Pacemaker activity generated by in vivo genome editing

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K19393
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Cardiovascular medicine
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: IHARA Kensuke 東京医科歯科大学, 難治疾患研究所, 助教 (50770210)
• Research Collaborator: FURUKAWA tetsushi ; KUROKAWA junko ; SASANO tetsuo
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: 生物学的ペースメーカ / ゲノム編集

Outline of Final Research Achievements

The current main therapy for bradycardia is electrical pacemaker implantation which has many problems due to its surgical procedure and device cost. To overcome them, one of the previously explored alternative therapy was biological pacemaker, however, its effect was transient so far. The purpose of this study is to generate permanently functional biological pacemaker utilizing genome editing tool CRISPR/Cas9, with which permanent effect can be expected.
We constructed CRISPR/Cas9 for Kcnj2 gene, of which gene knockout cause pacemaker activity, and injected it into the mouse heart muscle directly. CRISPR-injected hearts showed edited genome and pacemaker activity 1 month after injection. However, 6 months after injection, although genome editing was maintained, no pacemaker activity was observed. Finally, CRISPR/Cas9 for Kcnj2 can generate pacemaker activity in vivo, however, there are still hurdles to overcome for long term maintenance of pacemaker activity with this approach.

Free Research Field

循環器内科学、心臓電気生理学

Academic Significance and Societal Importance of the Research Achievements

生体内の心筋細胞においてCRISPR/Cas9を導入しゲノム編集を行うことで、非ペースメーカ細胞でもペースメーカ活動を誘導できることを初めて示した研究である。
高齢化社会において、徐脈性不整脈に対する機械的ペースメーカ治療は植え込み件数・交換件数ともに増え続け、その合併症リスク・デバイスコストに対する対応は社会的に急務である。その解決策として機械式ペースメーカの改良だけでなく、全く違う治療アプローチの可能性を提示することができた。