Antisense strategy

Stein, C.A., Benimetskaya, L., and Mani, S. 2005. Antisense strategies for oncogene inactivation. Seminars in Oncology 32(6), 563-572. 

Grunweller A, Wyszko E, Bieber B et al (2003) Comparison of different antisense strategies in mammalian cells using locked nucleic acids, 2 -O-methyl RNA, phosphorothioates and small interfering RNA. Nucleic Acids Res 31 3185-3193... 

Weiss B, Davidkova G, Zhang SP (1997) Antisense strategies in nemobiology. Neurochem Int 31 321-348... 

RNA structures constitute one of the limitations to the use of the antisense strategy. Intramolecular basepairing competes with the intermolecular assocation between the antisense sequence and the sense RNA strand, and thus weakens or even abolishes the effect of the regulatory sequence. A number of studies have been devoted to the identification of accessible sites in target RNA (Sczakiel, 2000 Sohail and Southern, 2000) or to the optimization of the hybridization site for minimizing the penalty to be paid to unfold the target structure (Ecker, 1993 Freier, 1993). 

Figure 14. Principle of antisense strategy applying a platinated oligonucleotide.

SMC. These regulatory effects were abrogated by the use of estrogen receptor (ER) antagonists, tamoxifen (Tam), 4-OH-tamoxifen, or Raloxifen (Ral) (33). More recently, it was demonstrated using an antisense strategy that these effects of l7(3-estradiol on EC were mediated through ERa, whereas the effects on SMC were mediated via ER(3 (34). 

Colman, A. (1990). Antisense strategies in cell and developmental biology. J. Cell Sci. 97, 399-409. 

Putnam, D. A., Antisense strategies and therapeutic applications, Am. J. Health-Syst. Pharmacol., 53, 151, 1996. 

In order to obtain therapeutic agents based on synthetic ribozymes, it is necessary to modify these structures chemically. Such modifications - as in the traditional antisense strategy - should confer resistance to nucleases, selectivity, and proper hybridization and uptake characteristics. In the case of ribozymes, the design of new modified nucleotides becomes more complex, since correct folding of the nucleic acid is needed in order to maintain the catalytic activity. Several studies (e.g.. X-ray structure elucidation and mapping with modified nucleotides) have shown that the presence of the 2 -hydroxyl group at specific positions in the catalytic core is essential for hydrolytic activity. Ribozymes are currently used in larger screens as a... 

Over a span of more than two decades, antisense strategies for gene therapy have expanded from AS-ODNs solely to the addition of ribozymes and, more recently, to... 

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