Genomic Medicine: Development of DNA as a therapeutic drug for sequence-specific modification of genomic DNA.
Extract: Given the recent sequencing of the human genome, we have entered into a new era of medicine, "Genome Medicine," that transcends our traditional notion of pharmacology and drug therapies. We now have the potential to address the genetic root of disease pathology, either by identifying and modifying the function of the gene product responsible for a given pathology through pharmacological means, or by directly modifying the gene with gene therapy. However, as is the case with most new pharmacological treatments, gene therapy has encountered numerous challenges that have limited its efficacy in both preclinical and clinical situations. Some of these challenges have been directly linked to the use of cDNA-based "mini-genes" to complement the genetic defect and ultimately correct the pathology stemming from the defect. This has been particularly poignant in the case of inherited diseases such as cystic fibrosis, severe combined immune deficiency and sickle cell anemia. Alternatives to the cDNA-based technologies have been proposed and rely on the correction of mutant sequences in genomic DNA with oligonucleotides or by the correction of mutant mRNA through modulation of cellular RNA splicing. While the RNA-based strategies complement the DNA-based ones, the focus of this article will be on approaches employing DNA oligonucleotides.
Gruenert
Dieter C
DC
California Pacific Medical Center Research Institute, 2330 Clay St., San Francisco, CA 94115, USA and Department of Medicine, University of Vermont College of Medicine, Burlington, VT 05401, USA.