Article

Potent and persistent in vivo anti-HBV activity of chemically modified siRNAs.

Sirna Therapeutics, Inc., 2950 Wilderness Place, Boulder, Colorado 80301, USA.
Nature Biotechnology (Impact Factor: 39.08). 08/2005; 23(8):1002-7. DOI: 10.1038/nbt1122
Source: PubMed

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.

0 Bookmarks
 · 
129 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Small interfering RNA (siRNA) has proved to be a powerful tool for target-specific gene silencing via RNA interference (RNAi). Its ability to control targeted gene expression gives new hope to gene therapy as a treatment for cancers and genetic diseases. However, siRNA shows poor pharmacological properties, such as low serum stability, off-targeting, and innate immune responses, which present a significant challenge for clinical applications. In addition, siRNA cannot cross the cell membrane for RNAi activity because of its anionic property and stiff structure. Therefore, the development of a safe, stable, and efficient system for the delivery of siRNA therapeutics into the cytoplasm of targeted cells is crucial. Several nanoparticle platforms for siRNA delivery have been developed to overcome the major hurdles facing the therapeutic uses of siRNA. This review covers a broad spectrum of non-viral siRNA delivery systems developed for enhanced cellular uptake and targeted gene silencing in vitro and in vivo and discusses their characteristics and opportunities for clinical applications of therapeutic siRNA.
    Theranostics 01/2014; 4(12):1211-1232. · 7.83 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: This paper presents a microfluidic method for precise control of the size and polydispersity of surfactant–DNA nanoparticles. A mixture of surfactant and DNA dispersed in 35% ethanol is focused between two streams of pure water in a microfluidic channel. As a result, a rapid change of solvent quality takes place in the central stream, and the surfactant-bound DNA molecules undergo a fast coil–globule transition. By adjusting the concentrations of DNA and surfactant, fine-tuning of the nanoparticle size, down to a hydrodynamic diameter of 70 nm with a polydispersity index below 0.2, can be achieved with a good reproducibility.
    Langmuir 11/2014; 30(44):13125-13136. · 4.38 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Chronic HBV infection is a major public health concern affecting over 240 million people worldwide. Although suppression of HBV replication is achieved in the majority of patients with currently available newer antivirals, discontinuation of therapy prior to hepatitis B surface antigen loss or seroconversion is associated with relapse of HBV in the majority of cases. Thus, new therapeutic modalities are needed to achieve eradication of the virus from chronically infected patients in the absence of therapy. The basis of HBV persistence includes viral and host factors. Here, we review novel strategies to achieve sustained cure or elimination of HBV. The novel approaches include targeting the viral and or host factors required for viral persistence, and novel immune-based therapies, including therapeutic vaccines.
    Future Virology 06/2014; 9(6):565-585. · 1.00 Impact Factor

Full-text (2 Sources)

Download
60 Downloads
Available from
Jun 3, 2014