Targeted Delivery of siRNA Nanoparticles to Prevent HIV-1 Transmission

DESCRIPTION (provided by applicant): According to estimates by the Joint United Nations Program on HIV/AIDS (UNAIDS), approximately 40 million people will be living with HIV/AIDS worldwide by the end of 2006. However, safe and effective AIDS vaccine remain s difficult to develop. Small interference RNA (siRNA) has emerged as a powerful tool in gene silencing, and appears promising in treatment of viral infections and cancers. The combination of siRNA and chitosan nanoparticle technology led to the developmen t nanocomplex antivirals capable of inhibiting respiratory syncytial virus infections (Zhang et. al. Nature Medicine, 2005). Based on the preliminary in vitro data for suppressing HIV replication, it is hypothesized that siRNA nanocomplexes comprise a pote ntial therapeutic approach against AIDS. The long-term goal of our proposal is to develop multifunctional siRNA nanoparticles to protect HIV transmission. However, we will only test the antiviral activities of the multifunctio intensified, since a safe and effective AIDS vaccine remains difficult to develop and won't be available in this decade. Small interfering RNA (siRNA) has emerged as a powerful tool in gene silencing, and preclinical studies have shown promise in treatment of viral infection and cance r. The potential of siRNA for inhibiting respiratory infections has been demonstrated using a nanoparticle delivery system in a mouse model of respiratory syncytoial virus (RSV) infection. Intranasal treatment before or after RSV infection with nanoparticl es containing siRNA targeting the NS1 gene of RSV showed substantially decreased virus titers in the lung and decreased inflammation and airway reactivity compared to controls. These results have led to the working hypothesis that multifunctional chitosan nanoparticles (MCNs) can effectively deliver siRNA without any significant adverse effects and provide significant protection against viral infections, specifically HIV. The specific aims of this proparticles in inhibiting SHVSF163P3 replication in human o r monkey peripheral blood mononuclear leukocytes (PBMCs). In vitro confirmation of the antiviral activity of the multifunctional siRNA nanoparticles will ensure the success in future studies in non-human primates. The proposed project is significant, succe ssful delivery of anti-HIV siRNA nanoparticles to prevent HIV-1 replication in vitro will help us in non-human primate studies or preclinical trials in the future. Thus, the novel chitosan nanoparticle drug delivery system will be useful not only in AIDS r esearch but also in studies in cancer and other diseases