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.
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), activeTNF-α silencing,CyD1silencing siRNA, or a combination of both active siRNAs by repeated oral administration of three NiMOS doses.
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 ofCyD1siRNA or the dual treatment was more potent than that ofTNF-αsiRNA alone.
Results of this study demonstrate the therapeutic potential of a NiMOS-based oral combinedTNF-αandCyD1gene silencing system for the treatment of IBD as shown in an acute colitis model.