Jump to content

Antisense therapy

From Wikipedia, the free encyclopedia

This is an old revision of this page, as edited by 24.197.148.213 (talk) at 01:45, 16 December 2013 (→Familial Hypercholesterolemia: replaced ] with )). The present address (URL) is a permanent link to this revision, which may differ significantly from the current revision.

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 a variety of diseases [[2] [3]] such as cancers (including lung cancer, colorectal carcinoma, pancreatic carcinoma, malignant glioma and malignant melanoma), diabetes, Amyotrophic lateral sclerosis (ALS), Duchenne muscular dystrophy and diseases such as asthma, arthritis and pouchitis with an inflammatory component. Most potential therapies have not yet produced significant clinical results [citation needed], though two antisense drugs have been approved by the U.S. Food and Drug Administration (FDA), fomivirsen (marketed as Vitravene) as a treatment for cytomegalovirus retinitis and mipomersen (marketed as Kynamro) for homozygous familial hypercholesterolemia.

Example antisense therapies

Some 40 antisense oligonucleotides and siRNAs are in clinical trials, including over 20 in advanced clinical trials (Phase II or III).[4][5]

Cytomegalovirus retinitis

Fomivirsen (marketed as Vitravene), was approved by the U.S. FDA in Aug 1998 as a treatment for cytomegalovirus retinitis.

Hemorrhagic fever viruses

In early 2006, scientists studying the Ebola hemorrhagic fever virus at USAMRIID announced a 75% recovery rate after infecting four rhesus monkeys and then treating them with an antisense Morpholino drug developed by Sarepta Therapeutics (formerly named AVI BioPharma), a U.S. biotechnology firm.[6] The usual mortality rate for monkeys infected with Ebola virus is 100%. In late 2008, AVI BioPharma successfully filed Investigational New Drug (IND) applications with the FDA for its two lead products for Marburg and Ebola viruses. These drugs, AVI-6002 [7] and AVI-6003 are novel analogs based on AVI's PMO antisense chemistry in which anti-viral potency is enhanced by the addition of positively-charged components to the morpholino oligomer chain. Preclinical results of AVI-6002 and AVI-6003 demonstrated reproducible and high rates of survival in non-human primates challenged with a lethal infection of the Ebola and Marburg viruses, respectively.[8]

Cancer

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.[9]

HIV/AIDS

Starting in 2004, researchers in the US have been conducting research on using antisense technology to combat HIV.[10]

In February 2010 researchers reported success in reducing HIV viral load using patient T-cells which had been harvested, modified with an RNA antisense strand to the HIV viral envelope protein, and re-infused into the patient during a planned lapse in retroviral drug therapy.[11]

Familial Hypercholesterolemia

In January 2013 mipomersen (marketed as Kynamro) was approved by the FDA for the treatment of homozygous familial hypercholesterolemia.[12][13]

See also

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. ^ Weiss, B. (ed.): Antisense Oligodeoxynucleotides and Antisense RNA : Novel Pharmacological and Therapeutic Agents, CRC Press, Boca Raton, FL, 1997
  3. ^ 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
  4. ^ Bennett, C.F. (2010). "RNA targeting therapeutics: molecular mechanisms of antisense oligonucleotides as a therapeutic platform". Annu. Rev. Pharmacol. Toxicol. 50: 259–293. doi:10.1146/annurev.pharmtox.010909.105654. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  5. ^ Watts, J.K. (2012). "Silencing Disease Genes in the Laboratory and in the Clinic". J. Pathol. 226 (2): 365–379. doi:10.1002/path.2993. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  6. ^ U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland. News Release: Gene-Specific Ebola Therapies Protect Nonhuman Primates from Lethal Disease. January 13, 2006.
  7. ^ Lu, X; Yu, Q; Binder, GK; Chen, Z; Slepushkina, T; Rossi, J; Dropulic, B (2004). "Antisense-Mediated Inhibition of Human Immunodeficiency Virus (HIV) Replication by Use of an HIV Type 1-Based Vector Results in Severely Attenuated Mutants Incapable of Developing Resistance". Journal of Virology. 78 (13): 7079–88. doi:10.1128/JVI.78.13.7079-7088.2004. PMC 421644. PMID 15194784.
  8. ^ Medical News Today. AVI BioPharma Announces FDA Clears IND Applications For Clinical Trials Of RNA Therapeutic Agents For Treatment Of Ebola And Marburg Viruses. 30 Dec 2008.
  9. ^ 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
  10. ^ Antisense-mediated inhibition of human immunodeficiency virus (HIV) replication by use of an HIV type 1-based vector results in severely attenuated mutants incapable of developing resistance.
  11. ^ University of Pennsylvania School of Medicine. "Phase II HIV Gene Therapy Trial Has Encouraging Results." ScienceDaily 19 February 2010.
  12. ^ Pollack, Andrew (29 January 2013) F.D.A. Approves Genetic Drug to Treat Rare Disease The New York Times, Retrieved 31 January 2013
  13. ^ Staff (29 January 2013) FDA approves new orphan drug Kynamro to treat inherited cholesterol disorder U.S. Food and Drug Administration, Retrieved 31 January 2013


Retrieved from "https://en.wikipedia.org/w/index.php?title=Antisense_therapy&oldid=586275203"