AR - Preventing immune system dysregulation during deep-space missions by Tocoflexol, a modified isomer of vitamin E

Background and Justification: At the inception of the Human Research Program in 2005, NASA identified immune dysregulation as a potential danger during long-term deep-space missions to the Moon and Mars (1-3 years beyond Earth’s magnetic field). Chronic irradiation (CIR, uninterrupted exposure to low-dose and low-dose–rate radiation) and microgravity (continuous experience of weightlessness) are 2 major space hazards that can induce immune dysregulation. Both of these enhance oxidative stress by increasing the generation of highly toxic reactive oxygen species (ROS), which can damage immune cells and result in inflammation. The compromised immune response may produce detrimental health effects for astronauts, impacting their quality of life as they age; such effects include increased risks for cancer, autoimmune conditions, cardiovascular disease, and cognitive dysfunction.

We and others showed that tocotrienols—a subgroup of vitamin E—are potent ROS scavengers and provide strong radio-protection with little to no serious side effects. Tocotrienols are also cardio-protective and have anti-cancer and anti-inflammatory properties. Unfortunately, tocotrienols have low bioavailability. Therefore, synthesizing a modified isomer of tocotrienol with greater bioavailability could be a valuable resource for protecting the immune system during and after deep-space missions. Better immune protection would reduce the risk of viral infection, inflammation, and genomic instability, which are the major risks of human space missions.

Approach and Novelty: We developed a ground-based facility at the University of Arkansas for Medical Sciences (UAMS) that is capable of exposing mice under simulated microgavity (SMG) to CIR concurrently. Very few similar facilities are operational in the US, and this is the first and only in Arkansas. In addition, we have successfully synthesized Tocoflexol, a modified form of tocotrienol with higher bioavailability, and plan to test its efficacy in reducing spacefactor-induced immune dysregulation compared to the parent group of tocotrienols. Tocoflexol was developed by the Arkansas-based company Tocol Pharmaceuticals, LLC, in collaboration with UAMS and the University of Arkansas at Little Rock. We hypothesize that CIR and SMG will cause immune system dysfunction, and treatment with Tocoflexol will provide immune protection.

Objective 1: Characterize immune dysregulation after exposure to SMG or CIR alone and in combination. Mice will be exposed to SMG and/or CIR for 30 days at the approximate dose-rate encountered in space. To assess acute effects, tissues will be harvested on day 30 (day 30=completion of exposure). To assess late effects, tissues will be harvested on day 90 (60 days after exposure). Immune dysregulation will be assessed as the change in the ratios of various immune cells and their functional activity in primary (bone marrow and thymus) and secondary (spleen and gut-associated lymphoid organ [GALT]) lymphoid organs.

Objective 2: Determine the efficacy of Tocoflexol in mitigating immune dysregulation after coexposure to SMG and CIR. Mice treated with either Tocoflexol or the parent compounds (3 times/week subcutaneously) will be exposed concurrently to SMG and CIR for 30 days. Immune dysregulation will be assessed in various primary and secondary lymphoid organs as in Aim 1 on day 30. Additionally, the efficacy Tocoflexol in reducing viral infection, inflammation, and genomic instability will be determined in mice subjected to 30 days coexposure. Opportunities for Collaboration: Our chronic irradiation facility will be made available to other research groups in Arkansas from academic or industrial areas to strengthen collaborations and optimize discoveries related to the adaptive and pathogenic mechanisms of deep-space travel. Such collaboration will allow us to explore potential therapeutics to improve the health outcome of astronauts engaged in space exploration.

This is a mature technology (TRL 7+) — the realistic path in is usually NASA's Technology Transfer Program: licensing an existing NASA patent, or a Space Act Agreement to use NASA facilities/expertise directly. NASA also runs a startup licensing program with no upfront fee for companies formed to commercialize a specific NASA technology.

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