Nucleic-acid therapeutics: basic principles and recent applications

Key Points Although conceptually elegant, the prospect of using nucleic-acid molecules for treating human diseases remains tantalizing, but uncertain. The main cause of this uncertainty is the apparent randomness with which these materials modulate the expression of their intended targets. Strategies for modulating gene expression can be directed towards perturbing the process of transcription, or post-transcriptional events, including mRNA processing and translation. Conveniently, these approaches can be categorized as 'anti-gene' or 'anti-mRNA.' Gene targeting can be accomplished by homologous recombination, triple-helix-forming oligodeoxynucleotides (TFOs) and decoy molecules. Targeting mRNA can be accomplished by various strategies as well, including the use of antisense DNA, antisense RNA and RNA-decoy molecules. A new approach that has received a great deal of attention in the past year is called post-transcriptional gene silencing, or RNA interference (RNAi). Molecule delivery to targeted cells specific compartments within cells, and identification of hybridization-accessible sequence within the genomic DNA or RNA remain core stumbling blocks that hold up progress in the field. Nucleic acids that are used for experimental purposes and those designed for the clinic are now routinely modified to enhance their stability, as well as the strength of their hybridization with RNA. Many successful uses of this strategy in the laboratory have been reported. Despite the fact that the mechanism whereby these molecules modulate gene expression is not always certain, clinical development of nucleic-acid compounds has proceeded to the point at which a number of these drugs have entered Phase I/II, and in a few cases, Phase III trials. RNA-encoding proteins that are involved in key signal-transduction pathways and transcription factors are the primary targets. Some encouraging reports of the clinical usefulness of these molecules, either alone, or predominantly in combination with other treatment modalities, have been reported. The sequencing of the human genome and the elucidation of many molecular pathways that are important in disease have provided unprecedented opportunities for the development of new therapeutics. The types of molecule in development are increasingly varied, and include antisense oligonucleotides and ribozymes. Antisense technology and catalytic nucleic-acid enzymes are important tools for blocking the expression of abnormal genes. One FDA-ap