In this week’s issue of Nature , two researchers at the Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center have published a review discussing the diverse contribution microRNA networks exhibit in cancer biology. Lujambio et. al. discuss both the oncogenic and tumor-suppressor roles microRNA have been attributed in the initiation and progression of multiple cancers. Discussion also focuses on microRNA as a driving/initiation factor in tumor biology and provides a thorough review of the dynamic between several microRNA genes and the TP53 tumor suppressor. The mouse model system is highlighted as a very useful tool validating and investigating the in vivo role specific microRNA contribute to tumor development and risk. The review concludes with a discussion concerning the potential roles of RNAi technology and its use as a therapeutic tool in cancer treatment.

The authors present insights into several areas of microRNA cancer research that requires further investigation in the near future, including: the impact of expression variation of several components of the microRNA biogenesis machinery, the direct role of microRNA epigenetic regulation of chromosomal DNA, and designing effective and safe microRNA drug-delivery systems. These three areas are highlighted by the authors as important steps into elucidating the total impact and use of microRNA biology in cancer development and treatment. Undoubtedly, further research in these areas will greatly enhance what is already know about microRNA regulation in cancer biology and may provide novel avenues for drug therapies.

Lujambio, A. and S.W. Lowe, The microcosmos of cancer.
Nature. 482(7385): p. 347-55.

http://www.ncbi.nlm.nih.gov/pubmed?term=the%20microcosmos%20of%20cancer

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In order to better understand microRNAs of interest it is of utmost importance to learn about the genomic conservation of these genes. The miRviewer web-server encompasses all known (and some novel) microRNAs of currently fully annotated animal genomes in a visual ‘birds-eye’ view representation. miRviewer provides a graphical outlook of the current microRNA world together with sequence alignments and secondary structures of each microRNA. As a test case the expression of several microRNAs in various animals were experimentally validated. Therefore miRviewer completes the homologous microRNA space with hundreds of unreported microRNAs.

miRviewer is available at: http://people.csail.mit.edu/akiezun/miRviewer

miRviewer: A multispecies microRNA homologous viewer.
Kiezun A, Artzi S, Modai S, Volk N, Isakov O, Shomron N.
BMC Res Notes. 2012 Feb 13;5(1):92. [Epub ahead of print]
PMID: 22330228 [PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov/pubmed/22330228

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-New study published in Science Translational Medicine demonstrates microRNA-21 contributes to fibrogenesis in the kidney
-Regulus, in partnership with Sanofi, developing novel anti-fibrotic therapies targeting microRNAs

B.N. Chau et al.
“MicroRNA-21 Promotes Fibrosis of the Kidney by Silencing Metabolic Pathways”
Sci Transl Med 15 February 2012:
Vol. 4, Issue 121, p. 121ra18
Sci. Transl. Med. DOI: 10.1126/scitranslmed.3003205

http://stm.sciencemag.org/content/4/121/121ra18

LA JOLLA, Calif., Feb. 16, 2012  /PRNewswire/ — Regulus Therapeutics Inc., a biopharmaceutical company leading the discovery and development of innovative medicines targeting microRNAs, today announced that new preclinical data investigating the role of microRNA-21 (miR-21) in the treatment of kidney fibrosis has been published in the journal Science Translational Medicine. Regulus’ lead program for fibrosis targets miR-21, which is up-regulated in fibrotic tissues of humans. Previous preclinical studies by Regulus scientists and collaborators have shown that therapeutic oligonucleotides targeting miR-21 (anti-miR-21) can decrease fibrosis in preclinical models by reducing the expression of extracellular matrix proteins.  Despite the current burden of fibrosis-related human disease, there are few therapies that can specifically treat this devastating disease.

“We are pleased with the published results demonstrating that targeting miR-21 with proprietary anti-miR oligonucleotides is effective at preventing kidney fibrosis in preclinical models,” said Neil W. Gibson, Ph.D., Regulus’ Chief Scientific Officer.  ”We plan to select an anti-miR-21 development candidate this year for advancement into the clinic in the near future and are excited about the potential to bring this innovative treatment to patients with fibrotic diseases.”

