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Towards clinical application of pronuclear transfer to prevent mitochondrial DNA disease (Jun 2016)

nature
Title:
Towards clinical application of pronuclear transfer to prevent mitochondrial DNA disease
Journal:
Nature, 08 June 2016
Author(s):
Hyslop LA1,2, Blakeley P3, Craven L4, Richardson J1, Fogarty NM3, Fragouli E5, Lamb M1, Wamaitha SE3, Prathalingam N1,2, Zhang Q1, O'Keefe H1, Takeda Y1, Arizzi L1,2, Alfarawati S5, Tuppen HA4, Irving L1, Kalleas D1, Choudhary M2, Wells D6, Murdoch AP2, Turnbull DM4, Niakan KK3, Herbert M1,2.
Author(s) affiliation:
1Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, Biomedicine West Wing, Centre for Life, Times Square, Newcastle upon Tyne NE1 3BZ, UK.
2Newcastle Fertility Centre, Biomedicine West Wing, Centre for Life, Times Square, Newcastle upon Tyne NE1 4EP, UK.
3The Francis Crick Institute, Human Embryo and Stem Cell Laboratory, Mill Hill Laboratory, Mill Hill, London NW7 1AA, UK.
4Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, The Medical School, Framlington Place, Newcastle upon Tyne NE2 4HH, UK.
5Reprogenetics UK, Institute of Reproductive Sciences, Oxford Business Park North, Oxford OX4 2HW, UK.
6University of Oxford, Nuffield Department of Obstetrics and Gynaecology, John Radcliffe Hospital, Oxford OX3 9DU, UK.
 

 

Short description:
Mitochondrial DNA (mtDNA) mutations are maternally inherited and are associated with a broad range of debilitating and fatal diseases1. Reproductive technologies designed to uncouple the inheritance of mtDNA from nuclear DNA may enable affected women to have a genetically related child with a greatly reduced risk of mtDNA disease. Here we report the first preclinical studies on pronuclear transplantation (PNT). Surprisingly, techniques used in proof-of-concept studies involving abnormally fertilized human zygotes2 were not well tolerated by normally fertilized zygotes. We have therefore developed an alternative approach based on transplanting pronuclei shortly after completion of meiosis rather than shortly before the first mitotic division. This promotes efficient development to the blastocyst stage with no detectable effect on aneuploidy or gene expression. After optimization, mtDNA carryover was reduced to less than 2% in the majority (79%) of PNT blastocysts. The importance of reducing carryover to the lowest possible levels is highlighted by a progressive increase in heteroplasmy in a stem cell line derived from a PNT blastocyst with 4% mtDNA carryover. We conclude that PNT has the potential to reduce the risk of mtDNA disease, but it may not guarantee prevention.
Link to the journal
 

 

Abstract taken from PubMed

Abstract:
Mitochondrial DNA (mtDNA) mutations are maternally inherited and are associated with a broad range of debilitating and fatal diseases1. Reproductive technologies designed to uncouple the inheritance of mtDNA from nuclear DNA may enable affected women to have a genetically related child with a greatly reduced risk of mtDNA disease. Here we report the first preclinical studies on pronuclear transplantation (PNT). Surprisingly, techniques used in proof-of-concept studies involving abnormally fertilized human zygotes2 were not well tolerated by normally fertilized zygotes. We have therefore developed an alternative approach based on transplanting pronuclei shortly after completion of meiosis rather than shortly before the first mitotic division. This promotes efficient development to the blastocyst stage with no detectable effect on aneuploidy or gene expression. After optimization, mtDNA carryover was reduced to less than 2% in the majority (79%) of PNT blastocysts. The importance of reducing carryover to the lowest possible levels is highlighted by a progressive increase in heteroplasmy in a stem cell line derived from a PNT blastocyst with 4% mtDNA carryover. We conclude that PNT has the potential to reduce the risk of mtDNA disease, but it may not guarantee prevention.
Link to the paper on PubMed
 




 

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