Engineering mucosal RNA interference in vivo.
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.
Article: Prevention of airway inflammation with topical cream containing imiquimod and small interfering RNA for natriuretic peptide receptor.[show abstract] [hide abstract]
ABSTRACT: Asthma is a complex disease, characterized by reversible airway obstruction, hyperresponsiveness and chronic inflammation. Principle pharmacologic treatments for asthma include bronchodilating beta2-agonists and anti-inflammatory glucocorticosteroids; but these agents do not target the main cause of the disease, the generation of pathogenic Th2 cells. We previously reported reduction in allergic inflammation in mice deficient in the ANP receptor NPRA. Here we determined whether siRNA for natriuretic peptide receptor A (siNPRA) protected against asthma when administered transdermally. Imiquimod cream mixed with chitosan nanoparticles containing either siRNA green indicator (siGLO) or siNPRA was applied to the skin of mice. Delivery of siGLO was confirmed by fluorescence microscopy. The anti-inflammatory activity of transdermal siNPRA was tested in OVA-sensitized mice by measuring airway hyperresponsiveness, eosinophilia, lung histopathology and pro-inflammatory cytokines. SiGLO appearing in the lung proved the feasibility of transdermal delivery. In a mouse asthma model, BALB/c mice treated with imiquimod cream containing siNPRA chitosan nanoparticles showed significantly reduced airway hyperresponsiveness, eosinophilia, lung histopathology and pro-inflammatory cytokines IL-4 and IL-5 in lung homogenates compared to controls. These results demonstrate that topical cream containing imiquimod and siNPRA nanoparticles exerts an anti-inflammatory effect and may provide a new and simple therapy for asthma.Genetic Vaccines and Therapy 02/2008; 6:7. · 2.10 Impact Factor
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ABSTRACT: RNA interference (RNAi) is a naturally occurring method of inhibition of gene expression in organisms. Chemically synthesized or vector-based short interference RNAs (siRNAs) are used to cause a specific and selective gene knockdown in cell lines or animal models. Different approaches to introduce siRNAs in human body with a higher selectivity and efficacy have been tried. In any way, RNAi is accepted as a revolutionary tool to suppress oncogenes and other highly expressed genes in human malignancies, which have been previously found by means of microarray strategies. In this review, we summarize the advantages and disadvantages of RNAi technologies, discuss the currently invented siRNA libraries and give some examples of their application in clinical oncology.Journal of Cancer Molecules. 01/2008;
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ABSTRACT: This potent ability of small interfering (si)RNAs to inhibit the expression of complementary RNA transcripts is being exploited as a new class of therapeutics for a variety of diseases. However, the efficient and safe delivery of siRNAs into specific cell populations is still the principal challenge in the clinical development of RNAi therapeutics. With the increasing enthusiasm for developing targeted delivery vehicles, nucleic acid-based aptamers targeting cell surface proteins are being explored as promising delivery vehicles to target a distinct disease or tissue in a cell-type-specific manner. The aptamer-based delivery of siRNAs can often enhance the therapeutic efficacy and reduce the unwanted off-target effects of siRNAs. In particular, for RNA interference-based therapeutics, aptamers represent an efficient agent for cell type-specific, systemic delivery of these oligonucleotides. In this review, we summarize recent attractive developments in creatively using cell-internalizing aptamers to deliver siRNAs to target cells. The optimization and improvement of aptamer-targeted siRNAs for clinical translation are further highlighted.Silence. 01/2010; 1(1):4.