. Gene therapy: a novel form of drug delivery. N Engl J Med 1995;333:1204-7. [Free Full Text]
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Mulligan RC. The basic science of gene therapy. Science 1993;260:926-33. [Abstract/Free Full Text]
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Rosenthal N. Regulation of gene expression. N Engl J Med 1994: 331:931-3.
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Introduction
References