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Blockmirs are examples of steric block oligonucleotides, meaning that they prevent other molecules from binding to a desired site on an mRNA molecule. They bind to specific sites on mRNA molecules, blocking the binding of microRNAs, and do not recruit any cellular enzyme machinery which normally induces the degradation of the target mRNA.[1]

Blockmir Technology

Mechanism of Blockmirs

Blockmirs are designed to have a sequence that is perfectly complementary to an mRNA sequence that serves as a binding site for microRNA. Upon binding, Blockmirs sterically block microRNA from binding to the same site, which prevents the degradation of the target mRNA via RNA-induced silencing complex (RISC). If a Blockmir binds to a non-intended RNA, it will only cause an effect if it prevents binding of a microRNA or another cellular factor. This occurrence is highly unlikely, meaning off-target effects will rarely be an issue. This mechanism is contrary to microRNA inhibitors such as antimirs and antagomirs because these oligonucleotides inhibit miRNAs entirely but, because of the promiscuity of microRNAs, this could affect the regulation of many different mRNA molecules. It is also contrary to mRNA inhibitors such as RNase H-recruiting antisense oligonucleotides and small interfering RNA (siRNA) which will mediate degradation if they bind to a non-intended target[2]. Hence, Blockmirs enable modulation of microRNA-based gene regulation with exquisite specificity. Importantly, Blockmirs are typically agonists of their target mRNA, i.e. they increase the synthesis of the protein encoded by the target mRNA. Blockmirs bind on the 3’ end of the untranslated region (UTR) of the mRNA strand, which adequately blocks microRNA from binding, as most microRNAs do not bind to the translated region. Blockmirs are likely displaced from mRNA before the molecule reaches the ribosomes, but additional research is needed to confirm this.

Comparison of Blockmirs to microRNAs

Overall, Blockmirs upregulate target mRNA expression, while microRNA represses mRNA through degradation. MicroRNAs are relatively flexible regarding their ability to bind to mRNA, and often can bind to a variety of mRNA sequences with incomplete complementarity. Functional microRNAs are bound to RISC, which is functional towards degrading mRNA. In contrast, Blockmirs can bind specifically to fully complementary mRNA sequences thus allowing Blockmirs to target specific microRNA binding sites. Blockmirs do not bind RISC and do not recruit other degradation machinery, so the bound mRNA is not degraded. Blockmirs can therefore block a single microRNA binding site without affecting other binding sites that are regulated by the same microRNA.

Current Application of Blockmirs

1) microRNA-122, cholesterol and Hepatitis C Virus (HCV)[3]

The primary method for using microRNA technology to target HCV is by knocking out the liver-specific microRNA. miRNA-122 binds to the 5' UTRregion of HCV's mRNA strand and, contrary to miRNA's normal function of repressing mRNA, actually upregulates the expression of the Hepatitis C Virus. Thus, the therapeutic goal in such a case would be to keep miRNA-122 from binding to HCV mRNA in order to prevent this mRNA from being expressed. However, miRNA-122 also regulates cholesterol (HDL) and the activity of tumor-suppressor genes (oncogenes).This means that not only will knocking out the microRNA-122 reduce the HCV infection, but it will also reduce the activity of oncogenes, potentially leading to liver cancer. In order to target HCV mRNA specifically (instead of miRNA-122 as a whole), Blockmir technology has been developed to solely target HCV mRNA, thus avoiding any sort of tampering with oncogene expression. This may be achieved by designing a Blockmir that matches seed 1.

2) microRNA-33a/b

Research has shown MicroRNA-33a/b inhibition in mice leads to increased blood high-density lipoprotein (HDL) levels. Abca1 is essential for production of HDL precursors in liver cells. In macrophages, Abca1 excretes cholesterol from oxidized cholesterol-carrying lipoproteins and thus counteracts atherosclerotic plaques. From this, it is hypothesized that microRNA-33 affects HDL via regulation of Abca1. Therefore, in order to target the regulation of Abca1, a Blockmir can be developed that specifically binds to Abca1 mRNA molecules, thus blocking its miRNA site and upregulating its expression. Such an application of Blockmir technology could lead to overall reduced HDL levels.

3) microRNA-103/107[4]

MicroRNA-103/107 inhibition in mice leads to increased insulin sensitivity and signalling.[5] It has been shown that Caveolin-1-deficient mice show insulin resistance. MicroRNA-103/107 inhibition in Caveolin-1-deficient mice has no effect on insulin sensitivity and signalling. Thus, micro103/107 may affect insulin sensitivity by targeting Caveolin-1.

Founding of Mirrx Therapeutics

Mirrx Therapeutics was founded in late 2009 by Thorleif Møller, the inventor of Blockmir technology. He earned a PhD degree in Molecular Biology in spring 2002 with the thesis: “Gene Regulation by Small RNAs.” He has worked with both RNA biology and RNA-based gene regulation on a continual basis. Møller gained experience with IP protection of new technologies during his 5-year position as an IP consultant from March 2005 to November 2009[6]. Before the foundation of Mirrx, Møller established his first venture-backed company, Hyscite Discovery A/S, in October 2002. Until his founding of Hyscite Discovery, however, he held a position as a research scientist working with siRNA at the Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense[7]. Between the collapse of Hyscite Discovery in 2006 and the foundation of Mirrx in 2009, Møller held the CEO position at Stealth Biotech Aps[6].