“Expression of miR-21 was found to be increased in fibrotic kidney samples from animal models and human patient samples. Genetic deletion of miR-21 in preclinical models protected kidneys from fibrosis and treatment with anti-miRs targeting miR-21 also blocked fibrosis in preclinical models,” said Dr. Duffield, M.D., Ph.D. Associate Professor of Medicine, in the Division of Nephrology, at the University of Washington. “Taken together, these data suggest that anti-miR-21 could have a therapeutic benefit in patients with chronic kidney disease.”

In the published study, Regulus and its collaborators from the University of Washington investigated the role of miR-21 in kidney fibrosis. Genetic deletion of miR-21 in mice resulted in no overt abnormality, however, these miR-21 knock out mice suffered less fibrosis in response to kidney injury, which was pheno-copied in wild-type mice treated with anti-miR-21 oligonucleotides. Analysis of gene expression profiles identified groups of genes involved in metabolic pathways that were up-regulated in the absence of miR-21, in particular genes involved in lipid metabolism and enhanced oxygen radical production.  Systemic administration of anti-miR-21 effectively reversed the deleterious effects of miR-21 in kidney injuries.  These animal studies demonstrate that miR-21 contributes to fibrogenesis and epithelial injury in the kidney in two mouse models and is a candidate target for anti-fibrotic therapies.

The journal article titled, “MicroRNA 21 Promotes Fibrosis of the Kidney by Silencing Metabolic Pathways,” is now available in Science Translational Medicine and on the publications page of the Regulus website at www.regulusrx.com.

About Fibrosis

Fibrosis is the harmful build-up of excessive fibrous tissue leading to scarring and ultimately the loss of organ function. Fibrosis can affect any tissue and organ system, and is most common in the heart, liver, lung, peritoneum, and kidney. The fibrotic scar tissue is made up of extracellular matrix proteins such as type I collagen, proteoglycans and fibronectin. Regulus has identified several microRNAs that are dysregulated in fibrosis.  Results from this new preclinical study demonstrate that miR-21 contributed to fibrogenesis and is a candidate target for anti-fibrotic therapies.

About microRNAs

The discovery of microRNA in humans during the last decade is one of the most exciting scientific breakthroughs in recent history. microRNAs are small RNA molecules, typically 20 to 25 nucleotides in length, that do not encode proteins but instead regulate gene expression. More than 700 microRNAs have been identified in the human genome, and over one-third of all human genes are believed to be regulated by microRNAs. A single microRNA can regulate entire networks of genes. As such, these molecules are considered master regulators of the human genome. microRNAs have been shown to play an integral role in numerous biological processes, including the immune response, cell-cycle control, metabolism, viral replication, stem cell differentiation and human development. Most microRNAs are conserved across multiple species, indicating the evolutionary importance of these molecules as modulators of critical biological pathways. Indeed, microRNA expression, or function, has been shown to be significantly altered in many disease states, including cancer, heart failure and viral infections. Targeting microRNAs with anti-miRs, antisense oligonucleotide inhibitors of microRNAs, or miR-mimics, double-stranded oligonucleotides to replace microRNA function opens potential for a novel class of therapeutics and offers a unique approach to treating disease by modulating entire biological pathways.

About Regulus Therapeutics, Inc.

