Oral Delivery of Short Interfering RNA Molecules

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trojan horseAlthough many studies have shown the potential for gene silencing using short interfering RNA (siRNA), a major hurdle to the therapeutic use of the technique has been the lack of effective delivery systems. Writing in the journal Nature, researchers at the University of Massachusetts Medical School now report a method of delivering siRNA to specific cell types following oral administration. The researchers exploited a characteristic of macrophages – the ability to engulf yeast particles – to deliver the siRNA. Macrophages are attractive targets for RNA interference therapy since they promote pathogenic inflammatory responses in diseases such as rheumatoid arthritis, atherosclerosis, inflammatory bowel disease and diabetes. Yeast particles were treated to remove components that would elicit an immune response to give β-1,3-D glucan, a polysaccharide formed from D-glucose, as the delivery vehicle. Oral delivery of β-1,3-D glucan-encapsulated siRNA particles containing as little as 20 µg kg-1 siRNA directed against tumour necrosis factor α (TNF-α) depleted messenger RNA in macrophages recovered from the peritoneum, spleen, liver and lung, and lowered serum TNF-α levels. The technique was also used to identify the mitogen-activated protein kinase kinase kinase kinase 4 (Map4k4) as a previously unknown mediator of cytokine expression. Silencing Map4k4 in macrophages protected mice from lipopolysaccharide-induced lethality by inhibiting TNF-α and interleukin-1β production. The siRNA-carrying particles were engulfed by macrophages in the gut and, over time, a large proportion of macrophages exhibited gene silencing, resulting in systemic immune suppression.

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