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, 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. In spaceflight missions, astronauts are subjected to increased amounts of radiation causing DNA damage and aging. Our Nanoligomer molecules act as radiation countermeasures by creating protective enzymes to counter and repair the damage caused by radiation. During Phase I SBIR, Sachi’s platform was used to identify best-in-class therapeutics. We propose to translate these radioprotective Nanoligomer molecules by assessing their safety and efficacy. This would also benefit applications for patients undergoing cancer radiotherapy. Additionally, space radiation induces increase in cerebral amyloid-b levels and elevated levels of microgliosis and astrocytosis, mimicking protein misfolding and Alzheimer’s Disease (AD) pathogenesis at an accelerated pace. Even exposure to low levels of radiation in short-term leads to neuropathy. The neuroprotective Nanoligomers that can cross the blood-brain barrier and reverse radiation-induced neurodegeneration, will be tested in relevant AD animal model and advanced, to potentially benefit both astronauts in spaceflights and AD patients on earth. In this SBIR Phase II project, we will translate two lead Nanoligomers by evaluating their safety and efficacy as radiation countermeasures.  During Phase I, we showed: 1) reversal of immune dysfunction (immunosuppression) caused due to radiation, tested in vitro; 2) validation at a cellular level with increase in Tregulatory cells; and 3) in vivo evidence using an animal radiation model, showing reversal of immunosuppression 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 intraperitoneally administered GM-CSF downregulator. Our work in Phase II SBIR will: 1) provide pharmacokinetic and pharmacodynamic (PK/PD, Aim 1.1) and biodistribution (Aim 1.2) data with 2 different routes of administration (intraperitoneal and intranasal); 2) determine dosing and dose frequency to obtain optimal therapeutic effect (Aim 1.2) for reversing radiation- and microgravity-induced immune dysfunction using simulated Galactic Cosmic Ray exposure (Aim 2.1, 2.2); and 3) conduct small (mice, Aim 1) and large animal (dogs, Aim 3) 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.

Sachi is teaming with Space Tango (and Sierra Space) for development and deployment of “on-the-fly” and “GMP-in-a-box” module, for therapeutic manufacturing and testing in space. Sachi and Space Tango are currently fundraising for the proposed space-based manufacturing and drug-screening (joint federal grants, and exploring joint company formation and dilutive fundraising efforts to launch the project). When funded, two spaceflight missions and therapeutic manufacturing at ISS is planned within 24-36 months. The space-based therapeutic screening can potentially accelerate drug-development for diseases such as neurodegeneration, cardiovascular, and cancer, by leveraging the accelerated disease progression due to microgravity and radiation. Commercialization objective also include translating the molecules developed here as combination therapy for cancer radiotherapy patients, to improve outcomes.

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