7th Annual BMRP Investigator Meeting - Abstract

Transient Gene Therapy for Inflammatory Bowel Disease

Bharat Ramratnam

Laboratory of Retrovirology, Division of Infectious Diseases, Rhode Island Hospital, Brown Medical School (Providence, U.S.A.)

We hypothesized that short interfering RNA (siRNA) targeting genes implicated in IBD pathogenesis can be effectively targeted to colonic epithelial cells in vivo, knock down corresponding mRNA expression and thereby prevent or decrease the severity of colitis in IBD. We achieved proof of principle in vivo by using siRNA targeting TNF-α. In DSS-treated animals receiving specific siRNA, macro- and micro-indices of colonic inflammation were significantly decreased compared to animals receiving a sham siRNA. However, regardless of dose or frequency of administration, all protective effects were limited to the peri-rectal area. Thus, a major challenge we encountered was the inability to target all areas of the colon using lipoplexed siRNA delivered by enema. We then tested a variety of other delivery agents including but not limited to carbon nanotubules and nanospheres. We have identified a first-generation nanoparticle with physical conditions appropriate for siRNA delivery and intracellular cargo release but the efficiency of tissue uptake is around 20-30%. We are now testing further modifications to improve uptake and retention. A positive attribute of our delivery spheres is their ability to be taken orally. The Foundation has jump started our work on siRNA delivery, the greatest hurdle in developing mucosal siRNA drugs.