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 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 (AON) 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 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), 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.

Example antisense therapies

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

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.[7]

Cytomegalovirus retinitis

Fomivirsen (marketed as Vitravene), was approved by the U.S. 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 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.[10] 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[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]

HIV/AIDS

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

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.[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 from FDA for use to treat spinal muscular atrophy.[15][16]

Duchenne muscular dystrophy

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

Hypertriglyceridemia

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

Delivery

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.[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 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.[17]

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; 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. ↑ Goodchild, J (2011). "Therapeutic oligonucleotides". Methods in Molecular Biology. 764: 1–15. doi:10.1007/978-1-61779-188-8_1. PMID 21748630.
  5. ↑ Bennett, C.F.; Swayze, E.E. (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. ↑ Watts, J.K.; Corey, D.R. (2012). "Silencing Disease Genes in the Laboratory and in the Clinic". J. Pathol. 226 (2): 365–379. doi:10.1002/path.2993. PMC 3916955.
  7. ↑ 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 Archive.is
  8. ↑ Pollack, Andrew (29 January 2013) F.D.A. Approves Genetic Drug to Treat Rare Disease The New York Times, Retrieved 31 January 2013
  9. ↑ 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
  10. ↑ 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.
  11. ↑ 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. ↑ 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.
  13. ↑ Lu, X; Yu, Q; Binder, GK; et al. (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". J. Virol. 78: 7079–88. doi:10.1128/JVI.78.13.7079-7088.2004. PMC 421644. PMID 15194784.
  14. ↑ University of Pennsylvania School of Medicine. "Phase II HIV Gene Therapy Trial Has Encouraging Results." ScienceDaily 19 February 2010.
  15. ↑ Wadman, Meredith (23 December 2016). "Updated: FDA approves drug that rescues babies with fatal neurodegenerative disease". Science.
  16. ↑ Grant, Charley (2016-12-27). "Surprise Drug Approval Is Holiday Gift for Biogen". Wall Street Journal. ISSN 0099-9660. Retrieved 2016-12-27.
  17. 1 2 Bennett 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. ↑ 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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