Gene therapy--why can it fail?

Abstract

The success of reductionism in medicine has enabled the experimental expression of individual genes in complex living systems. The promise of gene therapy, permanent reversal or amelioration of disease symptoms without dependence on a long-lasting intake of drugs, has come within reach because of these conceptual and technical advances in molecular biology. However, there have been setbacks posing serious questions for the medical community. The incidents came at a time when technical advances in the manipulation of DNA had led to wide-spread testing of gene based therapies. In fact, the major limiting factor of this approach had been perceived to be gene delivery rather than toxicity. Here we discuss the hypothesis that knowledge of DNA sequences for relevant genes alone will not be sufficient to allow this promise to come to fruition, unless additional factors are recognized and addressed. The physiologic consequences of gene expression depend on gene dosage, transcriptional regulation by promoters, posttranscriptional editing, and interdependence among gene products, all of which vary among cells. The success of gene therapy will depend, in part, on insight into the factors summarized here, very much like successful drug therapy has depended on an understanding of the manifold influences of pharmacokinetics and pharmacodynamics. In principle, these considerations apply to all transfections, gene disruptions, and transgenic approaches and to potential clinical applications derived from them. Gaining insight and control over those factors may allow gene therapy to live up to current expectations.