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Chapter: Pharmaceutical Biotechnology: Fundamentals and Applications - Oligonucleotides

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Transcription Factor Decoys - Oligonucleotides Interfering With Gene Expression

Transcription factors are nuclear proteins that usually stimulate and occasionally downregulate gene expres-sion by binding to specific DNA sequences, approxi-mately 6 to 10 base-pairs in length, in promoter or enhancer regions of the genes that they influence.

Transcription Factor Decoys

Transcription factors are nuclear proteins that usually stimulate and occasionally downregulate gene expres-sion by binding to specific DNA sequences, approxi-mately 6 to 10 base-pairs in length, in promoter or enhancer regions of the genes that they influence. The corresponding decoys are ONs that match the attach-ment site for the transcription factor, known as consensus sequence, thus luring the transcription factor away from its natural target and thereby altering gene expression (Fig. 5) (Tomita et al., 2004).

 

The facts that many transcription factors are involved in regulation of a certain gene and that many genes are controlled by a single transcription factor represent important limitations to the decoy ap-proach, especially when decoy action is only desired in the pathological tissue.

 

Clinically, this strategy has been evaluated in patients at risk of post-operative neo-intimal hyper-plasia after bypass vein grafting. The ONs, edifoli-gide, was delivered to grafts intraoperatively by ex vivo pressure-mediated transfection, and was de-signed to target E2F, a transcription factor that regulates a family of genes involved in smooth muscle cell proliferation. While pre-clinical studies demon-strated beneficial effects, a series of clinical trials yielded mixed results from reduced graft failure to no benefit compared to placebo (Conti and Hunter, 2005). The studies did indicate good safety of this local ex vivo treatment strategy. Current clinical studies focus on topical administration of NFkB decoys for atopic dermatitis (Dajee et al., 2006).


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