Journal ArticleDOI
Potent and persistent in vivo anti-HBV activity of chemically modified siRNAs
David Morrissey,Jennifer A. Lockridge,Lucinda Shaw,Karin Blanchard,Kristi Jensen,Wendy Breen,Kimberly Hartsough,Lynn Machemer,Susan Radka,Vasant Jadhav,Narendra K. Vaish,Shawn Zinnen,Chandra Vargeese,Keith Bowman,Chris S. Shaffer,Lloyd Jeffs,Adam Judge,Ian MacLachlan,Barry Polisky +18 more
TLDR
The advances demonstrated here, including persistence of in vivo activity, use of lower doses and reduced dosing frequency are important steps in making siRNA a clinically viable therapeutic approach.Abstract:
The efficacy of lipid-encapsulated, chemically modified short interfering RNA (siRNA) targeted to hepatitis B virus (HBV) was examined in an in vivo mouse model of HBV replication. Stabilized siRNA targeted to the HBV RNA was incorporated into a specialized liposome to form a stable nucleic-acid-lipid particle (SNALP) and administered by intravenous injection into mice carrying replicating HBV. The improved efficacy of siRNA-SNALP compared to unformulated siRNA correlates with a longer half-life in plasma and liver. Three daily intravenous injections of 3 mg/kg/day reduced serum HBV DNA >1.0 log(10). The reduction in HBV DNA was specific, dose-dependent and lasted for up to 7 d after dosing. Furthermore, reductions were seen in serum HBV DNA for up to 6 weeks with weekly dosing. The advances demonstrated here, including persistence of in vivo activity, use of lower doses and reduced dosing frequency are important steps in making siRNA a clinically viable therapeutic approach.read more
Citations
More filters
Journal ArticleDOI
Knocking down barriers: advances in siRNA delivery
TL;DR: An update on the progress of RNAi therapeutics is provided and novel synthetic materials for the encapsulation and intracellular delivery of nucleic acids are highlighted.
Journal ArticleDOI
Non-viral vectors for gene-based therapy
Hao Yin,Rosemary Lynn Kanasty,Ahmed A. Eltoukhy,Arturo J. Vegas,J. Robert Dorkin,Daniel G. Anderson +5 more
TL;DR: The biological barriers to gene delivery in vivo are introduced and recent advances in material sciences, nanotechnology and nucleic acid chemistry that have yielded promising non-viral delivery systems are discussed, some of which are currently undergoing testing in clinical trials.
Journal ArticleDOI
Delivery materials for siRNA therapeutics
TL;DR: An introduction to the biological challenges that siRNA delivery materials aim to overcome is provided, as well as a discussion of the way that the most effective and clinically advanced classes of si RNA delivery systems are designed to surmount these challenges.
Journal ArticleDOI
Rational design of cationic lipids for siRNA delivery
Sean C. Semple,Akin Akinc,Jianxin Chen,Ammen P. Sandhu,Barbara L. Mui,Connie K Cho,Dinah W.Y. Sah,Derrick Stebbing,Erin J Crosley,Ed Yaworski,Ismail M. Hafez,J. Robert Dorkin,June Qin,Kieu Lam,Kallanthottathil G. Rajeev,Kim F. Wong,Lloyd Jeffs,Lubomir Nechev,Merete L. Eisenhardt,Muthusamy Jayaraman,Mikameh Kazem,Martin Maier,Masuna Srinivasulu,Michael J Weinstein,Qingmin Chen,Rene Alvarez,Scott A Barros,Soma De,Sandra K. Klimuk,Todd Borland,Verbena Kosovrasti,William Cantley,Ying K. Tam,Muthiah Manoharan,Marco A. Ciufolini,Mark A Tracy,Antonin de Fougerolles,Ian MacLachlan,Pieter R. Cullis,Thomas D. Madden,Michael J. Hope +40 more
TL;DR: The best-performing lipid recovered after screening (DLin-KC2-DMA) was formulated and characterized in SNALP and demonstrated to have in vivo activity at siRNA doses as low as 0.01 mg/kg in rodents and 0.1 mg/ kg in nonhuman primates, a substantial improvement over previous reports of in vivo endogenous hepatic gene silencing.
Journal ArticleDOI
RNAi-mediated gene silencing in non-human primates
Tracy Zimmermann,Amy C.H. Lee,Akin Akinc,Birgit Bramlage,David Bumcrot,Matthew N. Fedoruk,Jens Harborth,James Heyes,Lloyd Jeffs,Matthias John,Adam Judge,Kieu Lam,Kevin McClintock,Lubomir Nechev,Lorne R. Palmer,Timothy Racie,Ingo Röhl,Stephan Seiffert,Sumi Shanmugam,Vandana Sood,Jürgen Soutschek,Ivanka Toudjarska,Amanda J. Wheat,Ed Yaworski,William Zedalis,Victor Koteliansky,Muthiah Manoharan,Hans-Peter Vornlocher,Ian MacLachlan +28 more
TL;DR: It is shown that siRNAs, when delivered systemically in a liposomal formulation, can silence the disease target apolipoprotein B in non-human primates, supporting RNAi therapeutics as a potential new class of drugs.
References
More filters
Journal ArticleDOI
Antiviral Actions of Interferons
TL;DR: Tremendous progress has been made in understanding the molecular basis of the antiviral actions of interferons (IFNs), as well as strategies evolved by viruses to antagonize the actions of IFNs.
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
TL;DR: 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.
Journal ArticleDOI
Hydrodynamics-based transfection in animals by systemic administration of plasmid DNA
Feng Liu,Young K. Song,Dexi Liu +2 more
TL;DR: A hydrodynamics-based procedure for expressing transgenes in mice by systemic administration of plasmid DNA is developed and which can be used as an effective means for studying gene function, gene regulation and molecular pathophysiology through gene transfer, as well as for expressing proteins in animals.
Journal ArticleDOI
Sequence-specific potent induction of IFN-alpha by short interfering RNA in plasmacytoid dendritic cells through TLR7.
Veit Hornung,Margit Guenthner-Biller,Carole Bourquin,Andrea Ablasser,Martin Schlee,Satoshi Uematsu,Anne Noronha,Muthiah Manoharan,Shizuo Akira,Antonin de Fougerolles,Stefan Endres,Gunther Hartmann +11 more
TL;DR: Injection into mice of immunostimulatory siRNA, when complexed with cationic liposomes, induced systemic immune responses in the same range as the TLR9 ligand CpG, including IFN-α in serum and activation of T cells and dendritic cells in spleen.
Journal ArticleDOI
Sequence-dependent stimulation of the mammalian innate immune response by synthetic siRNA.
TL;DR: It is reported that synthetic siRNAs formulated in nonviral delivery vehicles can be potent inducers of interferons and inflammatory cytokines both in vivo in mice and in vitro in human blood.
Related Papers (5)
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
RNAi-mediated gene silencing in non-human primates
Tracy Zimmermann,Amy C.H. Lee,Akin Akinc,Birgit Bramlage,David Bumcrot,Matthew N. Fedoruk,Jens Harborth,James Heyes,Lloyd Jeffs,Matthias John,Adam Judge,Kieu Lam,Kevin McClintock,Lubomir Nechev,Lorne R. Palmer,Timothy Racie,Ingo Röhl,Stephan Seiffert,Sumi Shanmugam,Vandana Sood,Jürgen Soutschek,Ivanka Toudjarska,Amanda J. Wheat,Ed Yaworski,William Zedalis,Victor Koteliansky,Muthiah Manoharan,Hans-Peter Vornlocher,Ian MacLachlan +28 more