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Morrissey, D.V. et al. Potent and persistent in vivo anti-HBV activity of chemically modified siRNAs. Nat. Biotechnol. 23, 1002-1007

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.

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    • "To mitigate siRNA-mediated immune stimulation, chemical modifications to the 2¢-OH group in the ribose backbone of siRNAs, including 2¢-O-methyl, 2¢-fluoro, and 2¢-deoxy modifications, and locked nucleic acids (LNAs), have been shown to be effective. Substituting more than 90% of the siRNA nucleotides with a combination of 2¢-O-methyl-, 2¢-fluoro-, and 2¢-deoxy-modified nucleotides can prevent the immunostimulatory response (Morrissey et al., 2005). However, caution must be taken if undertaking extensive chemical modifications to an siRNA as this can significantly impair its silencing activity ( Judge and MacLaclan, 2008). "
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