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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Subcellular Fate and Off-Target Effects of siRNA, shRNA, and miRNA
TL;DR: The challenges in the systemic delivery to target cells, cellular uptake, endosomal release and intracellular transport of RNAi drugs and recent progress in overcoming these barriers are discussed.
Journal ArticleDOI
Virtues and woes of AChE alternative splicing in stress-related neuropathologies
Eran Meshorer,Hermona Soreq +1 more
TL;DR: The ACh hydrolyzing enzyme acetylcholinesterase (AChE) is a combinatorial series of proteins with variant N and C termini generated from alternate promoter usage and 3' alternative splicing that raises the possibility that future therapeutic drugs might target specific AChE variant(s) or the corresponding RNA transcripts.
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Targeted Delivery of PLK1-siRNA by ScFv Suppresses Her2+ Breast Cancer Growth and Metastasis
Yandan Yao,Tianmeng Sun,Songyin Huang,Shuang Dou,Ling Lin,Jianing Chen,Jianbin Ruan,Chengqiong Mao,Fengyan Yu,Mu Sheng Zeng,Jianye Zang,Qiang Liu,Fengxi Su,Peter Zhang,Judy Lieberman,Jun Wang,Erwei Song +16 more
TL;DR: The results suggest that as a new platform to deliver siRNAs to specifically treat Her2+ breast cancers, F5-P may be on target.
Journal ArticleDOI
Aptamer-targeted cell-specific RNA interference
Jiehua Zhou,John J. Rossi +1 more
TL;DR: Recent attractive developments in creatively using cell-internalizing aptamers to deliver siRNAs to target cells are summarized and the optimization and improvement of aptamer-targeted si RNAs for clinical translation are further highlighted.
Journal ArticleDOI
BRAF is a therapeutic target in aggressive thyroid carcinoma.
Giuliana Salvatore,Valentina De Falco,Paolo Salerno,Tito Claudio Nappi,Stefano Pepe,Giancarlo Troncone,Francesca Carlomagno,Rosa Marina Melillo,Scott Wilhelm,Massimo Santoro +9 more
TL;DR: BRAF provides signals crucial for proliferation of thyroid carcinoma cells spontaneously harboring the V600 EBRAF mutation and, therefore, BRAF suppression might have therapeutic potential in V600EBRAF-positive thyroid cancer.
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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.
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.