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 cause 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 "antisense" oligonucleotide (ASO) 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 antisense 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, malignant glioma and malignant melanoma), diabetes, amyotrophic lateral sclerosis (ALS), Parkinson's disease,[5] Duchenne muscular dystrophy, spinal muscular atrophy, Ataxia-telangiectasia (in vitro) and diseases such as asthma, arthritis and pouchitis with an inflammatory component. As of 2016, several antisense drugs have been approved by the U.S. 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. In 2019, a report was published detailing the development of milasen, an antisense oligonucleotide drug for Batten disease believed to be the first example of a personalized therapy developed and approved for a single patient.[6][7]

Example antisense therapies[edit]

As of 2012, some 40 antisense oligonucleotides and siRNAs were in clinical trials, including over 20 in advanced clinical trials (Phase II or III).[8][9]

Batten disease[edit]

With U.S. FDA approval, milasen was rationally designed, tested, and deployed as a novel individualized therapeutic agent for the treatment of Batten disease in the eponymous patient, Mila(Mee-lah) Makovec. This therapy serves as a pioneering example of personalized medicine.[6][10]


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.[11]

Cytomegalovirus retinitis[edit]

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

Familial hypercholesterolemia[edit]

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

Hemorrhagic fever viruses[edit]

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.[14] 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[15] 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.[16]


Starting in 2004, researchers in the US have been conducting research on using antisense technology to combat HIV.[15]

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.[17]

Spinal muscular atrophy[edit]

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 from FDA for use to treat spinal muscular atrophy.[18][19]

Duchenne muscular dystrophy[edit]

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


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


The common stem for antisense oligonucleotides is -rsen. The substem -virsen designates antiviral antisense oligonucleotides.[20]


Because nucleases that cleave the phosphodiester linkage in DNA are expressed in almost every cell, unmodified DNA molecules are generally degraded before they reach their targets. Therefore, antisense drug candidate molecules are generally modified during the drug discovery phase of their development.[21][22] 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 nucleotides are altered. Additionally, other molecules may be conjugated to antisense molecules in order to improve their ability to target certain cells or to cross barriers like cell membranes or the blood brain barrier.[21]

See also[edit]


  1. ^ Morcos PA (June 2007). "Achieving targeted and quantifiable alteration of mRNA splicing with Morpholino oligos". Biochemical and Biophysical Research Communications. 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. ISBN 0849385520 ISBN 9780849385520
  3. ^ Weiss B, Davidkova G, Zhou LW (March 1999). "Antisense RNA gene therapy for studying and modulating biological processes". Cellular and Molecular Life Sciences. 55 (3): 334–58. doi:10.1007/s000180050296. PMID 10228554.
  4. ^ Goodchild J (2011). "Therapeutic oligonucleotides". Methods in Molecular Biology. 764: 1–15. doi:10.1007/978-1-61779-188-8_1. ISBN 978-1-61779-187-1. PMID 21748630.
  5. ^ Uehara T, Choong CJ, Nakamori M, Hayakawa H, Nishiyama K, Kasahara Y, et al. (May 2019). "Amido-bridged nucleic acid (AmNA)-modified antisense oligonucleotides targeting α-synuclein as a novel therapy for Parkinson's disease". Scientific Reports. 9 (1): 7567. doi:10.1038/s41598-019-43772-9. PMC 6527855. PMID 31110191.
  6. ^ a b Kim, Jinkuk; Hu, Chunguang; Moufawad El Achkar, Christelle; Black, Lauren E.; Douville, Julie; Larson, Austin; Pendergast, Mary K.; Goldkind, Sara F.; Lee, Eunjung A.; Kuniholm, Ashley; Soucy, Aubrie (2019-10-09). "Patient-Customized Oligonucleotide Therapy for a Rare Genetic Disease". New England Journal of Medicine. 0 (17): 1644–1652. doi:10.1056/NEJMoa1813279. ISSN 0028-4793. PMID 31597037.
  7. ^ "A Drug Was Made For Just One Child, Raising Hopes About Future Of Tailored Medicine". Retrieved 2019-10-14.
  8. ^ Bennett CF, Swayze EE (2010). "RNA targeting therapeutics: molecular mechanisms of antisense oligonucleotides as a therapeutic platform". Annual Review of Pharmacology and Toxicology. 50: 259–93. doi:10.1146/annurev.pharmtox.010909.105654. PMID 20055705.
  9. ^ Watts JK, Corey DR (January 2012). "Silencing disease genes in the laboratory and the clinic". The Journal of Pathology. 226 (2): 365–79. doi:10.1002/path.2993. PMC 3916955. PMID 22069063.
  10. ^ Gallagher, James (2019-10-12). "Unique drug for a girl with deadly brain disease". Retrieved 2019-10-14.
  11. ^ 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 Archived 2012-07-12 at
  12. ^ Pollack A (29 January 2013). "F.D.A. Approves Genetic Drug to Treat Rare Disease". The New York Times.
  13. ^ Staff (29 January 2013). "FDA approves new orphan drug Kynamro to treat inherited cholesterol disorder". U.S. Food and Drug Administration.CS1 maint: uses authors parameter (link)
  14. ^ 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. Archived June 9, 2007, at the Wayback Machine
  15. ^ a b Lu X, Yu Q, Binder GK, Chen Z, Slepushkina T, Rossi J, Dropulic B (July 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.
  16. ^ 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.
  17. ^ University of Pennsylvania School of Medicine. "Phase II HIV Gene Therapy Trial Has Encouraging Results." ScienceDaily 19 February 2010.
  18. ^ Wadman M (23 December 2016). "Updated: FDA approves drug that rescues babies with fatal neurodegenerative disease". Science.
  19. ^ Grant C (2016-12-27). "Surprise Drug Approval Is Holiday Gift for Biogen". Wall Street Journal. ISSN 0099-9660. Retrieved 2016-12-27.
  20. ^ International Nonproprietary Names (INN) for biological and biotechnological substances
  21. ^ a b Bennett CF, Swayze EE (2010). "RNA targeting therapeutics: molecular mechanisms of antisense oligonucleotides as a therapeutic platform". Annual Review of Pharmacology and Toxicology. 50: 259–93. doi:10.1146/annurev.pharmtox.010909.105654. PMID 20055705.
  22. ^ Xu L, Anchordoquy T (January 2011). "Drug delivery trends in clinical trials and translational medicine: challenges and opportunities in the delivery of nucleic acid-based therapeutics". Journal of Pharmaceutical Sciences. 100 (1): 38–52. doi:10.1002/jps.22243. PMC 3303188. PMID 20575003.

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