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

Abstract

The purpose of this study was to evaluate down-regulation of tumor necrosis factor (TNF)-α by oral RNA interference therapy. Control (scrambled sequence) or TNF-α 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-α silencing siRNA by oral administration. Successful gene silencing led to decreased colonic levels of TNF-α, suppressed expression of other pro-inflammatory cytokines (e.g., interleukin (IL)-1β, interferon (IFN)-γ) 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-α gene silencing system for the treatment of inflammatory bowel disease as demonstrated in an acute colitis model.

RNA interference-based nanosystems for inflammatory bowel disease therapy

“…The therapeutic effects of TNF-α NiMOS were reflected in increased body weight and reduced levels of MPO in colitis-induced mice. 81 These results demonstrated that NiMOS is a promising formulation for oral siRNA delivery in IBD treatment. NiMOS increased the loading capacity of siRNA due to the structural design of the delivery system.…”

Drug Targeting in IBD Treatment – Existing and New Approaches

“…Successful intracellular and intranuclear delivery of the stable NF-κB decoy to the site of inflammation and action in GI tract is a field yet to be explored (Tahara et al, 2011). Finaly, RNA interference therapy utilizing short interfering (siRNA), usually composed of 20-25 nucleotides targeted to cytosol will trigger gene silencing mechanism through RNA interference where siRNA can block the expression of a specific gene (TNF-or different proinflammatory gene expression in IBD) and proinflammatory protein synthesis, thus providing for successful therapeutic approach in IBD (Kriegel & Amiji, 2011). Gene therapy can be delivered to local sites in GI tract, produce and concentrate a therapeutic protein in intestinal tissue, and release negligible amounts into the circulation (Kriegel & Amiji, 2011).…”

“…Finaly, RNA interference therapy utilizing short interfering (siRNA), usually composed of 20-25 nucleotides targeted to cytosol will trigger gene silencing mechanism through RNA interference where siRNA can block the expression of a specific gene (TNF-or different proinflammatory gene expression in IBD) and proinflammatory protein synthesis, thus providing for successful therapeutic approach in IBD (Kriegel & Amiji, 2011). Gene therapy can be delivered to local sites in GI tract, produce and concentrate a therapeutic protein in intestinal tissue, and release negligible amounts into the circulation (Kriegel & Amiji, 2011). Examples presented through literature for design approaches for gene, peptide and protein targeting in IBD relay on the previous experience with nano-and micro-carriers for inflammation and vaccine non specific or specific targeting.…”

“…those expressed in a disease (Plevy & Targan, 2011). NiMOS was also used for oral TNF-specific siRNA delivery (Kriegel & Amiji, 2011) and the system was evaluated for the efficacy of oral TNFgene silencing using Balb/c mice's TNBS induced colitis model. It was pointed that the system is promising and that lower expression of TNF-due to silencing preceded the downregulation of other inflammatory cytokines and within time showed similar effect on the chemokine production.…”

Nanotherapeutics for the treatment of inflammatory bowel disease

“…The clinical goals of IBD treatment are to control inflammation, achieve mucosal healing, and reduce surgeries and hospitalizations [2,3]. Traditional treatment strategies have been limited to the daily administration of high doses of medications, including biologic therapies, corticosteroids, immunomodulators, aminosalicylates, and antibiotics [4,5]. Although some of these medications have proven effective in initially alleviating IBD, their long-term application had been largely restricted by poor efficacy and serious side effects [6].…”