Elucidation of pathogenesis of paroxysmal nocturnal hemoglobinuria (PNH) : Strategy to develop a novel therapy

2020 Fiscal Year Final Research Report

• Project/Area Number: 19K16606
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 49030:Experimental pathology-related
• Research Institution: The University of Tokyo
• Principal Investigator: Liao Jiyuan 東京大学, 定量生命科学研究所, 特任研究員 (90781857)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Keywords: PNH / ゲノム編集 / PIG-A / 造血幹細胞

Outline of Final Research Achievements

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal hematopoietic stem cell (HSC) disorder and characterized by complement-induced hemolysis. The cause of bone marrow failure remains unclear, which makes difficult to develop radical therapies. Therefore, we aimed to elucidate the pathogenesis of PNH using PNH patient-derived induced pluripotent stem cells (PNH-iPSCs).
PNH-iPSC-derived hematopoietic stem cells (HSCs) with PIG-A gene mutation showed highly impaired proliferation and differentiation potential compared to HSCs differentiated from PIG-A gene normal iPSCs (N-iPSC) established from the same patients. Unexpectedly, the reduced proliferation and differentiation ability was not fully recovered by correction of the mutated PIG-A gene, which suggest that additional genetic abnormality causes the hematopoietic disorder. We conduct genetic analyses to identify the causative abnormal genes.

Free Research Field

再生医療学

Academic Significance and Societal Importance of the Research Achievements

PNHにおける造血障害は、本邦を含むアジア各国で合併する事が極めて多いため、病因の特定と治療法開発は重要な課題である。本研究では、PNH造血障害におけるPIG-A変異の関与について、世界で初めて樹立したPNH-iPSCおよび同一患者由来N-iPSCを用いて検討を行ったが、PIG-A変異以外に内因性の病因(遺伝子異常等)が存在することを直接証明できた点で学術的意義が大きい。また、本研究成果は、PNH造血障害の病因遺伝子異常同定を進めるための重要な基礎であり、将来、造血障害発症予防法や治療法最適化法、さらに根治療法の開発に繋がることが期待される社会的意義の大きいものである。