Investigation of pathology and therapeutic approaches targeting ADH5/ALDH2 in iPSC models of Bone Marrow Failure Syndrome

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K15362
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 48040:Medical biochemistry-related
• Research Institution: Kyoto University
• Principal Investigator: MU A 京都大学, 生命科学研究科, 助教 (20894455)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: Fanconi anemia / ADDS / ADH5 / ALDH2 / UBE2T

Outline of Final Research Achievements

A research paper was published as the lead and corresponding author that analyzed the pathology of Fanconi Anemia (FA) and Aldehyde Dehydrogenase Deficiency Syndrome (ADDS) using zebrafish disease models. The study revealed that zebrafish models of FA with overexpressed ADH5 exhibited phenotypic improvements. Based on these findings, the potential for developing activators of ADH5 was proposed. Additionally, the utility of hematopoietic differentiation in iPSC models of ADDS and FA was demonstrated using inhibitors of histone demethylases and scavengers of formaldehyde. Furthermore, the paper explored the potential for gene therapy through genome editing techniques in iPSC models of FA and ADDS.

Free Research Field

ゲノム損傷応答学

Academic Significance and Societal Importance of the Research Achievements

ヒトiPS細胞モデルによって、Fanconi anemia（FA）及びAldehyde Dehydrogenase Deficiency Syndrome（ADDS）両疾患の発症メカニズムの解明およびホルムアルデヒド蓄積をターゲットとした治療法開発を目指した。ADD症候群やFAにおいて、ホルムアルデヒド蓄積を改善することにより、重篤な表現型をリバースし、造血不全の回復を示した。本研究は、造血幹細胞におけるホルムアルデヒド代謝の意義について重要な知見をあたえるものである。