Mirrx began when Møller formulated the idea of blocking a target for a more specific response. He proposed to carry out his formulation by targeting microRNA binding sites using Blockmirs.

Intellectual Property

Mirrx Therapeutics[8] holds a patent pending application for the following technology[9]:

1) Antisense compounds directed at microRNA binding sites in mRNA (Blockmirs)

2) methods of blocking specific microRNA:mRNA interactions[10]

3) methods of microRNA target identification using Blockmirs[11]

4) methods of microRNA target validations using Blockmirs[12]

Legal Implications

Since 2009, Mirrx has been at a research stand-still because of its current lawsuit with Santaris Pharma a/s, a pharmaceutical company that has accused Mirrx Therapeutics of using “illegally obtained trade secrets” in order to file a European patent application for this miRNA inhibiting technology with the aim of pursuing it for therapeutic applications. [13] The lawsuit is still underway, with the European Patent Office reviewing claims by both Santaris Pharma and Thorleif Møller of Mirrx. This involves reviewing Møller’s extensive patent application, which seeks to point out the differences between the technology Santaris Pharma claims as its own and that of Mirrx’s Blockmir technology.[14]

Future Implications of the Technology

In addition to the apparent applications as therapeutics, Blockmirs will prove highly important research tools, pivotal to the understanding of microRNA based regulatory pathways and the contributions of single microRNA:mRNA interactions.[4] In due course, science will use Blockmirs to study single microRNA:mRNA interactions, inadvertently leading to the discovery of Blockmirs with therapeutic potential.[1] The technology of Blockmirs has been incorporated into a Qiagen assay and research into similar concepts about miRNA:mRNA interference has already been published in scientific journals including Nature and Science.[15][16][17]

References

  1. 1.0 1.1 http://www.mirrx.dk/background.html
  2. http://www.eb.tuebingen.mpg.de/research/research-groups/remco-sprangers/mrna-degradation.html
  3. http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001329/
  4. 4.0 4.1 Trajkovski M, Hausser J, Soutschek J, Bhat B, Akin A, Zavolan M, Heim MH, Stoffel M (June 2011). "MicroRNAs 103 and 107 regulate insulin sensitivity". Nature 474 (7353): 649–53. DOI:10.1038/nature10112. PMID 21654750. 
  5. Kahn CR (December 1978). "Insulin resistance, insulin insensitivity, and insulin unresponsiveness: a necessary distinction". Metab. Clin. Exp. 27 (12 Suppl 2): 1893–902. PMID 723640. 
  6. 6.0 6.1 http://www.linkedin.com/pub/thorleif-m%C3%B8ller/23/466/310
  7. http://www.zoominfo.com/#!search/profile/person?personId=494162302&targetid=profile
  8. http://www.mirrx.dk/
  9. http://www.mirrx.dk/intellectual-property.html
  10. Stefani G, Slack FJ (March 2012). "A 'pivotal' new rule for microRNA-mRNA interactions". Nat. Struct. Mol. Biol. 19 (3): 265–6. DOI:10.1038/nsmb.2256. PMID 22388780. 
  11. Jin H, Tuo W, Lian H, Liu Q, Zhu XQ, Gao H (December 2010). "Strategies to identify microRNA targets: new advances". N Biotechnol 27 (6): 734–8. DOI:10.1016/j.nbt.2010.09.006. PMID 20888440. 
  12. Gäken J, Mohamedali AM, Jiang J, Malik F, Stangl D, Smith AE, Chronis C, Kulasekararaj AG, Thomas NS, Farzaneh F, Tavassoli M, Mufti GJ (May 2012). "A functional assay for microRNA target identification and validation". Nucleic Acids Res. 40 (10): e75. DOI:10.1093/nar/gks145. PMC 3378903. PMID 22323518. //www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=3378903. 
  13. http://www.genomeweb.com/rnai/santaris-sues-mirrx-founder-over-blockmir-technology?page=1
  14. http://wo.espacenet.com/publicationDetails/description?CC=WO&NR=2012069059A1&KC=A1&FT=D&ND=3&date=20120531&DB=wo.espacenet.com&locale=en_EP
  15. http://www.qiagen.com/products/miscripttargetprotectors.aspx#Tabs=t0
  16. Klein ME, Lioy DT, Ma L, Impey S, Mandel G, Goodman RH (December 2007). "Homeostatic regulation of MeCP2 expression by a CREB-induced microRNA". Nat. Neurosci. 10 (12): 1513–4. DOI:10.1038/nn2010. PMID 17994015. 
  17. Choi WY, Giraldez AJ, Schier AF (October 2007). "Target protectors reveal dampening and balancing of Nodal agonist and antagonist by miR-430". Science 318 (5848): 271–4. DOI:10.1126/science.1147535. PMID 17761850. 
This article uses material from the Wikipedia article Blockmir, that was deleted or is being discussed for deletion, which is released under the Creative Commons Attribution-ShareAlike 3.0 Unported License.
Author(s): Boghog Search for "Blockmir" on Google
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