Exploring therapeutic candidate compounds for LMNA-mutant dilated cardiomyopathy

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K16082
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53020:Cardiology-related
• Research Institution: The University of Tokyo
• Principal Investigator: Ito Maamichi 東京大学, 医学部附属病院, 特任助教 (70794642)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 拡張型心筋症 / 化合物スクリーニング / LMNA変異 / iPS創薬 / iPS細胞由来心筋細胞

Outline of Final Research Achievements

Dilated cardiomyopathy (DCM) with LMNA mutation is known to be associated with a progressive course and poor prognosis, but no specifc treatments are available. We aimed to identify novel candidate compounds for the treatment of LMNA-mutant DCM by using iPS cell-derived cardiomyocytes established from patients with LMNA p.Q353R mutantation, searching for compounds that reduce DNA damage accumulation in cardiomyocytes.
As a result of screening, vitamin D2 (VD) was found to be effective in reducing DNA damage in the LMNA mutant cardiomyocytes. Gene expression analysis revealed that VD upregulated the expression of several DNA repair enzymes in cardiomyocytes. In addition, LMNA Q353R mutant protein was found to repress the transcriptional activity of VD by binding to its receptor, VDR. Our findings provide a new seed for treatment of LMNA-mutatant cardiomyopathy.

Free Research Field

循環器内科学

Academic Significance and Societal Importance of the Research Achievements

本研究によって難病である特発性拡張型心筋症の新たな治療薬候補を提示することができた。同定されたvitamin Dは安全性が確立されている既存薬であり、drug repositionを目指した臨床試験のシーズとなる可能性がある。
また本研究の手法は心筋症のヒト変異iPS細胞由来心筋細胞を用いたスクリーニングの成功例として他変異の心筋症や疾患に応用できる可能性があり、個別化医療およびiPS創薬の１成功例として資するものである。