Generation of humanized rats expressing drug-metabolizing enzyme using human artificial chromosome and genome editing technologies

2019 Fiscal Year Final Research Report

• Project/Area Number: 15H04285
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Laboratory animal science
• Research Institution: Tottori University
• Principal Investigator: KAZUKI Yasuhiro 鳥取大学, 医学(系)研究科(研究院), 准教授 (90403401)
• Co-Investigator(Kenkyū-buntansha): 平林 真澄 生理学研究所, 行動・代謝分子解析センター, 准教授 (20353435)
• Project Period (FY): 2015-04-01 – 2020-03-31
• Keywords: リサーチバイオリソース / ヒト化モデル動物

Outline of Final Research Achievements

Humanized animals, in which drug metabolism-related genes of experimental animals are replaced into those of humans, are considered to play a major role in predicting human-specific drug metabolism and safety. In this study, we aimed to generate humanized animals using rats that can collect blood over time and have abundant background data such as toxicity tests among experimental animals. Specifically, following studies were performed. 1) CYP3A gene cluster and UGT2 gene cluster, which are related in human-specific drug metabolism, were introduced into rats using mouse artificial chromosome technology. 2) The rat gene cluster corresponding to the above human cluster was desrupted using the genome editing technique. 3) By mating 1) and 2), a fully humanized model rats showing human-specific metabolic ability were successfully generated.

Free Research Field

染色体工学

Academic Significance and Societal Importance of the Research Achievements

本研究で開発したヒト薬物代謝関連遺伝子をヒト化したモデルラットはこれまでに開発されたヒト化マウスの特徴と、マウスにはないラットの特徴（経時採血が容易、背景データが豊富など）の両方の特徴を兼ね備えており、これまでのヒト化マウスよりも、ヒトの薬物代謝や毒性を予測するために有用なモデルになると考えられる。また、本研究開発によって、ヒトに対する安全性予測が向上すると共に、医薬品開発のスピードアップと成功確率が向上し、新薬開発の低コスト化、ひいては国民医療負担を減らすことにつながるインパクトを与え、ライフ・イノベーションの推進に大きく貢献できるものと考える。