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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Available from: Shawn Zinnen, Jul 29, 2015
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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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    Human Gene Therapy Methods 10/2013; DOI:10.1089/hgtb.2013.016 · 1.64 Impact Factor
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    • "Nevertheless, those features are not enough to dictate an effective systemic siRNA delivery to distant sites of disease, like solid tumors localized in organs other than the liver. Actually, most of the studies involving sterically stabilized liposomes containing nucleic acids demonstrated that these particles naturally accumulate in the liver and spleen (Akinc et al., 2010; Geisbert et al., 2006; Judge et al., 2009; Kim et al., 2007; Morrissey et al., 2005; Zimmermann et al., 2006), being the accumulation into solid tumors still an enormous challenge. Despite this constraint, the aforementioned classes of liposomes represent an opportunity for further improvements on the targeted delivery to solid tumors upon covalently coupling of ligands targeting internalizing receptors. "
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    • "Morrissey et al. described the efficacies of SNALPs (with a size of 140± 12 nm) that encapsulate siRNAs targeted to HBV RNA in a mouse model of HBV replication. Here, they showed a longer half-life in plasma and liver and reduced toxic and immunostimulatory side effects (Morrissey et al. 2005). Yang et al. instead described cationic lipid-assisted polymeric nanoparticles of (poly(ethylene glycol)-b-poly(d,l-lactide) at around 170 to 200 nm in size, which were used to suppress tumor growth in an MDA-MB-435 murine xenograft model and which suggested therapeutic promise in disease treatment (Yang et al. 2011). "
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