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Validation of Gene Therapy for Mutant Mitochondria by Delivering Mitochondrial RNA Using a MITO-Porter

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Title: Validation of Gene Therapy for Mutant Mitochondria by Delivering Mitochondrial RNA Using a MITO-Porter
Authors: Kawamura, Eriko Browse this author
Maruyama, Minako Browse this author
Abe, Jiro Browse this author
Sudo, Akira Browse this author
Takeda, Atsuhito Browse this author
Takada, Shingo Browse this author
Yokota, Takashi Browse this author
Kinugawa, Shintaro Browse this author
Harashima, Hideyoshi Browse this author →KAKEN DB
Yamada, Yuma Browse this author →KAKEN DB
Keywords: mitochondrial delivery
nucleic acids medicine
mitochondrial gene therapy
heteroplasmic mutation
Issue Date: 5-Jun-2020
Publisher: Cell Press
Journal Title: Molecular therapy. Nucleic acids
Volume: 20
Start Page: 687
End Page: 698
Publisher DOI: 10.1016/j.omtn.2020.04.004
Abstract: Here, we report on validating a mitochondrial gene therapy by delivering nucleic acids to mitochondria of diseased cells by a MITO-Porter, a liposome-based carrier for mitochondrial delivery. We used cells derived from a patient with a mitochondrial disease with a G625A heteroplasmic mutation in the tRNA(Phe) of the mitochondrial DNA (mtDNA). It has been reported that some mitochondrial gene diseases are caused by heteroplasmic mutations, in which both mutated and wildtype (WT) genes are present, and the accumulation of pathological mutations leads to serious, intractable, multi-organ diseases. Therefore, the decrease of the mutated gene rate is considered to be a useful gene therapy strategy. To accomplish this, wild-type mitochondrial pre-tRNA(Phe) (pre-WT-tRNA(Phe)), prepared by in vitro transcription, was encapsulated in the MITO-Porter. The pre-WT-tRNA(Phe) encapsulated in the MITO-Porter was transfected into diseased mitochondrial cells, and the resulting mutant levels were examined by an amplification refractory mutation system (ARMS)-quantitative PCR. The mutation rate of tRNA(Phe) was decreased, and this therapeutic effect was sustained even on the 8th day after transfection. Furthermore, mitochondrial respiratory activity of the disease cells was increased after the transfection of therapeutic pre-WT-tRNA(Phe). These results support the conclusion that the mitochondrial delivery of therapeutic nucleic acids represents a viable strategy for mitochondrial gene therapy.
Type: article
Appears in Collections:薬学研究院 (Faculty of Pharmaceutical Sciences) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

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