Development of a Novel Factor VIII Formulation Targeting Prevention of Inhibitor Development in Hemophilia A Therapy

Research Project

Project/Area Number	19K17373
Research Category	Grant-in-Aid for Early-Career Scientists
Allocation Type	Multi-year Fund
Review Section	Basic Section 52050:Embryonic medicine and pediatrics-related
Research Institution	Nara Medical University
Principal Investigator	FURUKAWA Shoko 奈良県立医科大学, 医学部, 助教 (60596667)
Project Period (FY)	2019-04-01 – 2023-03-31
Project Status	Completed (Fiscal Year 2022)
Budget Amount *help	¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000) Fiscal Year 2022: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000) Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000) Fiscal Year 2020: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000) Fiscal Year 2019: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Keywords	血友病A / インヒビター / 遺伝子解析 / 第VIII因子製剤
Outline of Research at the Start	本研究は軽症・中等症血友病A患者様を対象として凝血学的および分子細胞免疫学的に解析を行うことによって、血友病診療における最も重要な課題であるインヒビター発生のメカニズムを解明し、インヒビターの発生率を抑制した新しい第VIII因子の創出やインヒビターを消失させる治療法の開発を目指す研究です。
Outline of Final Research Achievements	The purpose of this study was to obtain basic data to elucidate the mechanism of inhibitor development through hematological and molecular cellular immunological analysis of mild/moderate hemophilia A patients with inhibitors. We had experience with seven cases by the beginning of the study period, and one new case occurred during the study period and could be analyzed. The point mutation in this case was E272K, and the one of 7 previous cases had the same mutation, suggesting that it may be a risk for the development of inhibitors. We also generated a mouse model of mild hemophilia A by knock-in of the P1777L mutation, which is highly homologous to P1809L in one of our own cases, and established the inhibitor generation and analysis model.
Academic Significance and Societal Importance of the Research Achievements	本研究で解析できた新規症例では、過去にもインヒビター発生例のあった遺伝子変異が同定され、遺伝子変異がインヒビター発生リスクのひとつであるという過去の報告を支持する結果となった。また希少疾患である血友病A患者のうち軽症・中等症でインヒビターが発生する症例は少ないため、これまで十分な解析が不可能であったが、本研究で軽症血友病Aモデルマウスを作製しインヒビター解析系を確立できたことは、今後のインヒビター関連の解析に大いに役立つと考えられる。