Mitochondrial replacement therapy and assisted reproductive technology: A paradigm shift toward treatment of genetic diseases in gametes or in early embryos

Abstract

BackgroundRecent technological development allows nearly complete replacement of the cytoplasm of egg/embryo, eliminating the transmission of undesired defective mitochondria (mutated mitochondrial DNA: mtDNA) for patients with inherited mitochondrial diseases, which is called mitochondrial replacement therapy (MRT).MethodsWe review and summarize the mitochondrial biogenesis and mitochondrial diseases, the research milestones and future research agenda of MRT and also discuss MRT‐derived potential application in common assisted reproductive technology (ART) treatment for subfertile patients.Main findingsEmerging techniques, involving maternal spindle transfer (MST) and pronuclear transfer (PNT), have demonstrated in preventing carryover of the unbidden (mutated) mtDNA in egg or in early embryos. The House of Parliament in the United Kingdom passed regulations permitting the use of MST and PNT in 2015. Furthermore, the Human Fertilization and Embryology Authority (HFEA) to granted licenses world first use of those techniques in March 2017. However, recent evidence demonstrated gradual loss of donor mtDNA and reversal to the nuclear DNA‐matched haplotype in MRT derivatives.ConclusionWhile further studies are needed to clarify mitochondrial biogenesis responsible for reversion, ruling in United Kingdom may shift the current worldwide consensus that prohibits gene modification in human gametes or embryos, toward allowing the correction of altered genes in germline.

Improvement of early developmental competence of postovulatory‐aged oocytes using metaphase II spindle injection in mice

“…18 It is increasingly likely that a cytoplasmic replacement will be applied to humans. 19 The other method of a cytoplasmic replacement, which was reported recently, is the injection of karyoplasts into the cytoplast directly. [20][21][22] This is a promising method in which a mixed mtDNA used for the reconstruction of oocytes is decreased as compared to that in a cellular membrane fusion.…”

Development of mitochondrial replacement therapy: A review

“…Women are undeniably eligible to become mothers with genetically linked children ( Gallapher, 2019 ). MRT is an evolutionary technique that can begin a new era by removing defective genome at zygotic and gametic level ( Tachibiana et al., 2018 ).…”

Mitochondrial disease: Replacing the powerhouse of the cell

“…One of the earliest methods proposed to reduce inheritance of mutated mtDNA was co-injection of donor cytoplasm during in vitro fertilization (IVF), where the addition of healthy mitochondria was proposed to compensate for the naturally inherited mutant mtDNA. 6 However, this method is now considered largely unsuitable due to the large volumes of donor cytoplasm required to out-compete the pre-existing mtDNA. Though no longer used, the principle of the cytoplasmic transfer method remains the basis of more advanced methods, which continue to rely on replacement of the mutant mtDNA with healthy mitochondria from a donor.…”

“…One recently developed prevention strategy, mitochondrial replacement therapy (MRT), relies on non-Mendelian inheritance of mitochondria during fertilization to prevent mitochondrial disease in the next generation. 6 The general goal of MRT is reduction of mutated mtDNA by replacing the maternal mitochondria with donor mitochondria. This results in the child, who is often called a threeparent baby, not inheriting the mother's mitochondrial disease.…”