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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Composition and methods for modulating cell proliferation and cell death
TL;DR: In this article, compositions and methods for modulation of p53-dependent cell death and cell proliferation are described and evaluated. The compositions are microRNAs and associated nucleic acids.
Journal ArticleDOI
Efficient systemic delivery of siRNA by using high-density lipoprotein-mimicking peptide lipid nanoparticles.
Qiaoya Lin,Qiaoya Lin,Qiaoya Lin,Juan Chen,Honglin Jin,Honglin Jin,Honglin Jin,Kenneth K. Ng,Kenneth K. Ng,Mi Yang,Mi Yang,Weiguo Cao,Weiguo Cao,Lili Ding,Zhihong Zhang,Zhihong Zhang,Gang Zheng +16 more
TL;DR: High-density lipoprotein-mimicking peptide-phospholipid scaffold (HPPS) is developed and demonstrated its direct cytosolic delivery of siRNA in vitro, thereby bypassing endosomal trapping.
Journal ArticleDOI
VEGF-Targeted RNA Interference Suppresses Angiogenesis and Tumor Growth of Retinoblastoma
Renbing Jia,P. Zhang,Y.X. Zhou,X. Song,H.Y. Liu,L.Z. Wang,M. Luo,J. Lu,Shengfang Ge,Xianqun Fan +9 more
TL;DR: The suppression function on angiogenesis and tumor growth of retinoblastoma by VEGF-targeted RNAi is demonstrated by real-time PCR and Western blot compared to control.
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Nanomolar Cellular Antisense Activity of Peptide Nucleic Acid (PNA) Cholic Acid (“Umbrella”) and Cholesterol Conjugates Delivered by Cationic Lipids
TL;DR: The synthesis and cellular antisense activity in cultured HeLa pLuc705 cells of cholesterol and cholic acid ("umbrella") derivatives of splice correction antisense PNA oligomers are reported, and it is shown that increasing the transfection volume improved transfections efficiency, suggesting that accumulation (condensation) of the PNA/lipid complex on the cellular surface is part of the uptake mechanism.
Journal ArticleDOI
“DNA–Teflon” sequence-controlled polymers
Donatien de Rochambeau,Maciej Barłóg,Thomas G. W. Edwardson,Johans J. Fakhoury,Robin S. Stein,Hassan S. Bazzi,Hanadi F. Sleiman +6 more
TL;DR: Modulating the PFC tail length of “DNA–Teflon” block copolymers resulted in micelles that are almost monodisperse, have a low critical micelle concentration (CMC), are traceable by 19F NMR and are responsive to external stimuli.
References
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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.
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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.