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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Journal ArticleDOI
RNAi therapeutics: a potential new class of pharmaceutical drugs.
TL;DR: Therapeutics based on RNA interference offer a powerful method for rapidly identifying specific and potent inhibitors of disease targets from all molecular classes.
Journal ArticleDOI
Image-based analysis of lipid nanoparticle–mediated siRNA delivery, intracellular trafficking and endosomal escape
Jerome Gilleron,William Querbes,Anja Zeigerer,Anna Borodovsky,Giovanni Marsico,Undine Schubert,Kevin Manygoats,Sarah Seifert,Cordula Andree,Martin Stöter,Hila Epstein-Barash,Ligang Zhang,Victor Koteliansky,Kevin Fitzgerald,Eugenio Fava,Marc Bickle,Yannis Kalaidzidis,Akin Akinc,Martin Maier,Marino Zerial +19 more
TL;DR: It is estimated that escape of siRNAs from endosomes into the cytosol occurs at low efficiency (1–2%) and only during a limited window of time when the LNPs reside in a specific compartment sharing early and late endosomal characteristics.
Journal ArticleDOI
Cell type-specific delivery of siRNAs with aptamer-siRNA chimeras.
James O. McNamara,Eran R. Andrechek,Yong Wang,Kristi D. Viles,Rachel E. Rempel,Eli Gilboa,Bruce A. Sullenger,Paloma H. Giangrande +7 more
TL;DR: A aptamer-siRNA chimeric RNAs capable of cell type–specific binding and delivery of functional siRNAs into cells and specifically inhibit tumor growth and mediate tumor regression in a xenograft model of prostate cancer.
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Molecularly self-assembled nucleic acid nanoparticles for targeted in vivo siRNA delivery
Hyukjin Lee,Abigail K. R. Lytton-Jean,Yi Chen,Kevin T. Love,Angela I. Park,Emmanouil D. Karagiannis,Alfica Sehgal,William Querbes,Christopher Zurenko,Muthusamy Jayaraman,Chang G. Peng,Klaus Charisse,Anna Borodovsky,Muthiah Manoharan,Jessica S. Donahoe,Jessica Truelove,Matthias Nahrendorf,Robert Langer,Daniel G. Anderson +18 more
TL;DR: In this paper, a tetrahedral DNA strand self-assembles into tetrahedron nanoparticles that can deliver small interfering RNA molecules to cells and suppress genes in tumours.
Journal ArticleDOI
Mechanisms and optimization of in vivo delivery of lipophilic siRNAs
Christian Wolfrum,Shuanping Shi,K. Narayanannair Jayaprakash,Muthusamy Jayaraman,Gang Wang,Rajendra K. Pandey,Kallanthottathil G. Rajeev,Tomoko Nakayama,Klaus Charrise,Esther Ndungo,Tracy Zimmermann,Victor Koteliansky,Muthiah Manoharan,Markus Stoffel,Markus Stoffel,Markus Stoffel +15 more
TL;DR: It is shown that conjugation to bile acids and long-chain fatty acids, in addition to cholesterol, mediates siRNA uptake into cells and gene silencing in vivo and can be exploited to optimize therapeutic siRNA delivery.
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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
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