Modeling Inherited Arrhythmia Disorders Using Patient-Derived Induced Pluripotent Stem Cells

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K09499
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Cardiovascular medicine
• Research Institution: Kyoto University
• Principal Investigator: Makiyama Takeru 京都大学, 医学研究科, 助教 (30528302)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: 不整脈 / iPS細胞 / 遺伝子 / 突然死

Outline of Final Research Achievements

In this study, we performed clinical and basic researches based on the hereditary arrhythmia genome database to elucidate the genetic background of the familial arrhythmia disease (fatal inherited arrhythmia disorders).
As main results, the truncation mutation carriers exhibited earlier development of cardiac disorders in comparison with missense mutation carriers in lamin A/C-related cardiomyopathy.
In addition, we established iPS cell model of long-QT syndrome (LQT) type 1, calmodulin-related LQT (LQT15), and cardiac Na channelopathy. Using these models, we revealed the disease causing mechanisms and developed a novel gene therapy by mutant allele-specific knockout using the latest genome editing technology in LQT 15. Furthermore, we demonstrated the effectiveness of novel compounds in LQT1 iPS cell model which provides a new insight into tailor-made pharmacotherapy.

Free Research Field

循環器内科学

Academic Significance and Societal Importance of the Research Achievements

致死性遺伝性不整脈疾患は、明らかな基礎疾患がないにも関わらず心室細動を来たし突然死に至ることがあり、根本的な治療法は確立されておらず、社会的インパクトも大きい。ラミンA/C遺伝子関連心筋症に関しては、本研究にて得られた知見により、早期発症リスク患者に対する早期治療介入を考慮する重要な知見と考える。また、疾患特異的iPS細胞研究では、LQT15において最新のゲノム編集技術を用いた新規遺伝子治療法を提示し、学術的インパクトは大きいと考える。LQTに対する新規治療候補化合物の検討も行っており、遺伝型に応じた新規テーラーメード治療が開発されたあかつきには、診療、患者の生命予後改善に寄与できると考える。