2023 Fiscal Year Final Research Report
Development of novel gene therapy for MELAS by editing mitochondorial DNA
| Project/Area Number |
21K07782
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 52050:Embryonic medicine and pediatrics-related
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| Research Institution | Fujita Health University |
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Principal Investigator |
Hata Ryuji 藤田医科大学, 医学部, 教授 (90258153)
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| Co-Investigator(Kenkyū-buntansha) |
尾身 実 藤田医科大学, 医学部, 講師 (00400416)
八幡 直樹 藤田医科大学, 医学部, 講師 (60450607)
吉川 哲史 藤田医科大学, 医学部, 教授 (80288472)
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| Project Period (FY) |
2021-04-01 – 2024-03-31
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| Keywords | MELAS / iPS細胞 / TALEN / ゲノム編集 |
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| Outline of Final Research Achievements |
We successfully increased or decreased the percentage of mutant mtDNA in MELAS-specific iPS cells by using a novel genome editing method (development of TALEN pairs). In this study, we developed more efficient genome editing methods (TALEN pairs).
Moreover, to induce differentiation of MELAS-iPS cells into skeletal muscle cells, we generated iPS cells incorporating the Tet-On MyoD1 system (MyoD-iPSCs). Then, we examined whether the addition of Dox could induce differentiation into skeletal muscle. The results showed that even a high frequency (>90%) of mutant mtDNA could induce differentiation into skeletal muscle, and revealed a part of the pathological mechanism of MELAS.
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| Free Research Field |
神経科学
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| Academic Significance and Societal Importance of the Research Achievements |
MELAS の原因遺伝子変異の一つである G13513A 変異を標的とした新規のTALEN pairs の開発を行った。その結果MELAS特異的iPS細胞でのmtDNAのcopy数は減らさず、変異mtDNAの割合を、効率よく減らせる新規のTALEN pairsの開発に成功した。この結果はMELASに対する遺伝子治療の可能性を示す基礎的なデータと考えられる。またiPS細胞から骨格筋細胞分化の過程で、変異mtDNAを高頻度(90%以上)持っていても骨格筋への分化誘導が可能であることが明らかとなり、MELASの病態機構の一部が明らかとなった。
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