Investigation of cell transplantation therapy of iPS cell-derived hepatocytes in familial hypercholesterolemia

2022 Fiscal Year Final Research Report

• Project/Area Number: 19K17552
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53020:Cardiology-related
• Research Institution: Kanazawa University
• Principal Investigator: Okada Hirofumi 金沢大学, 医学系, 協力研究員 (10735161)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Keywords: 家族性高コレステロール血症

Outline of Final Research Achievements

We have performed the following studies with the aim of utilizing iPS cells (iPSCs) as a cell source for cell transplantation. Genome editing was performed on iPSCs derived from the patient with homozygous familial hypercholesterolemia (HoFH) to generate iPSCs with normal LDL receptor (LDLR) gene sequences. Differentiation induction of hepatocyte-like functional cells was confirmed by gene expression analysis and flow cytometry analysis, and functional analysis of the cells was performed. Functional cells derived from genetically corrected iPSCs showed improved LDL uptake ability. Immune responses were confirmed by co-culturing patient peripheral blood mononuclear cells with genetically corrected iPSCs and functional cells. These results indicate that LDL uptake of HoFH-derived iPSC-derived HLCs can be restored by genetic correction without further immunogenicity gain, suggesting that gene-corrected iPSC-derived HLCs can be applied to treat HoFH.

Free Research Field

循環器内科学

Academic Significance and Societal Importance of the Research Achievements

ホモ接合体性FH患者では、診断後早期より積極的な介入を必要とし、終生LDLアフェレーシスによる治療を必要とするものも少なくない。根治的な治療はなく永続的に必要とすることから、患者の身体的負担、医療費等を考慮すると、移植治療が可能となった場合の、社会的および学術的な影響は大きいものと思われる。加えて、ホモFHに対する、他の機序による新薬の開発を想定した場合においても、疾患特異的iPS細胞由来肝細胞を用いて疾患モデルを構築することは、ヒト個体での薬効と安全性をより精度高く予測する基盤技術として重要な役割を持つものと考える。