Antisense oligonucleotides as therapeutic agents--is the bullet really magical?

@article{Stein1993AntisenseOA,
  title={Antisense oligonucleotides as therapeutic agents--is the bullet really magical?},
  author={C. A. Stein and Y. C. Cheng},
  journal={Science},
  year={1993},
  volume={261 5124},
  pages={
          1004-12
        }
}
Because of the specificity of Watson-Crick base pairing, attempts are now being made to use oligodeoxynucleotides (oligos) in the therapy of human disease. However, for a successful outcome, the oligo must meet at least six criteria: (i) the oligos can be synthesized easily and in bulk; (ii) the oligos must be stable in vivo; (iii) the oligos must be able to enter the target cell; (iv) the oligos must be retained by the target cell; (v) the oligos must be able to interact with their cellular… 
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Certain therapeutic applications of antisense techniques currently under investigation in oncology, haematopathology and inflammatory diseases are described.
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Some of the progress that has been made with antisense pharmacology are reviewed, as well as the current status of this class of compound in clinical trials are described.
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TLDR
It is contention that a highly critical approach must still be taken in interpreting data derived from experiments using antisense oligonucleotides, as it remains relatively easy to claim that experimentally observed biological effects occur by an antisense mechanism.
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In theory, the use of antisense oligodeoxynucleotides provides a method to inhibit the intracellular expression of arty given targeted gene specifically. Such inhibition can be accomplished because…
Strategy for designing specific antisense oligonucleotide sequences
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In this review, hybridization simulation for designing optimal antisense sequences is introduced and length, location, specificity, hairpin potential, mRNA secondary structure, and dimer formation are calculated.
Antisense strategy for cancer therapy
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Preclinical investigations in AS-ODNs, chemically modified to survive nuclease attack, have been used systematically in murine models of human malignancies and a measurable anti-tumor effect has been observed and phase I clinical trials involving ex vivo and systemic administration of such compounds are now in progress.
Antisense oligonucleotides: strategies for delivery
Design and application of antisense oligonucleotides in cell culture,in vivo, and as therapeutic agents
TLDR
A number of factors such as the mode of action, specificity, chemistry, and pharmacology must be carefully considered for the design and successful application of antisense oligonucleotides are critically discussed.
Cellular delivery of antisense oligonucleotides.
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References

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TLDR
It is concluded that in this system it is probably not possible to obtain specific cleavage of an intended target RNA without also causing at least the partial destruction of many nontargeted RNAs.
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TLDR
This review discusses the various classes of compounds currently receiving attention, including unmodified oligodeoxynucleotides, methylphosphonates, phosphorothioates, and alpha-oligonucleotide, and notes that it holds the promise for specific gene therapy.
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It is suggested that a mechanism other than "antisense inhibition" may be operative in these systems, as judged by inhibition of syncytia formation and expression of viral proteins p17, p24, and reverse transcriptase for human immunodeficiency virus 1 in Molt-3 cells.
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TLDR
Oligodeoxynucleotides with a phosphorus atom in which one of the non-bridging oxygen atoms is substituted by selenium were prepared and investigated with respect to their antisense properties and diminished hybridization capability of phosphoroselenoate oligomers relative to both the unmodified phosphodiester oligomers and the phosphorothioate congeners.
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TLDR
It is suggested that chemotherapy for human immunodeficiency virus type 1 infection with antisense oligodeoxynucleotide phosphorothioates may be achieved by an initial high-dose treatment followed by a lower maintenance dose.
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TLDR
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TLDR
This work has investigated the mechanism by which oligonucleotides enter living cells and identified an 80-kDa surface protein that may mediate transport.
Mechanism of oligonucleotide uptake by cells: involvement of specific receptors?
TLDR
It was found that cellular uptake of oligodeoxynucleotide derivatives is achieved by an endocytosis mechanism, which suggests the involvement of specific receptor proteins in binding of oligomers to mammalian cells.
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