Regulus Therapeutics is a biopharmaceutical company leading the discovery and development of innovative medicines targeting microRNAs. Regulus is using a mature therapeutic platform based on technology that has been developed over 20 years and tested in more than 5,000 humans. The company works with a broad network of academic collaborators and leverages the oligonucleotide drug discovery and development expertise of its founding companies, Alnylam Pharmaceuticals (NASDAQ:ALNY) and Isis Pharmaceuticals (NASDAQ:ISIS). Regulus is advancing microRNA therapeutics toward clinical development in several areas, including fibrosis, hepatitis C, immuno-inflammatory diseases, metabolic diseases and oncology. Regulus’ intellectual property estate contains both the fundamental and core patents in the field and includes over 600 patents and more than 300 pending patent applications pertaining primarily to chemical modifications of oligonucleotides targeting microRNAs for therapeutic applications. In April 2008, Regulus formed a major alliance with GlaxoSmithKline to discover and develop microRNA therapeutics for immuno-inflammatory diseases. In February 2010, Regulus and GlaxoSmithKline entered into a new collaboration to develop and commercialize microRNA therapeutics targeting microRNA-122 for the treatment of hepatitis C infection. In June 2010, Regulus and sanofi-aventis entered into the largest-to-date strategic alliance for the development of microRNA therapeutics with an initial focus on fibrosis.

For more information, please visit http://www.regulusrx.com. Regulus is also on YouTube at http://www.youtube.com/user/RegulusRx#p/f and on Twitter at www.twitter.com/regulusrx .

Forward-Looking Statements

This press release includes forward-looking statements regarding the future therapeutic and commercial potential of Regulus’ business plans, technologies and intellectual property related to microRNA therapeutics being discovered and developed by Regulus, including statements regarding the therapeutic potential of targeting microRNA -21 for treating fibrosis and kidney injury. Any statement describing Regulus’ goals, expectations, financial or other projections, intentions or beliefs is a forward-looking statement and should be considered an at-risk statement. Such statements are subject to certain risks and uncertainties, particularly those inherent in the process of discovering, developing and commercializing drugs that are safe and effective for use as human therapeutics, and in the endeavor of building a business around such products. Such forward-looking statements also involve assumptions that, if they never materialize or prove correct, could cause the results to differ materially from those expressed or implied by such forward-looking statements. Although these forward-looking statements reflect the good faith judgment of Regulus’ management, these statements are based only on facts and factors currently known by Regulus. As a result, you are cautioned not to rely on these forward-looking statements. These and other risks concerning Regulus’, Alnylam’s, and Isis’ programs are described in additional detail in Alnylam’s and Isis’ annual reports on Form 10-K for the year ended December 31, 2010, and its most recent quarterly report on Form 10-Q.  Copies of these and other documents are available from Alnylam or Isis.

SOURCE Regulus Therapeutics Inc.

CONTACT: Zachary Zimmerman, Ph., of Regulus Therapeutics , +1-858-202-6300, busdev@regulusrx.com; or David Schull of Russo Partners, +1-212-845-4271, david.schull@russopartnersllc.com

Web Site: http://www.regulusrx.com

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Low-Level Expression of miR-375 Correlates with Poor Outcome and Metastasis While Altering the Invasive Properties of Head and Neck Squamous Cell Carcinomas.

Researchers at Department of Pathology, Albert Einstein College of Medicine used global miRNA expression profiling of head and neck squamous cell carcinoma (HNSCC) samples and adjacent normal tissue to rank those miRNAs that were most significantly altered in a patient population of 123. Harris et al. evaluated 736 of the currently known 1898 unique mature human microRNAs. Rank Consistency Score analysis revealed miR-375 to have the most significantly lowered miRNA levels in tumors relative to matched adjacent nonmalignant tissue from the same patient.

While this result has been previously observed by other groups, this latest study reveals that low miR-375 expression levels correlate significantly with cancer survival and distant metastasis. In a study of 123 primary HNSCC patients using multivariable Cox proportional hazard ratios (HR) and 95% confidence intervals (CI), both death from disease (HR: 12.8, 95% CI: 3 to 49) and incidence of distant metastasis (HR: 8.7, 95% CI: 2 to 31) correlated with lower expression levels of miR-375 regardless of the site or stage of the tumor. In addition, oral cavity tumor cell lines (eg, UMSCC1 and UMSCC47) overexpressing miR-375 were significantly less invasive in vitro than their matched empty vector controls.

