Medical research: Improved method for mitochondrial replacement therapy

09 June 2016

Image credit: Prof Mary Herbert lab

Image: Image credit: Prof Mary Herbert lab

A preclinical analysis of mitochondrial replacement therapy, using an optimized version of the pronuclear transfer (PNT) technique, is reported in Nature (8 June 2016). The study shows that the timing of PNT - conducting it sooner after fertilization than previous investigations - is crucial for its successful application in normally fertilized human eggs, and represents a step towards the therapeutic application of PNT for preventing transmission of mitochondrial disease. The research was carried out by teams in Newcastle, the Francis Crick Institute, and Oxford.

Unlike the DNA inherited from the nucleus of the mother's egg and father's sperm (nDNA), mitochondrial DNA (mtDNA) is inherited directly from the mother. Mutations in mtDNA are associated with various debilitating and fatal diseases (such as Leber's hereditary optic neuropathy), and mitochondrial replacement techniques, such as PNT, could help prevent their transmission. PNT transfers the still separate nDNA of the egg and the sperm from a fertilized egg - pronuclei - into a donor egg that contains healthy mtDNA but whose pronuclei have been removed. Previous studies have shown that PNT is technically feasible in abnormally fertilized human eggs (containing only one pronucleus or more than two pronuclei), but these eggs have a limited capacity for onward development.

Dr Kathy Niakan at the Crick performed cutting edge analysis of the gene expression of embryos generated using the modified pronuclear transfer techniques developed in Mary Herbert's lab. They also assisted with the derivation and characterisation of the human embryonic stem cell lines described in the study.

Mary Herbert from the Wellcome Trust Centre for Mitochondrial Research at the University of Newcastle and colleagues show that PNT can be improved if the pronuclei are transplanted from the mother's egg to the donor egg earlier in the developmental process - shortly after they first appear, after the completion of meiosis, rather than shortly before they disappear which happens before the first mitotic division. They find that this early PNT (ePNT) allows the fertilised egg to develop efficiently to the blastocyst stage: the stage at which implantation into the uterus occurs, with no detectable effect on gene expression or incidence of aneuploidy (abnormal number of chromosomes). By further optimizing the ePNT procedure, the authors are able to reduce the co-transfer of mtDNA to less than two percent in 79% of blastocysts: below the threshold for development of mild or severe disease symptoms, and in most cases below the threshold for mother-to-child transmission in subsequent generations.

These results suggest that ePNT has the potential to reduce the risk of mtDNA disease transmission. However, the authors also highlight the importance of keeping mtDNA co-transfer to the lowest possible levels, demonstrating the need for continued optimization and monitoring of mitochondrial replacement techniques for future clinical application.

The paper, Towards clinical application of pronuclear transfer to prevent mitochondrial DNA disease, is published in Nature

  • Dr Kathy Niakan at the Crick performed cutting edge analysis of the gene expression of embryos generated using the modified pronuclear transfer techniques developed in Mary Herbert's lab.