Oral TNF-α gene silencing using a polymeric microsphere-based delivery system for the treatment of inflammatory bowel disease

The purpose of this study was to evaluate down-regulation of tumor necrosis factor (TNF)-alpha by oral RNA interference therapy. Control (scrambled sequence) or TNF-alpha specific small interfering RNA (siRNA) was encapsulated in type B gelatin nanoparticles and further entrapped in poly(epsilon-caprolactone) (PCL) microspheres to form a nanoparticles-in-microsphere oral system (NiMOS). Upon confirmation of the dextran sulfate sodium (DSS)-induced acute colitis model, mice were divided into several treatment groups receiving no treatment, blank NiMOS, NiMOS with scramble siRNA, or NiMOS with TNF-alpha silencing siRNA by oral ad ministration. Successful gene silencing led to decreased colonic levels of TNF-alpha, suppressed expression of other pro-inflammatory cytokines (e.g.. interleukin (IL)-1 beta, interferon (IFN)-gamma) and chemokines (MCP-1), an increase in body weight, and reduced tissue myeloperoxidase activity. Results of this study established the clinical potential of a NiMOS-based oral TNF-alpha gene silencing system for the treatment of inflammatory bowel disease as demonstrated in an acute colitis model. (C) 2010 Elsevier B.V. All rights reserved.