Thioredoxin derivatives for radiation mitigation

Duke University, Durham NC

Investigators

Abstract

Escalating geopolitical instability, nuclear proliferation, and vulnerability of medical, radiological and nuclear power infrastructure are real and constant threats raising the likelihood of catastrophic radiation exposure. Hematopoietic stem cells (HSCs) and hematopoiesis are among the most sensitive tissues/organs to radiation injury with multiple organ systems also affected. Since incidents are likely to be unanticipated, therapeutic strategies need to be effective even if commenced hours or days post-exposure, and administration routes should be compatible with treatment in the field. Currently, there are very few - if any - agents that can be used to rescue injury from lethal radiation doses after 24 hours. This gap represents a critical unmet need for both public health and the armed forces. The human stress-protectant protein thioredoxin (TRX) has shown exciting potential as a broad-acting radiation protective agent but does not have suitable pharmacological properties for use as a drug. Preliminary rodent and non-human primate (NHP) studies by the applicant with ORP100S, an engineered pharmacologically optimized version of TRX, have demonstrated remarkable radiation survival when ORP100S was administered subcutaneously 24 hours after irradiation. Long-term goal: develop ORP100S into a “deliverable” agent for treatment of lethal radiation-related injury. Overall objectives: further define the efficacy of ORP100S in mitigating radiation-induced injury and determine the molecular mechanisms through which ORP100S regulates and protects HSCs from radiation injury. Central hypothesis: ORP100S has broad, pan-cytoprotective effects on multi-organ systems and can mitigate lethal dose radiation. These hypotheses have been formulated based on data produced in the applicant’s laboratory. The rationale for the proposed research is that, once it is known how ORP100S protects HSCs and its effectiveness is confirmed in both mice and non-human primates, we will be able to move ORP100S forward into clinical use as a new and innovative therapeutic for radiation-related injury. Guided by strong preliminary data, this hypothesis will be tested by pursuing three specific aims: Aim 1: determine the dose modifying factor of ORP100S and ability to rescue hPSC lung organoids from radiation injury. Efficacy of ORP100S in mitigating lethal radiation will be compared with the FDA approved agent (G-CSF) and any synergistic effects will be identified. Aim 2: define the molecular mechanisms through which ORP100S protects HSCs from radiation injury. Effects of ORP100S on the p53-ferroptosis pathway will be defined. Aim 3: determine efficacy, safety, PK, PD, and cytokine profiling of ORP100S in mitigating radiation-induced injury in non-human primates. The approach is innovative, because it focuses on a novel protein that is effective in mitigating toxic effects of radiation when given after 24 hr of radiation exposure. Humanized mouse model and hPSC induced lung organoids will be used and novel molecular pathway will be investigated. The proposed research is significant, because it will bring a new therapeutic agent to the national stockpile for the treatment of radiation injury.