The authors conclude that miR-375 may be suitable as a potential prognostic marker of poor outcome and metastasis in HNSCC and that it may function by suppressing the tumor’s invasive properties.

Harris T, Jimenez L, Kawachi N, Fan JB, Chen J, Belbin T, Ramnauth A, Loudig O, Keller CE, Smith R, Prystowsky MB, Schlecht NF, Segall JE, Childs G.
Low-Level Expression of miR-375 Correlates with Poor Outcome and Metastasis While Altering the Invasive Properties of Head and Neck Squamous Cell Carcinomas.
Am J Pathol., in press.

http://www.sciencedirect.com/science/article/pii/S0002944011010947

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Single nucleotide polymorphisms (SNPs) can lead to the susceptibility and onset of diseases through their effects on gene expression at the posttranscriptional level. Recent findings indicate that SNPs could create, destroy, or modify the efficiency of miRNA binding to the 3′UTR of a gene, resulting in gene dysregulation. With the rapidly growing number of published disease-associated SNPs (dSNPs), there is a strong need for resources specifically recording dSNPs on the 3′UTRs and their nucleotide distance from miRNA target sites. Bruno et al. from the Center for Computational Research SUNY at the University of Buffalo presents miRdSNP, a database incorporating three important areas of dSNPs, miRNA target sites, and diseases.

miRdSNP provides a unique database of dSNPs on the 3′UTRs of human genes manually curated from PubMed. The current release includes 786 dSNP-disease associations for 630 unique dSNPs and 204 disease types. miRdSNP annotates genes with experimentally confirmed targeting by miRNAs and indexes miRNA target sites predicted by TargetScan and PicTar as well as potential miRNA target sites newly generated by dSNPs. A robust web interface and search tools are provided for studying the proximity of miRNA binding sites to dSNPs in relation to human diseases. Searches can be dynamically filtered by gene name, miRBase ID, target prediction algorithm, disease, and any nucleotide distance between dSNPs and miRNA target sites. Results can be viewed at the sequence level showing the annotated locations for miRNA target sites and dSNPs on the entire 3′UTR sequences. The integration of dSNPs with the UCSC Genome browser is also supported.

miRdSNP provides a comprehensive data source of dSNPs and robust tools for exploring their distance from miRNA target sites on the 3′UTRs of human genes. miRdSNP enables researchers to further explore the molecular mechanism of gene dysregulation for dSNPs at posttranscriptional level.

miRdSNP is freely available on the web at http://mirdsnp.ccr.buffalo.edu.

The complete article is available as a provisional PDF. The fully formatted PDF and HTML versions are in production.

Andrew E. Bruno, Li Li, James L. Kalabus, Yuzhuo Pan, Aiming Yu, Zihua Hu.
miRdSNP: a database of disease-associated SNPs and microRNA target sites on 3′UTRs of human genes.
BMC Genomics 2012, 13:44
doi:10.1186/1471-2164-13-44
Published: 25 January 2012

http://www.biomedcentral.com/1471-2164/13/44/abstract

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Patent Protects Use of UNAs in Multiple Nucleic Acid Constructs Including siRNAs, microRNA Mimics, Antagomirs and Single-Stranded Constructs

Contact Information

Marina Biotech, Inc.
Philip Ranker
Interim Chief Financial Officer
(425) 908-3615
pranker@marinabio.com

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• The experiment tested a specific microRNA gene that was identified in
  corn and soybean, and confirmed the potential to develop plants capable
  of withstanding intermittent irrigation with seawater and growth in high
  salinity soils
• During the experiment, plants were intermittently irrigated with salt
  water with three times the salinity level of seawater
• Rosetta Green has previously demonstrated that microRNA genes are
  capable of improving plants under extreme drought conditions

REHOVOT, Israel, Jan. 10, 2012 (GLOBE NEWSWIRE) — The Israeli agro-biotechnology company Rosetta Green, which develops improved crops for the agriculture industry, reports successful experimental results in which plants were grown using seawater irrigation. The experiment was conducted on tobacco plants which are used as model plants for corn and soybean. The plants that were improved by a microRNA gene were found to have an enormous potential to grow under irrigation with seawater.

