Experience from the First Live-Birth Derived From Oocyte Nuclear Transfer as a Treatment Strategy for Mitochondrial Diseases

Our latest breakthrough involves the successful application of mitochondrial replacement therapy (MRT) and has attracted worldwide attention [1]. This has also raised a considerable debate regarding the safety of mitochondrial replacement therapy. In particular, there is a concern about carryover of small amounts of the mother’s mutant mtDNA into the baby, and whether the levels of this mutant mtDNA can drift over time to replace the donated, healthy mtDNA (thus defeating the entire purpose of the procedure). Such heteroplasmy drift could occur in a variety of ways; however, the most commonly debated mechanism involves nuclear-mitochondrial incompatibility. That is, in cases where nuclear transfer occurs between oocytes of women from widely divergent haplogroups, there is a possibility that the newly created combination of nuclear and mitochondrial genomes may experience deleterious interactions. Whether this originates from the mother’s nuclear genome or the donor’s mitochondrial genome, the ultimate effect would be the same; a selective pressure that favors the proliferation of the original, mutant mtDNA. It has been reported in several recent in vitro studies that, even though the low levels of heteroplasmy introduced into human oocytes often vanish, they can sometimes result in mtDNA genotypic drift and reversion to the original genotype in some of the reconstituted human embryonic-derived stem cell (hESC) lines [2–5]. There is, however, a serious question of the rigor of these studies and whether these in vitro experiments reflect the in vivo applications.