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Antisense RNA
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== Discovery and history in drug development == {{main|Antisense therapy}} Some of the earliest asRNAs were discovered while investigating functional proteins. An example was [[MicF RNA|micF asRNA]]. While characterizing the outer membrane [[Porin (protein)|porin]] {{not a typo|ompC}} in [[Escherichia coli|''E.coli'']], some of the {{not a typo|ompC}} promoter clones observed were capable of repressing the expression of other membrane porin such as {{not a typo|ompF}}. The region responsible for this repression function was found to be a 300 base-pair locus upstream of the {{not a typo|ompC}} promoter. This 300 base-pair region is 70% homologous in sequence with the [[5' end]] of the {{not a typo|ompF}} mRNA and thus the transcript of this 300 base pair locus was complementary to the {{not a typo|ompF}} mRNA. Later on, this transcript, denoted micF, was found to be an asRNA of {{not a typo|ompF}} and capable of downregulating the expression of {{not a typo|ompF}} under stress by forming a duplex with the {{not a typo|ompF}} mRNA. This induces the degradation of the {{not a typo|ompF}} mRNA.<ref name="Saberi_2016" /> Unlike micF RNA being discovered by accident, the majority of asRNAs were discovered by genome wide searches for small regulatory RNAs and by [[transcriptome]] analysis. Conventionally, the first step involves computational predictions based on some known characteristics of asRNAs. During computational searches, the encoding regions are excluded. The regions that are predicted to have conserved RNA structures and act as orphan promoters and [[Rho independent termination|Rho independent terminators]] are preferenced during analysis. Because computational searches focuses on the [[intergenic region]], the asRNAs that are transcribed from the opposite strand of an encoding gene are likely to be missed using this method. To detect asRNA transcribed from the encoding region, [[oligonucleotide microarray]]s can be used. In this method, one or both strands of encoding genes can be used as probes. In addition to computational searches and microarrays, some asRNAs were discovered by sequencing cDNA clones as well as mapping promoter elements.<ref>{{cite journal | vauthors = Thomason MK, Storz G | title = Bacterial antisense RNAs: how many are there, and what are they doing? | journal = Annual Review of Genetics | volume = 44 | issue = 1 | pages = 167β188 | date = 2010 | pmid = 20707673 | pmc = 3030471 | doi = 10.1146/annurev-genet-102209-163523 }}</ref> Although many findings from the approaches mentioned above gave rise to a lot of possible asRNAs, only few were proven to be actual asRNAs via further functional tests. To minimize the number of false positive results, new approaches from recent years have been focusing on strand-specific transcription, [[chromatin]] binding noncoding RNAs and single cell studies.<ref name="Pelechano_2013" /> The idea of asRNAs as drug targets started in 1978 when [[Paul Zamecnik|Zamecnik]] and Stephenson found an antisense oligonucleotide to the viral RNA of Rous scarcoma virus that was capable of inhibiting viral replication and protein synthesis. Since then, much effort has been devoted to developing asRNAs as drug candidates. In 1998, the first asRNA drug, [[fomivirsen]], was approved by FDA. Fomivirsen, a 21 base-pair oligonucleotide, was developed to treat [[cytomegalovirus retinitis]] in patients with AIDS. It works by targeting the transcribed mRNA of the virus and consequently inhibiting replication of cytomegalovirus. Despite fomivirsen being discontinued in 2004 due to the loss of the market, it served as a successful and inspiring example of using asRNAs as drug targets or drug candidates.<ref name="Kole_2012" /> Another example of using an asRNA as a therapeutic agent is [[mipomersen]], which was approved by FDA in 2013. Mipomersen was developed to manage the level of [[low-density lipoprotein cholesterol]] (LDL) in patients with homozygous [[familial hypercholesterolemia]] (HoFH), which is a rare autosomal dominant genetic condition. Because of the high level of total cholesterol (650β1000 mg/dL) and LDL receptor (above 600 mg/dL) in HoFH, patients with HoFH has a high risk for coronary heart disease. Because the protein [[Apolipoprotein B|apo-B-100]] has been found to be required to produce [[very low-density lipoprotein]] (VLDL) and LDL, mipomersen complements with the mRNA of apo-B-100 and target it for [[RNAse H]] dependent degradation. Ultimately, mipomersen is able to reduce the level of LDL.<ref>{{cite journal | vauthors = Wong E, Goldberg T | title = Mipomersen (kynamro): a novel antisense oligonucleotide inhibitor for the management of homozygous familial hypercholesterolemia | journal = P & T | volume = 39 | issue = 2 | pages = 119β122 | date = February 2014 | pmid = 24669178 | pmc = 3956393 }}</ref>
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