lifesciences
Innopsys

Towards clinical application of pronuclear transfer to prevent mitochondrial DNA disease

Abstract:

Mitochondrial DNA (mtDNA) mutations are maternally inherited and are associated with a broad range of debilitating and fatal diseases. 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 zygotes 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. Following optimisation, 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.

Credits:

Louise A. Hyslop,1,2 Paul Blakeley,3 Lyndsey Craven,4 Jessica Richardson,1 Norah M.E. Fogarty,3 Elpida Fragouli,5 Mahdi Lamb,1 Sissy E. Wamaitha,3 Nilendran Prathalingam,1,2 Qi Zhan,1 Hanna O’Keefe,1 Yuko Takeda,1 Lucia Arizzi,1,2 Samer Alfarawati,5 Helen A. Tuppen,4 Laura Irving,1 Dimitrios Kalleas,1 Meenakshi Choudhary,2, Dagan Wells,6 Alison P Murdoch,2 Douglass M. Turnbull, Kathy K. Niakan,3 and Mary Herbert1,2

  • 1. Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, Biomedicine West Wing, Centre for Life, Times Square, Newcastle upon Tyne, NE1 3BZ, UK
  • 2. Newcastle Fertility Centre, Biomedicine West Wing, Centre for Life, Times Square, Newcasltle upon Tyne, NE1 4EP, UK
  • 3. The Francis Crick Institute, Human Embryo and Stem Cell Laboratory, Mill Hill Laboratory Mill Hill, London, NW7 1AA, UK
  • 4. Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, The Medical School, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK
  • 5. Reprogenetics UK, Institute of Reproductive Sciences, Oxford Business Park North, Oxford OX4 2HW, UK
  • 6. University of Oxfor, Nuffield Department of Obstetrics and Gynaecology, John Radcliffe Hospital, Oxford OX 9DU, UK

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