Gene therapy for mitochondrial disease by delivering restriction endonucleaseSmaI into mitochondria

Tanaka, Masashi; Borgeld, Harm-Jan; Zhang, Jin; Muramatsu, Shin‐ichi; Gong, Jian; Yoneda, Makoto; Maruyama, Wakako; Naoi, Makoto; Ibi, Tohru; Sahashi, Ko; Shamoto, Masayo; Fuku, Noriyuki; Kurata, Miyuki; Yamada, Yoshiji; Nishizawa, Kumi; Akao, Yukihiro; Ohishi, Nobuko; Miyabayashi, Shigeaki; Umemoto, Hiraku; Muramatsu, T.; Furukawa, Koichi; Kikuchi, Akihiko; Nakano, Imaharu; Ozawa, Keiya; Yagi, Kazuichi

doi:10.1007/bf02254980

Cited by 47 publications

(32 citation statements)

References 23 publications

(11 reference statements)

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“…The number of nucleoids decreased with ApaLI induction but recovered along with the mtDNA levels. These observations are similar to those reported by Tanaka et al (9), who showed a reduction in mtDNA copy number upon expression of SmaI or EcoRI in mitochondria of cultured cells (9). Taken together, our results indicate that the shift in mtDNA heteroplasmy by mitochondrially targeted restriction endonucleases is rapid and specific.…”

Section: Discussionsupporting

confidence: 93%

“…Tanaka et al (9) showed that cultured cells with the T8399G mutation underwent a shift in heteroplasmy when a mitochondrially targeted SmaI was expressed. However, it took five cycles of transfection to completely eliminate the mutated mtDNA.…”

Section: Discussionmentioning

confidence: 99%

“…In a similar study, targeting the restriction endonuclease SmaI to mitochondria of cultured cells harboring the T8399G NARP mutation prompted specific elimination of mutated mtDNA, followed by repopulation by the wild-type mtDNA. This resulted in restoration of normal intracellular ATP level and mitochondrial membrane potential (9).…”

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confidence: 99%

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Rapid directional shift of mitochondrial DNA heteroplasmy in animal tissues by a mitochondrially targeted restriction endonuclease

Bayona‐Bafaluy

Blits

Battersby

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

144

122

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Frequently, mtDNA with pathogenic mutations coexist with wildtype genomes (mtDNA heteroplasmy). Mitochondrial dysfunction and disease ensue only when the proportion of mutated mtDNAs is high, thus a reduction in this proportion should provide an effective therapy for these disorders. We developed a system to decrease specific mtDNA haplotypes by expressing a mitochondrially targeted restriction endonuclease, ApaLI, in cells of heteroplasmic mice. These mice have two mtDNA haplotypes, of which only one contains an ApaLI site. After transfection of cultured hepatocytes with mitochondrially targeted ApaLI, we found a rapid, directional, and complete shift in mtDNA heteroplasmy (2-6 h). We tested the efficacy of this approach in vivo, by using recombinant viral vectors expressing the mitochondrially targeted ApaLI. We observed a significant shift in mtDNA heteroplasmy in muscle and brain transduced with recombinant viruses. This strategy could prevent disease onset or reverse clinical symptoms in patients harboring certain heteroplasmic pathogenic mutations in mtDNA.gene therapy ͉ mitochondria

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

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Rapid directional shift of mitochondrial DNA heteroplasmy in animal tissues by a mitochondrially targeted restriction endonuclease

Bayona‐Bafaluy

Blits

Battersby

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

144

122

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“…In a basic study of mitochondrial delivery using MTS, pDNA encoding an MTS-fused protein was used to transfect cultured cells. The MTS directs the cargo protein inside the mitochondria, where it is then cleaved, allowing for localization and function of the fused protein [146][147][148] (Fig. 6).…”

Section: Mitochondrial Protein Delivery Using the Mitochondrial Tamentioning

confidence: 99%

Mitochondrial drug delivery systems for macromolecule and their therapeutic application to mitochondrial diseases

