saRNA

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Small activating RNAs (saRNAs) are small double-stranded RNAs (dsRNAs) that target gene promoters to induce transcriptional gene activation in a process known as RNAa.

Small dsRNAs, such as small interfering RNAs (siRNAs) and microRNAs (miRNAs),are known to be the trigger of an evolutionary conserved mechanism known as RNA interference (RNAi). RNAi invariably leads to gene silencing via remodeling chromatin to thereby suppress transcription, degrading complementary mRNA, or blocking protein translation. Later it was found that dsRNAs can also act as saRNA. By targeting selected sequences in gene promoters, saRNAs induce target gene expression at the transcriptional/epigenetic level.[1][2]

saRNAs are typically 21 nucleotides in length with 2 nucleotides overhang at the 3' end of each strand, the same structure of a typical siRNA. To identify a saRNA that can activate a gene of interest, several saRNAs need to be designed within a 1- to 2-kb promoter region by following a set of rules [3][4] and tested in cultured cells. In some reports, saRNAs are designed in such a way to target non-coding transcripts that overlap the promoter sequence of a protein coding gene.[5][6] Both chemically synthesized saRNAs and saRNAs expressed as shRNA have been used in in vitro and in vivo experiments.

Therapeutic use of saRNAs has been tested in animal models to treat cancer,[7][8][9][10] liver disease,[8] ischemia,[11] and erectile dysfunction.[12]

In 2016, a phase I clinical trial (ClinicalTrials.gov Identifier: NCT02716012[13]) was launched for the saRNA drug MTL-CEBPA, the fist of its kind, to treat liver cancer.[14]

References[edit]

