Introduction

Antisense RNA and DNA techniques have been developed as a relatively recent approach to the specific modulation of gene expression. The development of antisense RNA techniques began with observations from the laboratories of J. Tomizawa and N. Kleckner that bacteria can regulate gene replication and transcription by the elaboration of small complementary or ‘antisense’ RNA molecules (for a review see Weintraub, 1990; or Inouye, 1988). Evidence also now exists that eukaryotic cells elaborate antisense RNA transcripts (Kochbin and Lawrence, 1989; Krystal, Armstrong and Battey, 1990), but the physiologic role of such molecules remains controversial. Nevertheless, in 1985, Izant and Weintraub reported that a transfected expression vector could generate RNA capable of modulating eukaryotic gene expression in a target-specific manner. Actually, prior to the discovery of regulatory RNAs, several laboratories had demonstrated that synthetic oligodeoxynucleotides complementary to mRNA sequences could downregulate mRNA translation in vitro and in cells (Zamecnik and Stephenson, 1978). A profusion of reports has followed, describing the modulation of various oncogenes by both DNA and RNA antisense techniques. Such manipulations offer the possibility of combining the specificity of genetic approaches with the reversibility and temporal control of more pharmacologic approaches. The continued development of antisense technology and related delivery systems has led to initial explorations of the in-vivo utility of antisense, particularly as it relates to oligonucleotides.

However, the excitement generated by initial in-vitro successes has been tempered by the dawning realization that antisense technology is not as ‘clean’ as previously thought.