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 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. 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. 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 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,, 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. As of 2012, some 40 antisense oligonucleotides and siRNAs were in clinical trials, including over 20 in advanced clinical trials (Phase II or III). 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. Fomivirsen (marketed as Vitravene), was approved by the U.S. FDA in Aug 1998 as a treatment for cytomegalovirus retinitis. In January 2013 mipomersen (marketed as Kynamro) was approved by the FDA for the treatment of homozygous familial hypercholesterolemia. 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.