The concept of using
nucleic acids to bind to and inhibit the activities of target proteins
grew out of early HIV gene therapy studies that employed RNA ligands,
termed decoys, to competitively inhibit the activities of essential HIV
proteins and in the process block viral replication (1).
TAR and RRE decoys were expressed in cells to bind and squelch the
activities of the HIV RNA-binding proteins tat and rev. Similarly,
double-stranded DNA decoys have been employed to squelch the activities
of a variety of transcription factors (2).
The use of combinatorial libraries of nucleic acids and in vitro
selection methods, termed SELEX, allow nucleic acid–based ligands
(aptamers) to be developed as specific, high-affinity antagonists to
virtually any target protein (3, 4).
The ability to modify nucleic acids to enhance the stability and
bioavailability of decoys and aptamers should allow these nucleic
acid–based therapeutics to be administered in a manner more like
traditional drug delivery than like gene therapy.
Three papers in this
series describe the development of therapeutic decoys and aptamers.
Hicke and Stephens discuss the potential utility of aptamers as imaging
reagents, and White, Sullenger, and Rusconi review the development of
therapeutic aptamers. Finally, Mann and Dzau provide the reader with an
overview of the transcription factor decoy approach and discuss results
from early clinical trials using this therapeutic strategy.