Bibliografisk note

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S.G. is also a part-time employee and stock-holder of Sana Biotechnology, a cell therapy company; he holds relevant patents and his lab receives sponsored research support from Sana.

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Mitochondrial replacement techniques (MRTs) involve the transfer of nuclear genetic material, notably the meiotic spindle with chromosomes attached before fertilization or both the maternal and paternal pronuclei at the zygote stage after fertilization, into an enucleated oocyte or zygote at the equivalent stages. (A third method, polar body transfer, might also be feasible, but published data on this are limited.) This has the effect of swapping the cytoplasm, which contains the mitochondria with their DNA (mtDNA), in order to effectively replace pathogenic mtDNA's causing serious disease with normal mtDNA. This should allow a woman (mitochondria are only inherited via the mother) at risk of having an affected child to have a genetically related child free from mitochondrial disease. The child would have contributions as normal from the mother's nuclear DNA as well as that from the father, but mtDNA from the oocyte donor. To date, the the UK is the only country to actively permit in law the use of MRTs specifically to avoid serious mitochondrial disease. Regulations were passed in 2015 by the UK Parliament and detailed guidelines were then drawn up and adopted by the regulator, the Human Fertilization and Embryology Authority (HFEA), who granted the first license to carry out the procedures to researchers in Newcastle in 2017. However, the techniques are now being used elsewhere, and not just to avoid mitochondrial disease, but as a way to overcome female infertility where preimplantation embryos generated by in vitro fertilization (IVF) repeatedly fail to develop. There is no established explanation for why MRTs should work for the latter women, and therefore application of these methods in such cases is speculative. The revised Guidelines therefore limit the clinical use of MRTs to those at high risk of transmitting serious mtDNA-based diseases to their offspring and when no other treatments are acceptable. Such use now falls under Category 2, whereas previously MRTs were in Category 3. Due to inadequate pre-clinical data and scientific rationale, the Guidelines also recommend not using MRTs for unexplained female infertility associated with poor oocyte/embryo quality. Notably, the Guidelines also encourage more research to refine and assess the safety and efficacy of MRTs, in particular to address a potential problem of ?reversion,? which was seen in preclinical data involving the culture of ES cells derived from MRT embryos, where the maternal mtDNA may come to predominate again (Greenfield et al., 2017)

Funding Information:
R.B. receives funding from UK NIHR, MRC, Wellcome, Cure Parkinson’s Trust, and EU. R.B. received funding from Parkinson’s UK, CHDI, Rosetrees Trust, and Evelyn Trust. R.B. receives royalties from Wiley and Springer and also has an ongoing consultancy role for the following companies: Novo Nordisk, UCB, Aspen Neuroscience, and BlueRock Therapeutics.

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