Analysis of the Proteomic Profile in Serum of Irradiated Nonhuman Primates Treated with Ex-Rad, a Radiation Medical Countermeasure

Abstract

There are currently four radiation medical countermeasures that have been approved by the United States Food and Drug Administration to mitigate hematopoietic acute radiation syndrome, all of which are repurposed radiomitigators. The evaluation of additional candidate drugs that may also be helpful for use during a radiological/nuclear emergency is ongoing. A chlorobenzyl sulfone derivative (organosulfur compound) known as Ex-Rad, or ON01210, is one such candidate medical countermeasure, being a novel, small-molecule kinase inhibitor that has demonstrated efficacy in the murine model. In this study, nonhuman primates exposed to ionizing radiation were subsequently administered Ex-Rad as two treatment schedules (Ex-Rad I administered 24 and 36 h post-irradiation, and Ex-Rad II administered 48 and 60 h post-irradiation) and the proteomic profiles of serum using a global molecular profiling approach were assessed. We observed that administration of Ex-Rad postirradiation is capable of mitigating radiation-induced perturbations in protein abundance, particularly in restoring protein homeostasis, immune response, and mitigating hematopoietic damage, at least in part after acute exposure. Taken together, restoration of functionally significant pathway perturbations may serve to protect damage to vital organs and provide long-term survival benefits to the afflicted population.

Proteomic Analysis of Plasma at the Preterminal Stage of Rhesus Nonhuman Primates Exposed to a Lethal Total-Body Dose of Gamma-Radiation

“…Extensive research evaluating the changes within proteomic pro les incited by lethal doses of ionizing radiation has been conducted in our laboratory 23 . Serum samples of irradiated NHPs 24,25 , tissue (jejunum) and bio uids (serum)…”

“…The radiation sources utilized in our studies contain high level cobalt-60 gamma radiation and various radiation countermeasures under development including tocopherol succinate 27 , gamma-tocotrienol 26,27 , BIO 300 24 , and Ex-Rad 25 . Tocopherol succinate and gamma-tocotrienol have been evaluated in murine models 26,27 (tocopherol succinate was also investigated using CD 34+ cells in vitro 28 ), while BIO 300 and Ex-Rad have been investigated using NHP models 24,25 . To assess these proteomic changes, methods including NanoUPLC-MS/MS 24,25 , twodimensional differential in-gel electrophoresis (2D-DIGE) 26,27 , and a high throughput antibody microarray platform 28 have been used.…”

“…Tocopherol succinate and gamma-tocotrienol have been evaluated in murine models 26,27 (tocopherol succinate was also investigated using CD 34+ cells in vitro 28 ), while BIO 300 and Ex-Rad have been investigated using NHP models 24,25 . To assess these proteomic changes, methods including NanoUPLC-MS/MS 24,25 , twodimensional differential in-gel electrophoresis (2D-DIGE) 26,27 , and a high throughput antibody microarray platform 28 have been used.…”

Modulation of Hematopoietic Injury by a Promising Radioprotector, Gamma-Tocotrienol, in Rhesus Macaques Exposed to Partial-Body Radiation

“…Blood was collected from NHPs at various time points during the study using either the cephalic or saphenous vein, and CBCs were analyzed with a Bayer Advia-120 cell counter as previously described ( 55 , 56 ).…”

We need irreversible elimination of all stockpiles of nuclear weapons

“…Singh and Seed advocate pharmacological repurposing and a massive stockpiling of agents for managing major radiation exposures from accidents or nuclear attack 2. Candidate drugs such as recilisib sodium (Ex-Rad), which have novel modes of action and may be taken orally, also show promise 3…”