Delivery strategies for developing siRNA-based vaginal microbicides

RNA interference (RNAi) is a mechanism of posttranscriptional gene silencing, initially described in plants and worms and more recently in mammals. The specificity of siRNAs makes them an attractive modality for therapeutic use, and they are being evaluated in various clinical trials. Studies have shown effective uptake of siRNAs across mucosal surfaces including the lung, rectum, and vagina. Targeting genes in the rectum and vagina could be useful for preventing sexually transmitted diseases such as HIV-1 and HSV-2. However, the main barrier for use of siRNAs in the clinic is delivery. Topically applied siRNAs need to traverse the mucosal layer present in the vagina and resist degradation in the acidic environment. Subsequent uptake of siRNAs by appropriate cells must result in access to the cytosolic compartment where the RNA-induced silencing complex resides. Effective RNAi-mediated gene-specific silencing must be accomplished while minimizing toxic bystander effects. In this chapter we will present the strategies that are being used to achieve these goals.