Concise reviews: Assisted reproductive technologies to prevent transmission of mitochondrial DNA disease.
Bottom Line: The available evidence indicates that cells removed from an eight-cell embryo are predictive of the mutation load in the entire embryo, indicating that PGD provides an effective risk reduction strategy for women who produce embryos with low mutation loads.For those who do not, research is now focused on meiotic nuclear transplantation techniques to uncouple the inheritance of nuclear and mtDNA.The scientific progress and associated regulatory issues are discussed.
Affiliation: Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, United Kingdom; Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.Show MeSH
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Mentions: The technique of pronuclear transfer (PNT) between fertilized mouse eggs (zygotes) was pioneered by McGrath and Solter more than 3 decades ago 35. The procedure involves treatment of zygotes with microtubule and actin-depolymerizing drugs to facilitate removal of the pronuclei without the need to penetrate the plasma membrane. The PN are pinched-off within a small volume of membrane-enclosed cytoplasm, known as a karyoplast, which is subsequently fused with an enucleated zygote. Membrane fusion is facilitated by inactivated Sendai virus or an electrical pulse 35,36. However, the latter is not well tolerated by human oocytes and zygotes 37,38. The experiments of McGrath and Solter 35 revealed that PNT between zygotes from different mouse strains can produce healthy and normally reproducing offspring. The possibility of using PNT to prevent transmission of mtDNA disease (Fig. 2A) was first proposed in the 1990s 21. Later experiments using zygotes from a mouse carrying a rearrangement in the mtDNA indicated that the fraction of mutant mtDNA could be greatly reduced by PN transfer into enucleated zygotes from females with wild-type mtDNA 21. More recently, proof of concept experiments with abnormally fertilized eggs explored the potential of PNT in human zygotes 38. Despite their large size (25–30 µm), transplantation of PN between human zygotes was technically feasible and compatible with development to the blastocyst stage 38. After optimization of the procedure, the level of the mtDNA “carried-over” within the karyoplast was reduced to <2% on average 38, which is well below the disease threshold for mutations studied to date 14.
Affiliation: Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, United Kingdom; Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.