Antisense therapy

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Antisense therapy is a form of treatment for genetic disorders or infections. When the genetic sequence of a particular gene is known to be causative of a particular disease, it is possible to synthesize a strand of nucleic acid (DNA, RNA or a chemical analogue) that will bind to the messenger RNA (mRNA) produced by that gene and inactivate it, effectively turning that gene "off". This is because mRNA has to be single stranded for it to be translated. Alternatively, the strand might be targeted to bind a splicing site on pre-mRNA and modify the exon content of an mRNA[1].

This synthesized nucleic acid is termed an "anti-sense" oligonucleotide because its base sequence is complementary to the gene's messenger RNA (mRNA), which is called the "sense" sequence (so that a sense segment of mRNA " 5'-AAGGUC-3' " would be blocked by the anti-sense mRNA segment " 3'-UUCCAG-5' ").

Antisense drugs are being researched to treat cancers (including lung cancer, colorectal carcinoma, pancreatic carcinoma, malignant glioma and malignant melanoma), diabetes, ALS, Duchenne muscular dystrophy and diseases such as asthma and arthritis with an inflammatory component. Most potential therapies have not yet produced significant clinical results, though one antisense drug, fomivirsen (marketed as Vitravene), has been approved by the US Food and Drug Administration (FDA) as a treatment for cytomegalovirus retinitis.

In early 2006, scientists studying the Ebola virus at USAMRIID announced a 75% recovery rate after infecting four rhesus monkeys and then treating them with antisense drugs (the usual mortality rate for monkeys infected with Ebola is 100%).[2]

Also in 2006, German physicians reported on a dose-escalation study for the compound AP 12009 (a phosphorothioate antisense oligodeoxynucleotide specific for the mRNA of human transforming growth factor TGF-beta2) in patients with high grade gliomas. At the time of the report, the median overall survival had not been obtained and the authors hinted at a potential cure.[3]


[edit] References

  1. ^ Morcos, PA (2007). "Achieving targeted and quantifiable alteration of mRNA splicing with Morpholino oligos.". Biochem Biophys Res Commun 358 (2): 521-7. doi:10.1016/j.bbrc.2007.04.172. PMID 17493584. 
  2. ^ http://www.usamriid.army.mil/press%20releases/warfield_press_release.pdf
  3. ^ Results of G004, a phase IIb actively controlled clinical trial with the TGF-b2 targeted compound AP 12009 for recurrent anaplastic astrocytoma - Hau et al. 24 (18 Supplement): 1566 - ASCO Meeting Abstracts

Weiss, B. (ed.): Antisense Oligodeoxynucleotides and Antisense RNA : Novel Pharmacological and Therapeutic Agents, CRC Press, Boca Raton, FL, 1997

Weiss, B., Davidkova, G., and Zhou, L-W.: Antisense RNA gene therapy for studying and modulating biological processes. Cell. Mol. Life Sci., 55:334-358, 1999

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