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.
This synthesized nucleic acid is termed an "anti-sense" 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 anti-sense mRNA segment " 3'-UUCCAG-5' ").
Antisense oligonucleotides have been researched as potential drugs 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 and diseases such as asthma, arthritis and pouchitis with an inflammatory component. As of 2014 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
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.
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. 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  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.
Starting in 2004, researchers in the US have been conducting research on using antisense technology to combat HIV.
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.
Spinal muscular atrophy
In 2004, development of an antisense therapy for spinal muscular atrophy was started and over the following years a drug candidate SMNRx was trialled by Ionis Pharmaceuticals. In July 2016, one of two phase III trials was ended early with encouraging results, with the sponsor company Biogen deciding to file for regulatory approval of the drug in Type 1 spinal muscular atrophy patients.
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. 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.
- Oligonucleotide synthesis
- Antisense mRNA
- Peptide nucleic acid
- Locked Nucleic Acid
- RNA interference (which uses double-strand RNA)
- 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.
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- 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
- Pollack, Andrew (29 January 2013) F.D.A. Approves Genetic Drug to Treat Rare Disease The New York Times, Retrieved 31 January 2013
- 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
- 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.
- 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 . PMID 15194784.
- 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.
- 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.
- University of Pennsylvania School of Medicine. "Phase II HIV Gene Therapy Trial Has Encouraging Results." ScienceDaily 19 February 2010.
- "Biogen and Ionis Pharmaceuticals Provide Important Update on First Ever SMA Regulatory Filings". CureSMA. 1 August 2016.
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- 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