In the said experiment, which took place in recent months in Rosetta Green’s controlled and unique growth rooms in Rehovot, the effect of the microRNA gene was tested on tobacco plants under conditions of seawater irrigation. For that purpose, plants that were improved by this microRNA gene and control plants that did not undergo such improvement were irrigated with salt water with triple the salinity level of seawater. Subsequently, both plant groups were put back on a normal irrigation regime. However, only improved plants were able to recover and continued to grow while control plants completely wilted.

Corn and soybean are among the best sold crops in the food and alternative fuel industries. In addition to the vast commercial value inherent in microRNA genes, this achievement is a significant milestone for Rosetta Green. These results validate its computational and biological platforms which are used to identify and implement microRNA genes, and of its capability to predict and discover genes affecting key traits in the agro-biotechnology world.

Rosetta Green continues its efforts to constantly develop new plant varieties resistant to harsh climate conditions, and believes that this year it will continue to test numerous genes in plants in order to develop varieties resistant to drought and with an increased yield. The company anticipates collaborations with industrial partners and gene validations in additional field crops.

According to the company’s CEO Amir Avniel, “The frequent droughts afflicting the world in recent years and the motivation to expand to arid lands containing brackish water, require the development of plant varieties resistant to drought and irrigation with salt water. Rosetta Green is making great effort towards this end using the innovative technologies we have developed. This experiment is another step in the company’s progress towards production of improved plants that will provide farmers with excellent yield even in drought conditions, and allow the growth of crops in wide areas that are currently unsuitable, due to soil salinity and weather conditions.”

The company’s CTO, Rudy Maor said that, “The extreme conditions under which the experiment was conducted reinforce the importance of these genes and their advantage over other techniques used to improve plants. Agricultural areas constitute only about 10% of global land area¹ and the development of advanced technologies that may render plants capable of growth in additional areas, such as deserts, is critical for food supply to the ever growing world population.”

About Rosetta Green

Rosetta Green (tase:RSTG) is an Israeli agro-biotechnology company specializing in developing improved plants to the agriculture industry using the unique technology of microRNA genes. The company has developed technological platforms for the identification and utilization of microRNAs. These microRNA genes possess the potential to improve key traits in important plants such as corn, wheat, rice, soybean, and more. Rosetta Green’s product development pipeline already consists of plants with improved traits including drought tolerance, increased yield production, disease resistance and more. For additional information please visit Rosetta Green’s website at: www.rosettagreen.com .

¹Source: Central Intelligence Agency — The World Factbook https://www.cia.gov/library/publications/the-world-factbook/fields/2097.html

This news release was distributed by GlobeNewswire, www.globenewswire.com

SOURCE: Rosetta Green

        CONTACT: Investor Relations
        Limor Zur-Stoller - CFO
        Limor.stoller@rosettagreen.com
        Research and Business Development
        Rudy Maor - CTO
        Rudy.maor@rosettagreen.com

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LONDON, January 9, 2012/PRNewswire-FirstCall/ –

- Third collaboration to investigate the potential application of Silence’s proprietary RNAi delivery technologies in the development of novel microRNA-based therapeutics

Silence Therapeutics plc (AIM: SLN) (“Silence”), a leading RNA interference (RNAi) therapeutics company, announces that it has signed an agreement with miRagen Therapeutics, Inc. (“miRagen”), to assess the delivery potential of Silence’s proprietary DBTC delivery system with miRagen’s novel microRNA- (miRNA-) based therapeutics. MiRagen is a pre-clinical stage biopharmaceutical company founded to develop innovative miRNA-based therapeutics for the treatment of cardiovascular and muscle disease.

