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Eliminate mitochondrial diseases by gene editing in germ-line cells and embryos.

Wang S, Yi F, Qu J - Protein Cell (2015)

Bottom Line: Nuclease-based gene editing technologies have opened up opportunities for correcting human genetic diseases.For the first time, scientists achieved targeted gene editing of mitochondrial DNA in mouse oocytes fused with patient cells.This fascinating progression may encourage the development of novel therapy for human maternally inherent mitochondrial diseases.

View Article: PubMed Central - PubMed

Affiliation: National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.

ABSTRACT
Nuclease-based gene editing technologies have opened up opportunities for correcting human genetic diseases. For the first time, scientists achieved targeted gene editing of mitochondrial DNA in mouse oocytes fused with patient cells. This fascinating progression may encourage the development of novel therapy for human maternally inherent mitochondrial diseases.

No MeSH data available.


Related in: MedlinePlus

A schematic representation of genetic approaches used for preventing mitochondrial DNA-based disease transmission in mammalian germ-line cells. (A) The traditional mitochondrial replacement therapy is performed by transferring the patient nuclear DNA to the enucleated donor oocyte containing normal mtDNAs, or transferring the pronuclei from patient zygote to the enucleated healthy zygote of a third individual. (B) According to the newly developed approach, the mutant mtDNAs in the oocyte or zygote are selectively eliminated by mitochondrion-locating TALENs
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Fig1: A schematic representation of genetic approaches used for preventing mitochondrial DNA-based disease transmission in mammalian germ-line cells. (A) The traditional mitochondrial replacement therapy is performed by transferring the patient nuclear DNA to the enucleated donor oocyte containing normal mtDNAs, or transferring the pronuclei from patient zygote to the enucleated healthy zygote of a third individual. (B) According to the newly developed approach, the mutant mtDNAs in the oocyte or zygote are selectively eliminated by mitochondrion-locating TALENs

Mentions: Dysfunction of mitochondria, the energy-producing organelle of eukaryotic cells, may lead to mitochondrial diseases with severe symptoms in many organs, such as Leber hereditary optic neuropathy (LHON), mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS), myoclonic epilepsy and ragged-red fibres (MERRF), etc. Some mitochondrial diseases arise from disorders of nuclear genes which are involved in mitochondrial metabolism as well as in the maintenance of mitochondrial DNA (mtDNA). It has been found that a number of mitochondrial diseases are caused by mutations in mtDNA, a multi-copy, circular dsDNA molecule which encodes 13 essential polypeptides of the mitochondrial respiratory chain as well as the necessary RNA machinery (2 rRNAs and 22 tRNAs) for mitochondrial protein translation (Taylor and Turnbull, 2005; Xu et al., 2013). Since mtDNA is exclusively transmitted through maternal inheritance, a traditional approach of therapy is to transfer the nuclear genomic DNA to a enucleated donor oocyte or zygote with the normal mtDNA (Paull et al., 2013; Tachibana et al., 2013; Wang et al., 2014). This approach involves the mtDNA from a third individual thereby may trigger both ethical and technical conflicts. The most recent report by Reddy et al., for the first time, has prevented the germ-line transmission of mitochondrial disease by selectively eliminating the mutant mtDNA in situ in oocytes and one-cell embryos (Reddy et al., 2015). Using mitochondria targeted restriction endonucleases, the authors first tested their system by selectively eliminating the mtDNA haplotype in mouse oocytes and one-cell embryos. Cheerfully, the progenies from the modified embryos were verified to be free of the mtDNA haplotype which was supposed to be selectively cut and degraded. After the successful manipulation in mouse oocytes and embryos, the authors subsequently succeeded in specifically reducing the mutant mtDNAs responsible for LHOND and NARP (neurogenic muscle weakness, ataxia, and retinitis pigmentosa) by applying mitochondria-targeted TALENs in artificial mammalian oocytes, which were derived by fusion of patient cells with mouse oocytes. The highly efficient targeting mutant mtDNA in both animal model and human cells demonstrated in this study is cheerful. As being widely commented in the field, this report may fundamentally shape the future development of mitochondrial disease therapies. It is exciting to imagine that in the future by applying this technology in human, healthy babies will be able to born from patient oocytes where most mutant mtDNA are cleaned and the copy number of residual mutant mtDNA is reduced to below the threshold needed for a disease manifestation. Compared with other mitochondrial replacement therapies currently under development, this new technology no longer requires donor oocytes from an independent individual, and is a less complex procedure which would be less traumatic to the oocytes. Despite all potential advantages discussed, the authors also warned a risk that the embryos might fail to implant in uterus when mtDNA copy number in the “edited” embryos was below a specific threshold. Nevertheless, it was the first time that gene editing of mtDNAs in germ-line cells is achieved, which may encourage and promote the future studies towards new therapies for maternally inherited mitochondrial diseases (Fig. 1).Figure 1


Eliminate mitochondrial diseases by gene editing in germ-line cells and embryos.