  1. ^ Li, Long-Cheng; Okino, Steven T.; Zhao, Hong; Pookot, Deepa; Place, Robert F.; Urakami, Shinji; Enokida, Hideki; Dahiya, Rajvir (2006-11-14). "Small dsRNAs induce transcriptional activation in human cells". Proceedings of the National Academy of Sciences of the United States of America. 103 (46): 17337–17342. doi:10.1073/pnas.0607015103. ISSN 0027-8424. PMC 1859931Freely accessible. PMID 17085592. 
  2. ^ Janowski, Bethany A.; Younger, Scott T.; Hardy, Daniel B.; Ram, Rosalyn; Huffman, Kenneth E.; Corey, David R. (2007-03-01). "Activating gene expression in mammalian cells with promoter-targeted duplex RNAs". Nature Chemical Biology. 3 (3): 166–173. doi:10.1038/nchembio860. ISSN 1552-4450. PMID 17259978. 
  3. ^ Huang, Vera; Qin, Yi; Wang, Ji; Wang, Xiaoling; Place, Robert F.; Lin, Guiting; Lue, Tom F.; Li, Long-Cheng (2010-01-01). "RNAa is conserved in mammalian cells". PloS One. 5 (1): e8848. doi:10.1371/journal.pone.0008848. ISSN 1932-6203. PMC 2809750Freely accessible. PMID 20107511. 
  4. ^ Wang, Ji; Place, Robert F.; Portnoy, Victoria; Huang, Vera; Kang, Moo Rim; Kosaka, Mika; Ho, Maurice Kwok Chung; Li, Long-Cheng (2015-03-11). "Inducing gene expression by targeting promoter sequences using small activating RNAs". Journal of Biological Methods. 2 (1): 14. doi:10.14440/jbm.2015.39. ISSN 2326-9901. PMC 4379447Freely accessible. PMID 25839046. 
  5. ^ Voutila, Jon; Sætrom, Pål; Mintz, Paul; Sun, Guihua; Alluin, Jessica; Rossi, John J; Habib, Nagy A; Kasahara, Noriyuki (2012-08-01). "Gene Expression Profile Changes After Short-activating RNA-mediated Induction of Endogenous Pluripotency Factors in Human Mesenchymal Stem Cells". Molecular Therapy: Nucleic Acids. 1 (8): e35. doi:10.1038/mtna.2012.20. ISSN 2162-2531. PMC 3437803Freely accessible. PMID 23344177. 
  6. ^ Matsui, Masayuki; Chu, Yongjun; Zhang, Huiying; Gagnon, Keith T.; Shaikh, Sarfraz; Kuchimanchi, Satya; Manoharan, Muthiah; Corey, David R.; Janowski, Bethany A. (2013-12-01). "Promoter RNA links transcriptional regulation of inflammatory pathway genes". Nucleic Acids Research. 41 (22): 10086–10109. doi:10.1093/nar/gkt777. ISSN 1362-4962. PMC 3905862Freely accessible. PMID 23999091. 
  7. ^ Kang, Moo Rim; Yang, Glen; Place, Robert F.; Charisse, Klaus; Epstein-Barash, Hila; Manoharan, Muthiah; Li, Long-Cheng (2012-10-01). "Intravesical delivery of small activating RNA formulated into lipid nanoparticles inhibits orthotopic bladder tumor growth". Cancer Research. 72 (19): 5069–5079. doi:10.1158/0008-5472.CAN-12-1871. ISSN 1538-7445. PMID 22869584. 
  8. ^ a b Reebye, Vikash; Sætrom, Pål; Mintz, Paul J.; Huang, Kai-Wen; Swiderski, Piotr; Peng, Ling; Liu, Cheng; Liu, Xiaoxuan; Lindkaer-Jensen, Steen (2014-01-01). "Novel RNA oligonucleotide improves liver function and inhibits liver carcinogenesis in vivo". Hepatology (Baltimore, Md.). 59 (1): 216–227. doi:10.1002/hep.26669. ISSN 1527-3350. PMC 4655108Freely accessible. PMID 23929703. 
  9. ^ Yoon, Sorah; Huang, Kai-Wen; Reebye, Vikash; Mintz, Paul; Tien, Yu-Wen; Lai, Hong-Shiee; Sætrom, Pål; Reccia, Isabella; Swiderski, Piotr (2016-03-17). "Targeted Delivery of C/EBPα -saRNA by Pancreatic Ductal Adenocarcinoma-specific RNA Aptamers Inhibits Tumor Growth In Vivo". Molecular Therapy. 24: 1106–16. doi:10.1038/mt.2016.60. ISSN 1525-0024. PMC 4923325Freely accessible. PMID 26983359. 
  10. ^ Huan, Hongbo; Wen, Xudong; Chen, Xuejiao; Wu, Lili; Liu, Weihui; Habib, Nagy A.; Bie, Ping; Xia, Feng (2016-01-01). "C/EBPα Short-Activating RNA Suppresses Metastasis of Hepatocellular Carcinoma through Inhibiting EGFR/β-Catenin Signaling Mediated EMT". PloS One. 11 (4): e0153117. doi:10.1371/journal.pone.0153117. ISSN 1932-6203. PMC 4822802Freely accessible. PMID 27050434. 
  11. ^ Turunen, Mikko P.; Lehtola, Tiia; Heinonen, Suvi E.; Assefa, Genet S.; Korpisalo, Petra; Girnary, Roseanne; Glass, Christopher K.; Väisänen, Sami; Ylä-Herttuala, Seppo (2009-09-11). "Efficient regulation of VEGF expression by promoter-targeted lentiviral shRNAs based on epigenetic mechanism: a novel example of epigenetherapy". Circulation Research. 105 (6): 604–609. doi:10.1161/CIRCRESAHA.109.200774. ISSN 1524-4571. PMID 19696410. 
  12. ^ Wang, Tao; Li, Mingchao; Yuan, Huixin; Zhan, Yin; Xu, Hua; Wang, Shaogang; Yang, Weiming; Liu, Jihong; Ye, Zhangqun (2013-08-01). "saRNA guided iNOS up-regulation improves erectile function of diabetic rats". The Journal of Urology. 190 (2): 790–798. doi:10.1016/j.juro.2013.03.043. ISSN 1527-3792. PMID 23523927. 
  13. ^ "First-in-Human Safety and Tolerability Study of MTL-CEBPA in Patients With Advanced Liver Cancer - Full Text View - ClinicalTrials.gov". clinicaltrials.gov. Retrieved 2016-06-12. 
  14. ^ "MiNA Therapeutics Announces Initiation of Phase I Clinical Study of MTL-CEBPA in Patients with Liver Cancer | Business Wire". www.businesswire.com. Retrieved 2016-06-12. 

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