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Mitochondrial replacement in human oocytes carrying pathogenic mitochondrial DNA mutations (Nov 2016)

nature
Title:
Mitochondrial replacement in human oocytes carrying pathogenic mitochondrial DNA mutations
Journal:
Nature. 2016 Dec 8;540(7632):270-275
Author(s):
Kang E1,2, Wu J3, Gutierrez NM1,2, Koski A1,2, Tippner-Hedges R1,2, Agaronyan K4, Platero-Luengo A3, Martinez-Redondo P3, Ma H1,2, Lee Y1,2, Hayama T1,2, Van Dyken C1,2, Wang X5, Luo S5, Ahmed R1,2, Li Y1,2, Ji D1,6, Kayali R7, Cinnioglu C7, Olson S8, Jensen J9, Battaglia D9, Lee D9, Wu D9, Huang T5, Wolf DP1,2, Temiakov D4, Belmonte JC3, Amato P9, Mitalipov S1,2,9,10,11.
Author(s) affiliation:
1Center for Embryonic Cell and Gene Therapy, Oregon Health &Science University, 3303 SW Bond Avenue, Portland, Oregon 97239, USA.
2 Division of Reproductive & Developmental Sciences, Oregon National Primate Research Center, Oregon Health &Science University, 505 NW 185th Avenue, Beaverton, Oregon 97006, USA.
3Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
4Department of Cell Biology School of Osteopathic Medicine, Rowan University, 2 Medical Center Drive, Stratford, New Jersey 08084, USA.
5 Division of Human Genetics, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229, USA.
6Reproductive Medical Centre, Anhui Medical University, No 218, Jixi Rd, Shushan District, Heifei, Anhui 230022, China.
7 IviGen Los Angeles, 406 Amapola Avenue, Suite 215, Torrance, California 90501, USA.
8 Research Cytogenetics Laboratory, Oregon Health &Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, USA.
9Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, Oregon Health &Science University, 3303 SW Bond Avenue, Portland, Oregon 97239, USA.
10Knight Cardiovascular Institute, Oregon Health &Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, USA.
11 Department of Biomedical Engineering, Oregon Health &Science University, 3303 SW Bond Avenue, Portland, Oregon 97239, USA.
 

 

Short description:
Maternally inherited mitochondrial (mt)DNA mutations can cause fatal or severely debilitating syndromes in children1, 2, 3, with disease severity dependent on the specific gene mutation and the ratio of mutant to wild-type mtDNA (heteroplasmy) in each cell and tissue4. Pathogenic mtDNA mutations are relatively common, with an estimated 778 affected children born each year in the United States5. Mitochondrial replacement therapies or techniques (MRT) circumventing mother–to–child mtDNA disease transmission involve replacement of oocyte maternal mtDNA6, 7, 8. Here we report MRT outcomes in several families with common mtDNA syndromes. The mother’s oocytes were of normal quality and mutation levels correlated with those in existing children. Efficient replacement of oocyte mutant mtDNA was performed by spindle transfer8, resulting in embryos containing >99% donor mtDNA. Donor mtDNA was stably maintained in embryonic stem cells (ES cells) derived from most embryos. However, some ES cell lines demonstrated gradual loss of donor mtDNA and reversal to the maternal haplotype. In evaluating donor–to–maternal mtDNA interactions, it seems that compatibility relates to mtDNA replication efficiency rather than to mismatch or oxidative phosphorylation dysfunction. We identify a polymorphism within the conserved sequence box II region of the D-loop as a plausible cause of preferential replication of specific mtDNA haplotypes. In addition, some haplotypes confer proliferative and growth advantages to cells. Hence, we propose a matching paradigm for selecting compatible donor mtDNA for MRT.
Link to the journal
 

 

Abstract taken from PubMed

Abstract:
Maternally inherited mitochondrial (mt)DNA mutations can cause fatal or severely debilitating syndromes in children, with disease severity dependent on the specific gene mutation and the ratio of mutant to wild-type mtDNA (heteroplasmy) in each cell and tissue. Pathogenic mtDNA mutations are relatively common, with an estimated 778 affected children born each year in the United States. Mitochondrial replacement therapies or techniques (MRT) circumventing mother-to-child mtDNA disease transmission involve replacement of oocyte maternal mtDNA. Here we report MRT outcomes in several families with common mtDNA syndromes. The mother's oocytes were of normal quality and mutation levels correlated with those in existing children. Efficient replacement of oocyte mutant mtDNA was performed by spindle transfer, resulting in embryos containing >99% donor mtDNA. Donor mtDNA was stably maintained in embryonic stem cells (ES cells) derived from most embryos. However, some ES cell lines demonstrated gradual loss of donor mtDNA and reversal to the maternal haplotype. In evaluating donor-to-maternal mtDNA interactions, it seems that compatibility relates to mtDNA replication efficiency rather than to mismatch or oxidative phosphorylation dysfunction. We identify a polymorphism within the conserved sequence box II region of the D-loop as a plausible cause of preferential replication of specific mtDNA haplotypes. In addition, some haplotypes confer proliferative and growth advantages to cells. Hence, we propose a matching paradigm for selecting compatible donor mtDNA for MRT.
Link to the paper on PubMed
Comment in:
Mitochondrial Donation - Clearing the Final Regulatory Hurdle in the United Kingdom. [N Engl J Med. 2017]
Biomedicine: Replacing the cell's power plants. [Nature. 2016]
 




 

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