Article

Engineering Mucosal RNA Interference in Vivo

Laboratory of Retrovirology, Division of Infectious Diseases, Department of Medicine, Brown Medical School, 55 Claverick Street, Providence, RI 02903, USA.
Molecular Therapy (Impact Factor: 6.43). 10/2006; 14(3):336-42. DOI: 10.1016/j.ymthe.2006.04.001
Source: PubMed

ABSTRACT Mucosal surfaces serve as a gateway to disease. Here, we demonstrate that RNA interference can be used to manipulate mucosal gene expression in vivo. Using a murine model, we show that direct application of liposome-complexed siRNA mediates gene-specific silencing in cervicovaginal and rectal mucosa. A single vaginal or rectal administration of siRNA targeting hematopoietic or somatic cell gene products reduced corresponding mRNA levels by up to 90%. Using a murine model of inflammatory bowel disease, we found that the rectal application of siRNA targeting TNF-alpha led to relative mucosal resistance to experimental colitis. Liposomal siRNA formulations proved nontoxic, did not elicit a nonspecific interferon response, and provide a means for genetic engineering of mucosal surfaces in vivo.

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    • "problem, many strategies have been employed to enhance endosomal escape. Lipid or lipid-like molecules responsive to pH and viral fusogenic proteins and peptides have promoted endosomal escape via membrane destabilization, which can result from pHdependent changes in conformation (Akinc et al., 2008; Hughson, 1995; Morrissey et al., 2005; Pal et al., 2005; Palliser et al., 2005; Ren et al., 1999; Skehel and Wiley, 2000; Sørensen et al., 2003; Zhang et al., 2006; Zimmermann et al., 2006). Ideally, such mediators of cellular entry, and any potential toxicity, would be masked within a complex or via 'shielding' prior to arrival at the target tissue (Sawant et al., 2006). "
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    International Journal of Pharmaceutics 08/2011; 427(1):134-42. DOI:10.1016/j.ijpharm.2011.08.012 · 3.65 Impact Factor
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    • "siRNAs were observed in the vaginal epithelial cells and were detectable deep into the lamina propria. Furthermore, targeting an endogenous gene resulted in more durable silencing, with reduced expression of mRNA and protein observed for at least 7 days (Palliser et al., 2006; Zhang et al., 2006). A similar observation had been reported for siRNA-mediated inhibition of HIV-1 replication in macrophages in vitro. "
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    Discovery medicine 02/2011; 11(57):124-32. · 3.50 Impact Factor
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    • "were effective when administered around the time of viral challenge or within a few hours after exposure. Effective siRNA delivery to the cervicovaginal and anal epithelium using lipoplexed siRNAs was also shown by Ramratnam and colleagues (Zhang et al. 2006). "
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