Figure 582

Translation arrest or nuclease digestion by exogenously applied antisense oligonucleotides or by antisense mRNA produced from DNA delivered by a plasmid. Heterogeneous nuclear RNA is hnRNA.

degradation of the mRNA species due to activation of ri-bonuclease H or disruption of translation. Cells and organisms protect themselves against foreign DNA and RNA by producing nucleases that degrade phosphodi-ester bonds in oligodeoxynucleotides. Chemical modification of the phosphodiester moiety can produce nucle-ase-resistant oligomers. In the two most common chemical analogues, the backbone phosphate is replaced either with a methyl group to form a methyl phosphonate or with a sulfur group to form a phosphorothioate (Fig. 58.3). These modifications grant extra stability to the oligonucleotides, allowing for a longer half-life in vivo.

The antisense RNA can also be generated within cells after delivery via a plasmid or attenuated virus containing a suitable promoter that controls expression of the antisense strand using methods of gene insertion described later (Fig. 58.2). In addition to the strict antisense strategies, several related approaches have been considered. Catalytic RNA, catalytic DNA, or ribo-zymes capable of degrading complementary mRNA may decrease translation of targeted sequences. Oligomers designed to interact with genes directly via Hoogsteen hydrogen binding in a triplex formation have been suggested as a means of disrupting transcrip tion (Fig. 58.4). Transcription factor decoys that are duplexes designed to bind to a particular transcription factor and prevent its normal function are another approach examined in the context of NFkB blockade. These strategies, like antisense itself, do not require integration into the genome, and thus they share the pharmacological problems of absorption, distribution, metabolism, and elimination of any traditional drug not based on nucleic acid.

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