Under the terms of the agreement, miRagen will provide Silence with specific miRNA sequences, which Silence will formulate with its proprietary DBTC delivery system in order to develop multiple candidate drugs. MiRagen will undertake in vitro and in vivo studies of the candidate drugs developed under the agreement and select lead candidates for further evaluation. Financial terms of the collaboration are not disclosed.

DBTC is a proprietary RNAi delivery system developed by Silence. It is a novel lipid-based formulation that functionally delivers short interfering RNA (siRNA) to liver endothelial cells, hepatocytes and other liver cell types with high efficiency.

Thomas Christely, Chief Executive Officer of Silence Therapeutics, said: “We are delighted to be collaborating with miRagen. This is the third collaboration that we have recently signed to explore the use of Silence’s delivery technologies for microRNAs, and the second that utilizes our novel DBTC delivery system that specifically delivers RNAi therapeutics to the liver. Whilst we remain internally focused on the delivery of our siRNA therapies, we continue to broaden the potential value of our proprietary delivery systems by collaborating with partners. Functional delivery to target cells is widely recognized as one of the greatest challenges facing most nucleic acid therapies. Our three proprietary RNAi delivery systems, AtuPLEX(TM), DACC and DBTC deliver effective doses of RNAi to key intracellular targets in vascular endothelium, lung and liver respectively, and provide our partners with a growing range of solutions to overcome their delivery challenges.”

William S. Marshall, President and Chief Executive Officer of miRagen Therapeutics, said: “We are very pleased to have entered into this agreement with Silence Therapeutics, which gives us the opportunity to evaluate the efficacy of a promising delivery system in the context of microRNA manipulation. This is another example of miRagen’s commitment to explore the potential of cutting-edge technologies with the ultimate goal of better serving patients in need.”

Notes for editors

About Silence Therapeutics plc (http://www.silence-therapeutics.com)

Silence Therapeutics plc (AIM: SLN) is a leading biotechnology company dedicated to the discovery, development and delivery of targeted, systemic RNA interference (RNAi) therapeutics for the treatment of serious diseases. Silence offers one of the most comprehensive short interfering RNA (siRNA) therapeutic platforms available today based on a strong intellectual property portfolio and large clinical safety database. Silence’s clinical siRNA product pipeline is one of the broadest in the industry. The Company possesses multiple proprietary siRNA delivery technology platforms including AtuPLEX(TM), DACC and DBTC. AtuPLEX enables the broad functional delivery of siRNA molecules to targeted diseased tissues and cells, while increasing their bioavailability and intracellular uptake. The DACC delivery system allows functional delivery of siRNA molecules selectively to the lung endothelium with a long duration of target mRNA and protein knock-down. The DBTC delivery system enables functional delivery of siRNA molecules selectively to liver cells including hepatocytes. Additionally, the Company has a platform of novel siRNA molecules based around its AtuRNAi chemical modification technology, which provides a number of advantages over conventional siRNA molecules. Silence’s unique RNAi assets also include structural features for RNAi molecules and specific design rules for increased potency and reduced off-target effects of siRNA sequences.

The Company’s lead internal drug candidate is Atu027, a liposomal formulation in clinical development for systemic cancer indications and one of the most clinically advanced RNAi therapeutic candidates in the area of oncology. Atu027 incorporates two of the Company’s technologies, AtuRNAi and AtuPLEX(TM). Silence is currently conducting an open-label, single-centre, dose-escalation Phase I study with Atu027 in patients with advanced solid tumors involving single, as well as repeated, intravenous administration. Encouraging interim safety and pharmacokinetic data were presented at the American Society of Clinical Oncology Annual Meeting in June 2011. The study is expected to be completed in the first half of 2012.

The Company’s RNAi therapeutic platform has received key validation through multiple partnerships with pharmaceutical companies including AstraZeneca, Dainippon Sumitomo, Pfizer/Quark, and Novartis/Quark. Silence is actively pursuing the establishment of additional partnerships. Silence Therapeutics has operations in both Berlin and London.

