Antisense therapy

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 feasible to synthesize a strand of nucleic acid ( DNA, RNA or a similar chemical) 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 been translated. Alternatively, the strand might be targeted to 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 (AON) because its base sequence is complementary to the gene 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 oligonucleotides have been researched as potential drugs [2] [3] [4] for diseases such as cancers (including lung cancer , colorectal carcinoma , pancreatic carcinoma , malignancy glioma and malignant melanoma ), diabetes , amyotrophic lateral sclerosis (ALS), Duchenne muscular dystrophy , spinal muscular atrophy and diseases such as asthma , arthritis and pouchitis with an inflammatorycomponent. As of 2016, Several antisense drugs-have-been approved by the US Food and Drug Administration (FDA): Fomivirsen as a treatment for cytomegalovirus retinitis , mipomersen for homozygous familial hypercholesterolemia , eteplirsen for Duchenne muscular dystrophy, and nusinersen for spinal muscular atrophy.

Example antisense therapies

As of 2012, some 40 antisense oligonucleotides and siRNAs have been in clinical trials, including over 20 in advanced clinical trials (Phase II or III). [5] [6]


Also in 2006, German physicians reported a dose-escalation study for the AP 12009 compound (a phosphorothioate antisense oligodeoxynucleotide specific for the mRNA of 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. [7]

Cytomegalovirus retinitis

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

Familial hypercholesterolemia

In January 2013 mipomersen (Marketed as Kynamro) Was approved by the FDA for the treatment of homozygous familial hypercholesterolemia . [8] [9]

Hemorrhagic fever viruses

In early 2006, scientists studying the Ebola hemorrhagic fever viruses at USAMRIID annoncé 75% recovery rate after-oven infecting rhesus monkeys And Then Treating Them with an antisense morpholino drug developed by Sarepta Therapeutics (formerly named AVI BioPharma ), a US biotechnology firm. [10] The general 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[11] 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. [12]


Starting in 2004, researchers in the US have been conducting research on antisense technology to combat HIV. [13]

In the past, the virus has been harvested, modified with an antisense RNA virus viral envelope protein, and re-infused into the patient during a planned lapse in retroviral drug therapy. [14]

Spinal muscular atrophy

In 2004, development of an antisense therapy for spinal muscular atrophy was started. Over the Following years, an antisense oligonucleotide later named nusinersen Was developed by Ionis Pharmaceuticals under a licensing agreement with Biogen . In December 2016, nusinersen received regulatory approval of FDA for the treatment of spinal muscular atrophy. [15] [16]

Duchenne muscular dystrophy

In September 2016, eteplirsen received FDA approval for the treatment of Duchenne muscular dystrophy .


Volanesorsen is in phase 3 clinical trials for hypertriglyceridemia as of December 2016.


Because nucleases that cleave the phosphodiester linkage in DNA are expressed in almost every cell, unmodified DNA molecules are degraded before they reach their targets. Therefore, antisense drug candidate molecules are modified Generally During the drug discovery stage of Their Development. [17] [18] Additionally, most targets of antisense are located inside cells, and getting nucleic acids across cell membranes is also difficult. Therefore, most clinical candidates have modified DNA “backbones”, or the nucleobase or sugar moieties of the nucleotidesare altered. Additionally, other molecules May be conjugated to antisense molecules in order to Improve Their Ability to target some cells or to cross barriers like cell membranes or the blood brain barrier . [17]

See also

  • Oligonucleotide synthesis
  • antisense
  • Antisense mRNA
  • morpholino
  • Peptide nucleic acid
  • Locked nucleic acid
  • RNA interference (which uses double-strand RNA)


  1. Jump up^ 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. Jump up^ Weiss, B. (ed.): Antisense oligodeoxynucleotide and Antisense RNA: Novel Pharmacological and Therapeutic Agents, CRC Press, Boca Raton, FL, 1997.
  3. Jump up^ Weiss, B; Davidkova, G; Zhou, LW (March 1999). “Antisense RNA gene therapy for studying and modulating biological processes.” Cellular and molecular life sciences: CMLS. 55 (3): 334-58. doi:10.1007 / s000180050296. PMID 10228554.
  4. Jump up^ Goodchild, J (2011). “Therapeutic oligonucleotides”. Methods in Molecular Biology (Clifton, NJ) . 764 : 1-15. doi : 10.1007 / 978-1-61779-188-8_1 . PMID  21748630 .
  5. Jump up^ Bennett, CF; Swayze, EE (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 . PMID  20055705 .
  6. Jump up^ Watts, JK; Corey, DR (2012). “Silencing Disease Genes in the Laboratory and in the Clinic”. J. Pathol . 226 (2): 365-379. doi : 10.1002 / path.2993 .
  7. Jump up^ Results of G004, a phase IIb focused controlled clinical trial with TGF-b2 targeted compound AP 12009 for recurrent anaplastic astrocytoma – Hau et al. 24 (18 Supplement): 1566 – ASCO Meeting Abstracts Archived2012-07-12
  8. Jump up^ Pollack, Andrew (29 January 2013)FDA Approves Genetic Drug to Treat Rare DiseaseThe New York Times, Retrieved 31 January 2013
  9. Jump up^ Staff (29 January 2013)FDA approves new orphan drug Kynamro to treat inherited cholesterol disorderUS Food and Drug Administration, Retrieved 31 January 2013
  10. Jump up^ US 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. ArchivedJune 9, 2007, at theWayback Machine.
  11. Jump up^ 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 .
  12. Jump up^ Medical News Today. AVI BioPharma Announces FDA Clears IND Applications For Clinical Trials Of RNA Therapeutic Agents For Ebola Treatment And Marburg Viruses. 30 Dec 2008.
  13. Jump up^ Lu, X; Yu, Q; Binder, GK; et al. (July 2004). “Antisense-mediated inhibition of human immunodeficiency virus (HIV) replication by HIV-type 1-based vector results in severely attenuated mutants incapable of developing resistance . ” J. Virol . 78 : 7079-88. doi : 10.1128 / JVI.78.13.7079-7088.2004 . PMC  421644  . PMID  15194784 .
  14. Jump up^ University of Pennsylvania School of Medicine. “HIV Phase II Gene Therapy Trial Has Encouraging Results.” ScienceDaily 19 February 2010.
  15. Jump up^ Wadman, Meredith (23 December 2016). “Updated: FDA approves drug that rescues babies with fatal neurodegenerative disease” . Science .
  16. Jump up^ Grant, Charley (2016-12-27). “Surprise Drug Approval Is Holiday Gift for Biogen” . Wall Street Journal . ISSN  0099-9660 . Retrieved 2016-12-27.
  17. ^ Jump up to:a Bennett B CF, Swayze EE. RNA targeting therapeutics: molecular mechanisms of antisense oligonucleotides as a therapeutic platform . Annu Rev Pharmacol Toxicol. 2010; 50: 259-93. doi : 10.1146 / annurev.pharmtox.010909.105654 . PMID  20055705
  18. Jump up^ Xu L, Anchordoquy T.Drug delivery trends in clinical trials and translational medicine: challenges and opportunities in the delivery of nucleic acid-based therapeutics. J Pharm Sci. 2011 Jan; 100 (1): 38-52. doi:10.1002 / jps.22243. PMID 20575003

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