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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Gene transfer efficacies of serum-resistant amino acids-based cationic lipids: dependence on headgroup, lipoplex stability and cellular uptake.
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Small non-coding RNAs as magic bullets.
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Intracellular delivery of oligonucleotide conjugates and dendrimer complexes.
TL;DR: It is found that CPP‐antisense oligonucleotide conjugates can be taken up by cells and can effectively modify gene expression in cell culture and in tissues.
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Non-viral vectors for RNA delivery
TL;DR: In this article , the authors introduce the biological barriers to RNA delivery in vivo and discuss recent advances in non-viral delivery systems, such as lipid-based nanoparticles, polymeric nanoparticles and biomimetic nanovectors, which can protect RNAs against degradation by ribonucleases, accumulate in specific tissue, facilitate cell internalization, and allow for the controlled release of the encapsulated therapeutics.
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Aptamers as radiopharmaceuticals for nuclear imaging and therapy.
TL;DR: The use of aptamers as targeting biomolecules of radiopharmaceuticals are described and the chemical modifications which are needed to turn aptamer into valuable (radio-)pharm pharmaceuticals are discussed, as well as the different radiolabeling strategies that can be used to Radiolabel oligonucleotides and, in particular, aptamered.
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Expression profiling reveals off-target gene regulation by RNAi
Aimee L. Jackson,Steven R. Bartz,Janell M. Schelter,Sumire V. Kobayashi,Julja Burchard,Mao Mao,Bin Li,Guy Cavet,Peter S. Linsley +8 more
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.
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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.
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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.