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Pronuclear transfer in human embryos to prevent transmission of mitochondrial DNA disease


Mutations in mitochondrial DNA (mtDNA) are a common cause of genetic disease. Pathogenic mutations in mtDNA are detected in approximately 1 in 250 live births1,2,3 and at least 1 in 10,000 adults in the UK are affected by mtDNA disease4. Treatment options for patients with mtDNA disease are extremely limited and are predominantly supportive in nature. Mitochondrial DNA is transmitted maternally and it has been proposed that nuclear transfer techniques may be an approach for the prevention of transmission of human mtDNA disease5,6. Here we show that transfer of pronuclei between abnormally fertilized human zygotes results in minimal carry-over of donor zygote mtDNA and is compatible with onward development to the blastocyst stage in vitro. By optimizing the procedure we found the average level of carry-over after transfer of two pronuclei is less than 2.0%, with many of the embryos containing no detectable donor mtDNA. We believe that pronuclear transfer between zygotes, as well as the recently described metaphase II spindle transfer, has the potential to prevent the transmission of mtDNA disease in humans.

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Figure 1: Pronuclear transfer using abnormally fertilized human zygotes.
Figure 2: Mitochondrial DNA analysis of pronuclear-transfer embryos.
Figure 3: Mitochondrial DNA analysis of individual blastomeres disaggregated from pronuclear-transfer embryos.

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We thank M. Nesbitt, L. Burgess and S. Byerley for help with embryo donation and collection, and V. Wilson and S. Abbs for help with the nuclear genotyping. We thank the patients and staff at Newcastle Fertility Centre, and J. Lawford-Davies, K. Stern, Sir John Burn and Lord Walton of Detchant for helping us to obtain a Human Fertilisation and Embryology Authority research licence and guidance with the legislation. This work was funded by the Muscular Dystrophy Campaign, the Wellcome Trust (074454/Z/04/Z), the Medical Research Council (G0601157, G0601943), One North East, the UK National Institute for Health Research Biomedical Research Centre for Ageing and Age-related Disease and the Newcastle University Centre for Brain Ageing and Vitality supported by the Biotechnology and Biological Sciences Research Council, the Engineering and Physical Sciences Research Council, the Economic and Social Research Council and the Medical Research Council (G0700718). P.F.C. is a Wellcome Trust Senior Fellow in Clinical Science.

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M.H., A.P.M., R.N.L. and D.M.T. conceived the project and designed the experiments. L.C., H.A.T., S.J.H., G.D.G., J.L.M., L.M.C., P.F.C. and R.W.T. performed experiments and analysed data. L.C., M.H., H.A.T. and D.M.T. wrote the manuscript.

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Correspondence to Mary Herbert or Douglass M. Turnbull.

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The authors declare no competing financial interests.

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Craven, L., Tuppen, H., Greggains, G. et al. Pronuclear transfer in human embryos to prevent transmission of mitochondrial DNA disease. Nature 465, 82–85 (2010).

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