About miRagen Therapeutics (http://www.miragentherapeutics.com)

MiRagen Therapeutics, Inc., a pre-clinical stage biopharmaceutical company, was founded in 2007 to develop innovative microRNA-based therapeutics for cardiovascular and muscle disease. MicroRNAs are short, single-stranded RNA molecules encoded in the genome that regulate gene expression and play a vital role in influencing cardiovascular and muscle disease. Cardiovascular disease is the leading cause of death globally and represents an enormous burden on global healthcare systems. MiRagen combines world recognized leadership in cardiovascular medicine with unprecedented in-house expertise in microRNA biology and chemistry. In October 2011, miRagen and Les Laboratoires Servier, a leading European pharmaceutical company, entered into a strategic alliance for the research and development of microRNA-based therapeutics in cardiovascular disease. For more information, please visit http://www.miragentherapeutics.com [http://www.miragentherapeutics.com/1/Home ].

About MicroRNAs (miRNAs)

MicroRNAs have emerged as an important class of small RNAs encoded in the genome. They act to control the expression of sets of genes and entire pathways and are thus thought of as master regulators of gene expression. Recent studies have demonstrated that microRNAs are associated with many disease processes. Because they are single molecular entities that dictate the expression of fundamental regulatory pathways, microRNAs represent potential drug targets for controlling many biologic and disease processes.

Forward-Looking Statements

This press release includes forward-looking statements that are subject to risks, uncertainties and other factors. These risks and uncertainties could cause actual results to differ materially from those referred to in the forward-looking statements. All forward-looking statements are based on information currently available to Silence Therapeutics and Silence Therapeutics assumes no obligation to update any such forward-looking statements.

For further information, please contact:

Silence Therapeutics
Thomas Christely / Max Herrmann
+49-30-9489-2800/+44-20-7491-6520
t.christely@silence-therapeutics.com
m.herrmann@silence-therapeutics.com

miRagen Therapeutics
Tammy Egan
+1-720-407-4588
tegan@miragenrx.com

Singer Capital Markets
Shaun Dobson / Claes Spang
+44-20-32057500
shaun.dobson@singercm.com
claes.spang@singercm.com

M:Communications
Mary-Jane Elliott / Emma Thompson / Claire Dickinson
+44-20-7920-2345
silencetherapeutics@mcomgroup.com [healthcare@mcomgroup.com ]

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This is an amazing video animation from Nature Reviews Genetics!

This animation introduces the principles of RNAi involving small interfering RNAs (siRNAs) and microRNAs (miRNAs). It takes you on an audio-visual journey through the steps of gene expression and shows you an up-to-date view of how RNAi can silence specific mRNAs in the cytoplasm.

There is an accompanying slideshow which provides further information about RNAi and small RNAs.

High-resolution version can be found here:
http://www.nature.com/nrg/multimedia/rnai/animation/index.html

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Stabilization of hepatitis C virus RNA by an Ago2–miR-122 complex

MicroRNAs regulate eukaryotic gene expression by binding to regions of imperfect complementarity in mRNAs, typically in the 3′ UTR, recruiting an Argonaute (Ago) protein complex that usually results in translational repression or destabilization of the target RNA. The translation and decay of mRNAs are closely linked, competing processes, and whether the miRNA-induced silencing complex (RISC) acts primarily to reduce translation or stability of the mRNA remains controversial.

miR-122 is an abundant, liver-specific miRNA that is an unusual host factor for hepatitis C virus (HCV), an important cause of liver disease in humans. Prior studies show that it binds the 5′ UTR of the messenger-sense HCV RNA genome, stimulating translation and promoting genome replication by an unknown mechanism. In this study the authors show that miR-122 binds HCV RNA in association with Ago2 and that this slows decay of the viral genome in infected cells. The stabilizing action of miR-122 does not require the viral RNA to be translationally active nor engaged in replication, and can be functionally substituted by a nonmethylated 5′ cap.

