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Towards clinical application of pronuclear transfer to prevent mitochondrial DNA disease

Lookup NU author(s): Dr Louise Hyslop, Dr Lyndsey Butterworth, Mahdi Lamb, Dr Nilendran Prathalingam, Qi Zhang, Hannah O'Keefe, Dr Yuko Takeda, Lucia Arizzi, Dr Helen Tuppen, Dr Laura Irving, Dimitri Kalleas, Dr Meenakshi Choudhary, Professor Alison Murdoch, Emeritus Professor Doug Turnbull, Professor Mary Herbert

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This is the authors' accepted manuscript of an article that has been published in its final definitive form by Nature Publishing Group, 2016.

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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 <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.

Publication metadata

Author(s): Hyslop LA, Blakeley P, Craven L, Richardson J, Fogarty NME, Fragouli E, Lamb M, Wamaitha SE, Prathalingam N, Zhang Q, O'Keefe H, Takeda Y, Arizzi L, Alfarawati S, Tuppen H, Irving L, Kalleas D, Choudhary M, Wells D, Murdoch AP, Turnbull DM, Niakan KK, Herbert M

Publication type: Article

Publication status: Published

Journal: Nature

Year: 2016

Volume: 534

Issue: 7607

Pages: 383-386

Print publication date: 16/06/2016

Online publication date: 08/06/2016

Acceptance date: 03/05/2016

Date deposited: 28/07/2016

ISSN (print): 0028-0836

ISSN (electronic): 1476-4687

Publisher: Nature Publishing Group

URL: http://dx.doi.org/10.1038/nature18303

DOI: 10.1038/nature18303

PubMed id: 27281217

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