Trends in Endocrinology & Metabolism
Science & SocietyClinical and ethical implications of mitochondrial gene transfer
Section snippets
Mitochondrial gene disorders
These are distinct genetic diseases attributable to mutations in the cytoplasmic DNA residing in the cellular mitochondria, organelles involved in cellular respiration and energy production. Each cell contains thousands of circular mtDNA molecules comprising 37 genes (13 proteins, 22 tRNAs and 2 rRNAs) crucial for energy production by oxidative phosphorylation (OXPHOS). The mitochondrial genome is inherited maternally because only mtDNA from the unfertilized egg is found in offspring. Mutations
Techniques for mtDNA replacement
A promising recent advancement in assisted reproductive technologies (ARTs) involves the efficient replacement of mutant mtDNA in unfertilized oocytes or zygotes with normal donor mitochondria, thereby allowing women carrying mtDNA mutations to circumvent passage of the condition to their children 3, 4. Two microsurgical nuclear transfer procedures, termed spindle transfer (ST) and pronuclear transfer (PNT), have been developed. The first approach is conducted at the mature oocyte stage when
Safety and efficacy of mtDNA replacement
The safety and efficacy of the ARTs has been established over many years of clinical application without much attention or dependence on animal based research, let alone controlled clinical trials. Clearly, establishing safety and efficacy for any new technology, especially when involving germline gene therapy, represents a major challenge. Several relevant observations are cited below.
In the case of mitochondrial gene replacement, the possibility that the procedure might fail secondary to the
Regulatory, legal, and ethical questions
The techniques of ST and PNT described herein induce permanent changes to mtDNA that would be transmitted through generations, thus qualifying as germline gene therapy. As such, in the USA, reproductive applications of mtDNA transfer fall under the jurisdiction of the Food and Drug Administration (FDA) requiring that first applications for patient treatment must be done as part of clinical trials. In the UK, current regulations set by the Human Fertilisation and Embryology Act (HFEA) 1990 ‘only
Acknowledgments
Research supported by National Institutes of Health grants HD063276, HD057121, HD059946, 8P51OD011092 and the Leducq Foundation. The authors wish to thank Eric Baker for help with illustrative material.
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(2010)
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2020, Cell Reports MedicineCitation Excerpt :PNT may enable development of blastocyst-stage embryos without increasing the incidence of aneuploidy or gene expression patterns and with a carryover of mutant maternal mitochondrial DNA (mtDNA) that is less than 2% in most PNT-derived blastocysts.22,23 Maternal spindle transfer (MST) involves isolation and transfer of the metaphase II spindle complex of an at-risk oocyte to an enucleated disease-free donor egg to reconstitute and fertilize oocytes to produce potentially transferrable embryos.24,25 It is thus an embryo-sparing option.
Mitochondrial genetics
2020, Human Reproductive Genetics: Emerging Technologies and Clinical Applications