Journal ArticleDOI
Therapeutic silencing of an endogenous gene by systemic administration of modified siRNAs
Jürgen Soutschek,Akin Akinc,Birgit Bramlage,Klaus Charisse,Rainer Constien,Mary Donoghue,Sayda Elbashir,Anke Geick,Philipp Hadwiger,Jens Harborth,Matthias John,Venkitasamy Kesavan,Gary Lavine,Rajendra K. Pandey,Timothy Racie,Kallanthottathil G. Rajeev,Ingo Röhl,Ivanka Toudjarska,Gang Wang,Silvio Wuschko,David Bumcrot,Victor Koteliansky,Stefan Limmer,Muthiah Manoharan,Hans-Peter Vornlocher +24 more
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TLDR
In this article, chemically modified short interfering RNAs (siRNAs) were used to silence an endogenous gene encoding apolipoprotein B (apoB) after intravenous injection in mice.Abstract:
RNA interference (RNAi) holds considerable promise as a therapeutic approach to silence disease-causing genes, particularly those that encode so-called 'non-druggable' targets that are not amenable to conventional therapeutics such as small molecules, proteins, or monoclonal antibodies. The main obstacle to achieving in vivo gene silencing by RNAi technologies is delivery. Here we show that chemically modified short interfering RNAs (siRNAs) can silence an endogenous gene encoding apolipoprotein B (apoB) after intravenous injection in mice. Administration of chemically modified siRNAs resulted in silencing of the apoB messenger RNA in liver and jejunum, decreased plasma levels of apoB protein, and reduced total cholesterol. We also show that these siRNAs can silence human apoB in a transgenic mouse model. In our in vivo study, the mechanism of action for the siRNAs was proven to occur through RNAi-mediated mRNA degradation, and we determined that cleavage of the apoB mRNA occurred specifically at the predicted site. These findings demonstrate the therapeutic potential of siRNAs for the treatment of disease.read more
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Achieving successful delivery of oligonucleotides--From physico-chemical characterization to in vivo evaluation.
TL;DR: This is the first review to deal with the difficulties in appropriate characterization of small interfering RNA (siRNA) or microRNA (miRNA) polyplexes and conjugates which limit the clinical translation of this promising technology.
Journal ArticleDOI
Molecular Aspects of Ischemic Heart Disease: Ischemia/Reperfusion–Induced Genetic Changes and Potential Applications of Gene and RNA Interference Therapy
TL;DR: This review describes recent studies documenting genetic changes associated with myocardial ischemia and infarction as well as those investigating the safety and effectiveness of gene therapy for stimulating angiogenesis, protecting the heart against reperfusion injury, and treating heart failure.
Patent
Rna interference in ocular indications
Lyn Libertine,Anastasia Khvorova,William Salomon,Joanne Kamens,Dmitry Samarsky,Tod M. Woolf,James Cardia +6 more
TL;DR: In this article, the authors proposed a method which is used for delivering a nucleic acid to an eye of a subject in need of it, comprising administering to the eye of the subject an sd-rxRNA, in an effective amount to promote RNA interference by the sdrxRNA in the eye.
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Immunotherapy of cancer
TL;DR: Immunogenic modulators and compositions comprising oligonucleotide agents capble of inhibiting suppression of immune response by reducing expression of one or more gene involved with an immune suppression mechanism.
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Activation of Dendritic Cells by the Novel Toll-Like Receptor 3 Agonist RGC100
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References
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TL;DR: This paper used gene expression profiling to characterize the specificity of gene silencing by siRNAs in cultured human cells and found that siRNA-specific rather than target-specific signatures revealed direct silencing of nontargeted genes containing as few as eleven contiguous nucleotides of identity to the siRNA.
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MicroRNA-directed cleavage of HOXB8 mRNA
TL;DR: This article showed that miR-196, a miRNA encoded at three paralogous locations in the A, B, and C mammalian HOX clusters, has extensive, evolutionarily conserved complementarity to messages of HOXB8, HOXC8, and HOXD8.
Journal ArticleDOI
Cleavage of Scarecrow-like mRNA Targets Directed by a Class of Arabidopsis miRNA
TL;DR: This work shows that Arabidopsis thaliana miRNA 39 (also known as miR171), a 21-ribonucleotide species that accumulates predominantly in inflorescence tissues, is produced from an intergenic region in chromosome III and functionally interacts with mRNA targets encoding several members of the Scarecrow-like (SCL) family of putative transcription factors.
Journal ArticleDOI
RNA interference targeting Fas protects mice from fulminant hepatitis
Erwei Song,Sang-Kyung Lee,Jie Wang,Nedim Ince,Nengtai Ouyang,Jun Min,Jisheng Chen,Premlata Shankar,Judy Lieberman +8 more
TL;DR: In a more fulminant hepatitis induced by injecting agonistic Fas-specific antibody, 82% of mice treated with siRNA that effectively silenced Fas survived for 10 days of observation, whereas all control mice died within 3 days.