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Changing therapeutic approaches: RNA level

  1. May 4, 2009 #1
    The way we design therapeutics for many conditions is set up to undergo a radical change. Traditionally, herbs and animal parts were used as sources of bioactive small molecules. Once we realized the small molecules were the useful part, we started to isolate them from the natural world and use them as purified medicines. Then came chemical synthesis of small molecule drugs. More recently, large molecules like monoclonal antibodies have been purified from living systems and used as medicines. Now we are synthesizing large molecules, such as synthetic oligonucleotide analogs. Using larger molecules means the molecules can specifically recognize larger molecular surfaces, presenting a new possibility -- manipulating RNA through molecules targeted by Watson-Crick pairing to specific RNA sequences.

    The field of RNA therapeutics started with molecules such as phosphorothioate antisense and, with the discovery of the RNAi system in cells, has branched into siRNA/shRNA and their modifications. While the attention of pharmaceutical companies has shifted mostly toward siRNA, therapeutics based on siRNA struggle with a set of recalcitrant problems: innate immune activation, off-target gene modulation, and delivery into cells in vivo. Meanwhile, antisense structural types like Morpholino oligos have been developed which don't activate immune responses, are far more specific (affecting their targeted RNA with little to no off-target RNA interaction), and can be delivered into cells in vivo by attachment of small moieties such as cell-penetrating peptides or guanidinium dendrimers.

    These "delivery-enabled" antisense molecules can be used to prevent expression of targeted genes or to alter splicing of pre-mRNA, clipping targeted exons out during formation of mature RNA. Potential applications include antiviral drugs and treatments for genetic diseases. Here are a few citations to the literature showing the emergence of this new sort of medicine.

    Clinical trial:

    Open access paper:
    Wu B, Li Y, Morcos PA, Doran TJ, Lu P, Lu QL. Octa-guanidine Morpholino Restores Dystrophin Expression in Cardiac and Skeletal Muscles and Ameliorates Pathology in Dystrophic mdx Mice. Mol Ther. 2009 May;17(5):864-71. Epub 2009 Mar 10.

    Open-access review:
    Moulton JD, Jiang S. Gene Knockdowns in Adult Animals: PPMOs and Vivo-Morpholinos. Molecules. 2009 Mar 25;14(3):1304-23.
  2. jcsd
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