Spherical Nucleic Acids for In Vivo Therapeutics

A research program is proposed to address the specific objectives of the IVN:Tx by developing a revolutionary biocompatible and programmable nanotherapeutic gene regulation platform based upon spherical nucleic acid (SNAs) for the treatment of military-relevant diseases. Based on the programmable nature of the platform, SNAs can be designed to respond to a multitude of military-relevant medical conditions caused by battlefield injuries or biological and chemical attack. Importantly, and in addition to being unified by SNAs, this proposal leverages the unique ability of SNAs to traffic and accumulate in difficult biological compartments including the central nervous system, skin, and inside of bacterial pathogens. Accordingly, examples include treatments for traumatic brain injury, infection by multi-drug resistant organisms, and battlefield wounds. The novel SNA system will be shown to be: 1) programmable, 2) bioavailable, 3) biocompatible, and 4) potent in vivo. In the first phase, the appropriate nucleic acid target(s) of interest will be identified and target knockdown will be demonstrated in appropriate cell culture model systems using well-established Au nanoparticle-based SNAs. In the second phase, starting at month 13, we will demonstrate a series of gold-free, second generation biocompatible SNAs and demonstrate in vivo accumulation in the target tissues. In phases 3, we will demonstrate the utility of SNA-based nanotherapeutics in vivo in a large animal model. This work will be high-risk, high-reward, but will bridge the gap between fundamental research and militarily relevant application. The assembled team will take a multipronged approach to tackle several interest areas to DARPA, which will both de-risk the effort as well as establish the breadth and applicability of the platform across multiple therapeutic spaces. The IVN:Tx team includes world-renown academic researchers (Northwestern University, Stanford University) as well as scientists, engineers, and medical doctors from SRI, MRI Global and AuraSense Therapeutics (AST). In addition to making all of the key discoveries that have laid the groundwork for the proposal, this team has extensive experience in nanoconstructs development, in vivo testing, and commercialization of translational research.