2-5A-ANTISENSE We have described [Proc. Natl. Acad. Sci. USA 90, 1300 (1993); Bioconjugate Chem. 4, 467 (1993); Science 265, 789 (1994)] a targeted mRNA destruction method which derives from the covalent linkage of a 3',5'-antisense oligodeoxyribonucleotide and a 2',5'- oligoadenylate activator of the 2-5A-dependent RNase. This composite nucleic acid, through the antisense domain, targets the chimera to a particular mRNA sequence which is then degraded by the 2-5A component which provides a localized activation of the latent 2-5A-dependent RNase. The antisense component of the chimera provides a high degree of specificity normally missing from 2-5A-dependent RNase cleavages. The antisense region of the composite molecule also might facilitate uptake of 2-5A since antisense oligonucleotides seem to be taken up by intact cells. Finally, this approach brings into play the potent catalytic action of the latent 2-5A-dependent endonuclease, perhaps thereby substantially increasing the potency of the antisense approach. Research in this section is proceeding on two fronts. First, we are attempting to define the appropriate RNA sequences and best chemical modifications that will optimize the 2-5A-antisense potency. Secondly, we are applying current knowledge of this system to several potential therapeutic targets, including herpes simplex virus, human immunodeficeincy virus, human respiratory syncytial virus, and steroid alpha-reductase and the androgen receptor. Promising activity has been obtained against respiratory syncytial virus in tissue culture. A provisional patent has been filed on this observation, and research is proceeding toward application in an animal model.
