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Christina Kriegel

Christina Kriegel, a postdoctoral associate in Dr. Mansoor Amiji’s group received the 2009 American Association of Pharmaceutical Scientist’s (AAPS) Postdoctoral Fellow Award. The Award is sponsored by FMC Corporation. Christina’s research focuses on “Oral Gene Silencing of TNF-alpha using a Nanoparticles-in-Microsphere Delivery System in an Inflammatory Bowel Disease Model”

The pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-α) plays a central role in inflammatory bowel disease (IBD). The purpose of this study is to evaluate down-regulation of TNF- α by oral RNA interference therapy in order to restore the delicate balance between pro- and anti-inflammatory markers alleviating severity of the disease. For this, small interfering RNA (siRNA) specific for TNF-α was encapsulated into nanoparticles-in-microsphere oral system (NiMOS) and administered to dextran sulfate-induced acute colitis model established in Balb/c mice. Control (scrambled sequence) and TNF-α silencing siRNA was encapsulated in type B gelatin nanoparticles, which were further entrapped in poly(epsilon-caprolactone) microspheres in a double emulsion like technique to form NiMOS. Acute colitis was induced in 5-7 weeks old female Balb/c mice by addition of dextran sodium sulfate (DSS) to the drinking water for the duration of 8 days, while mice receiving regular tap water served as a control. Animals exposed to DSS were divided into four groups and received either no treatment, blank NiMOS, NiMOS encapsulating siRNA with a scrambled TNF-α sequence, or NiMOS incorporating siRNA specific for TNF-α by oral administration on day 1, 3, and 6 of the study. After non-treated control mice developed typical symptoms associated with IBD including rectal bleeding, loose and bloody stools in addition to significant weight loss, animals were sacrificed and the gastrointestinal tissue was harvested and analyzed for levels of several pro- and anti-inflammatory cytokines as well as histological abnormalities. After 7 days of DSS exposure, non-treated control mice showed typical symptoms of IBD and further signs of inflammation including elevated levels of pro-inflammatory markers including TNF-α, IFN-γ, and IL-1β. Histological analysis revealed disruption of the mucosal architecture and cellular infiltration in the inflamed tissue. Successful RNA interference of the disease site led to tissue structure resembling that of naïve colon, decreased colonic levels of TNF-α and also suppressed expression of other pro-inflammatroy cytokines. Results of this study demonstrated the preliminary potential for an oral RNA interference therapy system using NiMOS in an acute colitis model.

This study was supported by a grant (R01-DK080477) from the National Institute of Diabetes, Digestive Diseases, and Kidney Diseases of the National Institutes of Health.