Mitigation of total body irradiation-induced mortality and hematopoietic injury of mice by a thrombopoietin mimetic (JNJ-26366821).

Abstract

The threat of a nuclear attack has increased in recent years highlighting the benefit of developing additional therapies for the treatment of victims suffering from Acute Radiation Syndrome (ARS). In this work, we evaluated the impact of a PEGylated thrombopoietin mimetic peptide, JNJ-26366821, on the mortality and hematopoietic effects associated with ARS in mice exposed to lethal doses of total body irradiation (TBI). JNJ-26366821 was efficacious as a mitigator of mortality and thrombocytopenia associated with ARS in both CD2F1 and C57BL/6 mice exposed to TBI from a cobalt-60 gamma-ray source. Single administration of doses ranging from 0.3 to 1 mg/kg, given 4, 8, 12 or 24 h post-TBI (LD70 dose) increased survival by 30-90% as compared to saline control treatment. At the conclusion of the 30-day study, significant increases in bone marrow colony forming units and megakaryocytes were observed in animals administered JNJ-26366821 compared to those administered saline. In addition, enhanced recovery of FLT3-L levels was observed in JNJ-26366821-treated animals. Probit analysis of survival in the JNJ-26366821- and saline-treated cohorts revealed a dose reduction factor of 1.113 and significant increases in survival for up to 6 months following irradiation. These results support the potential use of JNJ-26366821 as a medical countermeasure for treatment of acute TBI exposure in case of a radiological/nuclear event when administered from 4 to 24 h post-TBI.

• Authors: Vidya P Kumar, Gregory P Holmes-Hampton, Shukla Biswas, Sasha Stone, Neel Kamal Sharma, Bernadette Hritzo, Mary Guilfoyle, Gary Eichenbaum, Chandan Guha, Sanchita P Ghosh
• Journal: Scientific reports (Sci Rep) Vol. 12 Issue 1 Pg. 3485 (03 03 2022) ISSN: 2045-2322 [Electronic] England
• PMID: 35241733 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: © 2022. The Author(s).

Chemical References

• Thrombopoietin

Topics

• Acute Radiation Syndrome (drug therapy, pathology)
• Animals
• Biomimetic Materials (pharmacology)
• Hematopoietic System (pathology, radiation effects)
• Mice
• Mice, Inbred C57BL
• Radiation Injuries, Experimental (drug therapy, pathology)
• Thrombopoietin (pharmacology)
• Whole-Body Irradiation