The data demonstrate that a RISC-like complex mediates the stability of HCV RNA and suggest that Ago2 and miR-122 act coordinately to protect the viral genome from 5′ exonuclease activity of the host mRNA decay machinery. miR-122 thus acts in an unconventional fashion to stabilize HCV RNA and slow its decay, expanding the repertoire of mechanisms by which miRNAs modulate gene expression.

The University of North Carolina School of Medicine released the following related statement:

CHAPEL HILL, N.C. – Viral diseases are still one of the biggest challenges to medical science.  Thanks to thousands of years of co-evolution with humans, their ability to harness the biology of their human hosts to survive and thrive makes them very difficult to target with medical treatment.

Scientists at the University of North Carolina at Chapel Hill, working with colleagues from the University of Colorado, have shown for the first time how a small RNA molecule that regulates gene expression in human liver cells has been hijacked by the hepatitis C virus to ensure its own survival – helping medical scientists understand why a new antiviral drug appears to be effective against the virus.

MicroRNAs are involved in regulating the expression of genes in cells, usually by blocking the production of key proteins or by destabilizing the messenger RNAs that encode the cell’s proteins as it grows and divides.  Normally they act by downregulating gene expression.  The research team found that the binding of a prominent microRNA in liver cells, called miR-122, to the viral RNA results in its stabilization, promoting efficient replication of the virus genome in the liver and supporting the virus’ lifecycle.

“The hepatitis C virus has done two very interesting things with miR-122,” says Stanley M. Lemon, MD, professor of medicine and microbiology and immunology and a member of UNC Lineberger Comprehensive Cancer Center and the Center for Translational Immunology.

“First, it has evolved a unique relationship with a key regulator, since miR-122 represents about half of all microRNAs present in the liver.  Second, the virus has usurped a process that usually downregulates gene expression to upregulate the stability of its RNA and expression of viral proteins needed for its lifecycle. It’s a classic example of how viruses subvert normally beneficial functions of the cell to their own nefarious purposes.”

Work by Dr. Lemon and his colleagues in 2005 helped to demonstrate that miR-122 was required for hepatitis C to replicate itself, but the mechanism was not understood.  Now the UNC research team has shown how it works, which helps to explain how a new experimental antiviral drug target the virus.  The drug, called an “antagomer”, binds to miR-122 and sequesters it in the liver and thus destabilizes the viral genome, accelerating its degradation in the liver.  Results of the most recent study are published online this week in the journal Proceedings of the National Academy of Sciences.

Hepatitis C is a continuing public health problem, which is difficult to measure because symptoms occur months to years after infection.  The Centers for Disease Control and Prevention estimates as many as 4 million people in the United States may be persistently infected with hepatitis C virus, and most do not know they are infected.  More than a third of those who are long-term carriers may develop chronic liver disease or liver cancer, a deadly form of cancer that is becoming increasingly common due to the spread of this virus.

Other members of the research team include Tetsuro Shimakami, Daisuke Yamane, Rohit Jangra and Carolyn Spaniel from UNC Lineberger Comprehensive Cancer Center and the division of infectious diseases at UNC-Chapel Hill School of Medicine and Brian J. Kempf and David Barton from the department of microbiology at the University of Colorado School of Medicine.

The research was funded in part by UNC Lineberger’s University Cancer Research Fund and the National Institutes of Health as well as a Gastrointestinal Special Program of Research Excellence (SPORE) Grant at the University of Kentucky Markey Cancer Center.

Sources:
University of North Carolina School of Medicine

Tetsuro Shimakami, Daisuke Yamane, Rohit K. Jangra, Brian J. Kempf, Carolyn Spaniel, David J. Barton, and Stanley M. Lemon
Stabilization of hepatitis C virus RNA by an Ago2–miR-122 complex
PNAS 2012 : 1112263109v1-201112263.
http://www.pnas.org/content/early/2012/01/02/1112263109.abstract

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