Wang S, Yi F, Qu J - Protein Cell (2015)

A schematic representation of genetic approaches used for preventing mitochondrial DNA-based disease transmission in mammalian germ-line cells. (A) The traditional mitochondrial replacement therapy is performed by transferring the patient nuclear DNA to the enucleated donor oocyte containing normal mtDNAs, or transferring the pronuclei from patient zygote to the enucleated healthy zygote of a third individual. (B) According to the newly developed approach, the mutant mtDNAs in the oocyte or zygote are selectively eliminated by mitochondrion-locating TALENs
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4491053&req=5

Fig1: A schematic representation of genetic approaches used for preventing mitochondrial DNA-based disease transmission in mammalian germ-line cells. (A) The traditional mitochondrial replacement therapy is performed by transferring the patient nuclear DNA to the enucleated donor oocyte containing normal mtDNAs, or transferring the pronuclei from patient zygote to the enucleated healthy zygote of a third individual. (B) According to the newly developed approach, the mutant mtDNAs in the oocyte or zygote are selectively eliminated by mitochondrion-locating TALENs
Mentions: Dysfunction of mitochondria, the energy-producing organelle of eukaryotic cells, may lead to mitochondrial diseases with severe symptoms in many organs, such as Leber hereditary optic neuropathy (LHON), mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS), myoclonic epilepsy and ragged-red fibres (MERRF), etc. Some mitochondrial diseases arise from disorders of nuclear genes which are involved in mitochondrial metabolism as well as in the maintenance of mitochondrial DNA (mtDNA). It has been found that a number of mitochondrial diseases are caused by mutations in mtDNA, a multi-copy, circular dsDNA molecule which encodes 13 essential polypeptides of the mitochondrial respiratory chain as well as the necessary RNA machinery (2 rRNAs and 22 tRNAs) for mitochondrial protein translation (Taylor and Turnbull, 2005; Xu et al., 2013). Since mtDNA is exclusively transmitted through maternal inheritance, a traditional approach of therapy is to transfer the nuclear genomic DNA to a enucleated donor oocyte or zygote with the normal mtDNA (Paull et al., 2013; Tachibana et al., 2013; Wang et al., 2014). This approach involves the mtDNA from a third individual thereby may trigger both ethical and technical conflicts. The most recent report by Reddy et al., for the first time, has prevented the germ-line transmission of mitochondrial disease by selectively eliminating the mutant mtDNA in situ in oocytes and one-cell embryos (Reddy et al., 2015). Using mitochondria targeted restriction endonucleases, the authors first tested their system by selectively eliminating the mtDNA haplotype in mouse oocytes and one-cell embryos. Cheerfully, the progenies from the modified embryos were verified to be free of the mtDNA haplotype which was supposed to be selectively cut and degraded. After the successful manipulation in mouse oocytes and embryos, the authors subsequently succeeded in specifically reducing the mutant mtDNAs responsible for LHOND and NARP (neurogenic muscle weakness, ataxia, and retinitis pigmentosa) by applying mitochondria-targeted TALENs in artificial mammalian oocytes, which were derived by fusion of patient cells with mouse oocytes. The highly efficient targeting mutant mtDNA in both animal model and human cells demonstrated in this study is cheerful. As being widely commented in the field, this report may fundamentally shape the future development of mitochondrial disease therapies. It is exciting to imagine that in the future by applying this technology in human, healthy babies will be able to born from patient oocytes where most mutant mtDNA are cleaned and the copy number of residual mutant mtDNA is reduced to below the threshold needed for a disease manifestation. Compared with other mitochondrial replacement therapies currently under development, this new technology no longer requires donor oocytes from an independent individual, and is a less complex procedure which would be less traumatic to the oocytes. Despite all potential advantages discussed, the authors also warned a risk that the embryos might fail to implant in uterus when mtDNA copy number in the “edited” embryos was below a specific threshold. Nevertheless, it was the first time that gene editing of mtDNAs in germ-line cells is achieved, which may encourage and promote the future studies towards new therapies for maternally inherited mitochondrial diseases (Fig. 1).Figure 1

Bottom Line: Nuclease-based gene editing technologies have opened up opportunities for correcting human genetic diseases.For the first time, scientists achieved targeted gene editing of mitochondrial DNA in mouse oocytes fused with patient cells.This fascinating progression may encourage the development of novel therapy for human maternally inherent mitochondrial diseases.

View Article: PubMed Central - PubMed

Affiliation: National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.

ABSTRACT
Nuclease-based gene editing technologies have opened up opportunities for correcting human genetic diseases. For the first time, scientists achieved targeted gene editing of mitochondrial DNA in mouse oocytes fused with patient cells. This fascinating progression may encourage the development of novel therapy for human maternally inherent mitochondrial diseases.

No MeSH data available.


Related in: MedlinePlus