Yamada

Harashima

2008

Advanced Drug Delivery Reviews

225

148

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Key words: Mitochondria, mitochondrial drug delivery, mitochondrial macromolecule delivery, MITO-Porter, membrane fusion, multifunctional envelope-type nano device (MEND), mitochondrial protein therapy, mitochondrial gene therapy, mitochondrial protein import machinery, mitochondrial DNA. Yamada, Y., et al. AbstractMitochondrial dysfunction has been implicated in a variety of human disorders-the so-called mitochondrial diseases. Therefore, the organelle is a promising therapeutic drug target. In this review, we describe the key role of mitochondria in living cells, a number of mitochondrial drug delivery systems and mitochondria-targeted therapeutic strategies. In particular, we discuss mitochondrial delivery of macromolecules, such as proteins and nucleic acids. The discussion of protein delivery is limited primarily to the mitochondrial import machinery. In the section on mitochondrial gene delivery and therapy, we discuss mitochondrial diseases caused by mutations in mitochondrial DNA, several gene delivery strategies and approaches to mitochondrial gene therapy. This review also summarizes our current efforts regarding liposome-based delivery system including use of a multifunctional envelope-type nano device (MEND) and mitochondrial liposome-based delivery as anti-cancer therapies. Furthermore, we introduce the novel MITO-Porter-a liposome-based mitochondrial delivery system that functions using a membrane-fusion mechanism.Yamada, Y., et al. 3

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“…On the other hand, oligo DNA (linear DNA), as a therapeutic agent for muted mtDNA, was investigated, in order to repair mutated mtDNA and inhibit the replication of mutated mtDNA [34,35]. Moreover, the use of a restriction enzyme (protein) would be expected to be useful and productive for the selective digestion of mutated mtDNA [36]. We conclude that the flexibility associated with the design of such a MEND will meet the requirements for drug delivery systems for mitochondrial gene therapy and diagnosis.…”

Section: Discussionmentioning

confidence: 99%

Delivery of bioactive molecules to the mitochondrial genome using a membrane-fusing, liposome-based carrier, DF-MITO-Porter

Yamada

Harashima

2012

Biomaterials

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Mitochondrial dysfunction has been implicated in a variety of human diseases. It is now well accepted that mutations and defects in the mitochondrial genome form the basis of these diseases. Therefore, mitochondrial gene therapy and diagnosis would be expected to have great medical benefits. To achieve such an innovative a strategy, it will be necessary to deliver therapeutic agents into mitochondria in living cells. We report here on a novel an approach to accomplish this via the use of a Dual Function (DF)-MITO-Porter, aimed at the mitochondrial genome, so-called mitochondrial DNA (mtDNA). The DF-MITO-Porter, an innovative a nano carrier for mitochondrial delivery, has the ability to penetrate the endosomal and mitochondrial membranes via step-wise membrane fusion. We first constructed a DF-MITO-Porter encapsulating DNase I protein as a bioactive cargo. It was expected that mtDNA would be digested, when the DNase I was delivered to the mitochondria.We observed the intracellular trafficking of the carriers, and then measured mitochondrial activity and mtDNA-levels after the delivery of DNase I by the DF-MITO-Porter. The findings confirm that the DF-MITO-Porter effectively delivered the DNase I into the mitochondria, and provides a demonstration of its potential use in therapies that are selective for the mitochondrial genome. 3

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Gene therapy for mitochondrial disease by delivering restriction endonucleaseSmaI into mitochondria

Cited by 47 publications

References 23 publications

Rapid directional shift of mitochondrial DNA heteroplasmy in animal tissues by a mitochondrially targeted restriction endonuclease

Rapid directional shift of mitochondrial DNA heteroplasmy in animal tissues by a mitochondrially targeted restriction endonuclease

Mitochondrial drug delivery systems for macromolecule and their therapeutic application to mitochondrial diseases

Delivery of bioactive molecules to the mitochondrial genome using a membrane-fusing, liposome-based carrier, DF-MITO-Porter

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