FAST Technology for Reversing Immune Dysregulation During Spaceflight Missions

In long space exploration missions, astronauts are subjected to increased amounts of radiation exposure, which can lead to Acute Radiation Syndrome (ARS). While specific haemopoietic protein variants have been used as medical countermeasures (MCM) for ARS, several recent studies have identified need for inclusion of other targets to provide more effective radiation-exposure treatment. Recent multi-omics studies and radiobiological insights have also provided new gene targets to act as radiation MCM. Using a range of different proteins poses significant challenges and associated logistical challenges in their safe transportation and storage during space travel. Existing genetic manipulation methods are laborious, expensive, and inefficient. We propose to address this market and technology void by rapid design, build, and test of molecules using a proprietary FAST platform to target any gene in any organism. Our platform generates FASTmers (nucleic acid-nanoparticle-based high-throughput synthesis, purification, and delivery) to up- or down- regulate any desired gene. In our preliminary work, we have designed, built, and tested FASTmers in an accelerated fashion for several radiation markers. Eg., GM-CSF FASTmer demonstrated large-scale immunomodulation and specific haemopoietic protein regulation in human PBMCs during acute radiation exposure (3Gy). During this proposal, we will use individual FASTmers targeting specific genes related to ARS, and evaluate their efficacy using specific haemopoietic proteins and cytokine markers. Based on their efficacy, the top-ranked candidates will be evaluated as a combination therapy. Using detailed fractional factorial design and ensuing statistical analysis, we will identify the: 1) top therapeutic targets for ARS, both in monotherapy and combinations; and 2) ranked FASTmers as therapeutic assets for mono- and combination therapy, to further test and validate in animal and clinical testing (Phase II SBIR).