Reversing Immune Dysregulation During Spaceflight Missions

Our proposed work will result in pre-clinical and animal model testing and translation of two radiation countermeasures developed during NASA SBIR Phase I, for deployment in deep-space missions. During Phase I SBIR, we developed,nbsp; tested and validated these radiation countermeasures for: 1) reversal of immune dysregulation (immunosuppression) caused due to radiation, tested in vitro using human donor derived peripheral blood mononuclear cells (PBMCs) as a screening method; 2) validation at a cellular level shown with increase in Tregulatory (Treg) cells reversing the immunosuppressive and radiation-induced ARS; and 3) in vivo testing and validation using an animal (mice) radiation model, showing reversal of immunosuppression in lungs by administration of EPO activating Nanoligomers, to reduce potential development of carcinogenesis. Additionally, we also showed reversal of radiation-induced neurodegeneration caused by neuroinflammation in brain, using transcriptional downregulation of intraperitoneally administered GM-CSF downregulator. These two therapeutics were developed using our proprietary Sachi platform for high-throughput, rapid, and targeted gene expression manipulation (reversible) of immune and other hematopoietic proteins, to utilize our own body to create these protective enzymes to counter and repair the damage caused by deep space radiation. Our work in Phase II SBIR will: 1) provide pharmacokinetic and pharmacodynamic (PK/PD) and biodistribution data with 2 different routes of administration (intraperitoneal IP and intranasal IN); 2) determine dosing and dose frequency to obtain optimal therapeutic effect for reversing radiation- and microgravity-induced immune dysfunction; and 3) conduct small (mice) and large animal (dogs) safety, toxicity, and maximum tolerable dose studies (IND-enabling studies), for translating the developed therapeutic into human clinical trials and filling for FDA-approval for clinical investigations.