RRC ID 55947
Author Yoshida H, Yamada H, Nogami W, Dohi K, Kurino-Yamada T, Sugiyama K, Takahashi K, Gahara Y, Kitaura M, Hasegawa M, Oshima I, Kuwabara K.
Title Development of a new knock-in mouse model and evaluation of pharmacological activities of lusutrombopag, a novel, nonpeptidyl small-molecule agonist of the human thrombopoietin receptor c-Mpl.
Journal Exp Hematol
Abstract Lusutrombopag (S-888711), an oral small-molecule thrombopoietin receptor (TPOR) agonist, has gained first approval as a drug to treat thrombocytopenia of chronic liver disease in patients undergoing elective invasive procedures in Japan. Preclinical studies were performed to evaluate its efficacy against megakaryopoiesis and thrombopoiesis. To investigate the proliferative activity and efficacy of megakaryocytic colony formation via human TPOR, lusutrombopag was applied to cultured human c-Mpl-expressing Ba/F3 (Ba/F3-hMpl) cells and human bone marrow-derived CD34-positive cells, respectively. Lusutrombopag caused a robust increase in Ba/F3-hMpl cells by activating pathways in a manner similar to that of thrombopoietin and induced colony-forming units-megakaryocyte and polyploid megakaryocytes in human CD34-positive cells. Because lusutrombopag has high species specificity for human TPOR, there was no suitable experimental animal model for drug evaluation, except for immunodeficient mouse-based xenograft models. Therefore, a novel genetically modified knock-in mouse, TPOR-Ki/Shi, was developed by replacing mouse Mpl with human-mouse chimera Mpl. In TPOR-Ki/Shi mice, lusutrombopag significantly increased circulating platelets in a dose-dependent manner during 21-day repeated oral administration. Histopathological study of the TPOR-Ki/Shi mice on day 22 also revealed a significant increase in megakaryocytes in the bone marrow. These results indicate that lusutrombopag acts on human TPOR to upregulate differentiation and proliferation of megakaryocytic cells, leading to platelet production.
Volume 59
Pages 30-39.e2
Published 2018-3-1
DOI 10.1016/j.exphem.2017.12.005
PII S0301-472X(17)30904-9
PMID 29274361
MeSH Animals Blood Platelets / cytology Blood Platelets / metabolism Cell Line Cell Proliferation / drug effects* Cinnamates / pharmacology* Drug Evaluation, Preclinical Gene Knock-In Techniques Humans Megakaryocytes / cytology Megakaryocytes / metabolism* Mice Mice, Transgenic Models, Biological* Receptors, Thrombopoietin / agonists* Receptors, Thrombopoietin / genetics Receptors, Thrombopoietin / metabolism Thiazoles / pharmacology*
IF 2.462
Times Cited 4
Human and Animal Cells Ba/F3(RCB0805)