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
Reads0
Chats0
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
Citations
More filters
Journal ArticleDOI
Small interfering RNA-induced TLR3 activation inhibits blood and lymphatic vessel growth
Won Gil Cho,Romulo Albuquerque,Mark E. Kleinman,Valeria Tarallo,Adelaide Greco,Miho Nozaki,Martha G. Green,Judit Z. Baffi,Balamurali K. Ambati,Massimo De Falco,Jonathan Steven Alexander,Arturo Brunetti,Sandro De Falco,Jayakrishna Ambati +13 more
TL;DR: These findings introduce TLR3 activation as a method of jointly suppressing blood and lymphatic neovascularization and simultaneously raise new concerns about the undesirable effects of siRNAs on both circulatory systems.
Journal ArticleDOI
Supramolecular assemblies in functional siRNA delivery: where do we stand?
TL;DR: Non-viral approaches to siRNA delivery are summarized, emphasizing the current obstacles to delivery and the mechanisms employed to overcome these obstacles, and a perspective on the future of siRNA therapeutics is focused on the possible impact of non-Viral carriers in the field.
Patent
Compositions and methods for inhibiting expression of anti-apoptotic genes
TL;DR: In this article, a double-stranded ribonucleic acid (dsRNA) was used to inhibit the expression of an anti-apoptotic gene, comprising an antisense strand having a nucleotide sequence which is less than 25 nucleotides in length and which is substantially complementary to at least a part of an apoptotic gene.
Journal ArticleDOI
Biomimetic High Density Lipoprotein Nanoparticles For Nucleic Acid Delivery
Kaylin M. McMahon,R. Kannan Mutharasan,Sushant Tripathy,Dorina Veliceasa,Mariana Bobeica,Dale K. Shumaker,Andrea J. Luthi,Andrea J. Luthi,Brian T. Helfand,Hossein Ardehali,Chad A. Mirkin,Olga V. Volpert,C. Shad Thaxton +12 more
TL;DR: The ability to directly image the AuNP core within cells, the chemical tailorability of the HDL AuNP platform, and the potential for cell-specific targeting afforded by HDL biomimicry make this platform appealing for nucleic acid delivery.
Journal ArticleDOI
Aptamers: A Review of Their Chemical Properties and Modifications for Therapeutic Application.
Tatsuo Adachi,Yoshikazu Nakamura +1 more
TL;DR: Aptamers are short, single-stranded oligonucleotides that bind to specific target molecules that provide high affinity and excellent specificity toward targets and can be used as analogs of antibodies.
References
More filters
Journal ArticleDOI
A receptor-mediated pathway for cholesterol homeostasis.
TL;DR: The approach was to apply the techniques of cell culture to unravel the postulated regulatory defect in FH, which led to the discovery of a cell surface receptor for a plasma cholesterol transport protein called low density lipoprotein (LDL) and to the elucidation of the mechanism by which this receptor mediates feedback control of cholesterol synthesis.
Journal ArticleDOI
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.
Journal ArticleDOI
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.