Dual TNF-α/Cyclin D1 Gene Silencing With an Oral Polymeric Microparticle System as a Novel Strategy for the Treatment of Inflammatory Bowel Disease

OBJECTIVES: RNA silencing utilizing short interfering RNA (siRNA) offers a new and exciting means to overcome the limitations of current treatment options of many diseases. However, delivery of these molecules still poses a great challenge to date. METHODS: In the present study, a multicompartmental biodegradable polymer-based nanoparticles-in-microsphere oral system (NiMOS) using gelatin nanoparticles encapsulating a combination of siRNA duplexes specifically targeted against tumor necrosis factor-α (TNF-α) and cyclin D1 (Ccnd1) was employed to study its effects on a dextran sulfate sodium (DSS)-induced acute colitis mouse model mimicking inflammatory bowel disease (IBD). DSS colitis-bearing animals were divided into several control and treatment groups and received either no treatment, blank NiMOS, NiMOS-encapsulating inactive (scrambled), active TNF-α silencing, CyD1 silencing siRNA, or a combination of both active siRNAs by repeated oral administration of three NiMOS doses. RESULTS: Successful gene silencing with the aid of dual siRNA treatment led to decreased colonic levels of TNF-α or CyD1, suppressed expression of certain pro-inflammatory cytokines (interleukin-1α and -β, interferon-γ), an increase in body weight, and reduced tissue myeloperoxidase activity, while the silencing effect of CyD1 siRNA or the dual treatment was more potent than that of TNF-α siRNA alone. CONCLUSION: Results of this study demonstrate the therapeutic potential of a NiMOS-based oral combined TNF-α and CyD1 gene silencing system for the treatment of IBD as shown in an acute colitis model.