Two papers published in NEJM look at the use of mitochondrial donation an preimplantation genetic testing for mitochondrial disease.
Dr David J Clancy, Lecturer in Biogerontology, Lancaster University, said:
“This comment is to discuss Mitochondrial Replacement Therapy (MRT) in terms of costs and benefits in light of what we now know.
Benefits
“Mitochondrial replacement therapy allows women with pathogenic mitochondrial DNA to have a baby which bears her own chromosomes, while reducing or replacing the pathogenic mtDNA. If the primary purpose is to avoid mitochondrial disease, then women could also have IVF by donor sperm or donor egg (or donor embryo), or they might choose adoption if IVF technologies don’t suit them for clinical or personal reasons.
“In chromosomal dominant diseases like Huntington’s disease, affected people are offered pre-implantation genetic testing (PGT) and they are also offered IVF using donor eggs or embryos if the patient is a woman. For these sorts of genetic disease there is currently no alternative. In these cases a woman cannot have a child bearing her own chromosomes.
“When having a family there are two ways to break genetic lineages – inheritance down generations: one is to adopt and another is to have IVF by donor sperm or donor egg (or donor embryo). It is difficult to value genetic lineage. It will be more valuable to some, less to others. While maternity is never in doubt, paternity often is. Perhaps we should then value maternal genetic lineage more than paternal. Mitochondrial replacement therapy allows unbroken maternal lineage.
I cannot determine whether the Mitochondrial Reproductive Advice Clinic suggests IVF by donor egg or embryo (or adoption). The paper says “Patients with heteroplasmy (part pathogenic mitochondrial DNA, part healthy) were offered PGT, and patients with homoplasmy or elevated heteroplasmy (all or mostly pathogenic mitochondrial DNA) were offered pronuclear transfer.”
Costs
“The money cost is presumably significant. The work was funded by Wellcome and NHS England and carried out by Newcastle University, UK and the Newcastle upon Tyne Hospitals NHS Foundation Trust. Presumably they could give an idea of the cost. This might be considered important, in an environment of limited resources for national healthcare.
Possible harms
“Because these babies would not exist without the MRT intervention, we want to know about possible problems; in medicine the saying is “First, do no harm”, though in current healthcare, harm is often inevitable. While the babies so far seem probably unaffected, assessing the potential for future harm as they develop by looking at the degree of heteroplasmy in the infants is a large part of the reason for the publications.
“Measurements were on white blood cells so we don’t know about tissue mosaicism, which is where you can have high heteroplasmy in some tissues and low in others, and is common in many mitochondrial diseases. In tissues demanding high energy production (e.g. neurons), lower levels of heteroplasmy can still be symptomatic. In a mouse model, a proportion of >20% energy-deficient neurons in the brain was necessary for observable symptoms.
“Three of eight newborns from MRT had heteroplasmy levels of 5%, 12%, and 16% (the other five were <1%). It is unlikely that increased carryover of maternal mtDNA accounts for the relatively high heteroplasmy levels (12% and 16%) observed in two cases of MRT. This means that the increase in pathogenic mtDNA levels from embryos to infants is a/ probably not due to the technique, and therefore b/ not in the control of the technicians/clinicians. This suggests that, at some point (if not already), a baby will be born with heteroplasmy levels which are pathogenic.
“All of these things were mostly known before these publications, so apparently the Human Fertilization and Embryology Authority (HFEA), who approved it, is happy with the cost-benefit ratio. It also appears that other countries also approve, because the technique is spreading; there is a clinic in North Cyprus, and Prof Mary Herbert, the study’s lead, has moved to a pioneer institution in IVF, Monash University in Melbourne, Australia, partly to introduce a mitochondrial replacement program.”
Prof Joanna Poulton, Professor and Honorary Consultant in Mitochondrial Genetics, Nuffield Department of Women’s and Reproductive Health, said:
“From this study, it isn’t clear that MD (mitochondrial donation) has any advantage over PGT (pre-implantation genetic testing, an alternative strategy) for heteroplasmic mtDNA disorders (where patients have mixtures of normal and mutant mtDNA and severity depends on the “dose” of mutant). The “take home baby” rate and the reduction in mutant load is similar (if anything less good for MD).
“MD has a clear theoretical advantage for homoplasmic disorders (where the mother’s mtDNA is 100% mutant), because while PGT while can be used to reduce risk, it cannot be used to reduce the load of mutant mtDNA. Over half of the MD children were from Leber Hereditary Optic Neuropathy (LHON) families, where the chance of male offspring going blind in adolescence is around 20% but only 4% for females. The risk of blindness can be reduced 5 fold using PGT to select female embryos, but they risk transmitting it to their children. Happily, male identical twins were born by MD with undetectable mutant mtDNA, they will be very low risk for blindness and as males, they will not transmit the problem to their children (because LHON is a maternally transmitted disorder). Slightly worryingly, one baby from a m.4300A>G family, where the mother has a heart disorder (cardiomyopathy) for which she may ultimately need a heart transplant, has an unspecified heart defect: they conclude it is probably unrelated to m.4300A>G but this remains uncertain. Another from a m.3260A>G family had a mutant load of 16% in blood. While this probably means the risk of symptoms is low, one symptomatic m.3260A>G woman had a blood level that was lower than this (11% with 81% in muscle). Happily, male identical twins were born by MD with undetectable mutant mtDNA, they will be very low risk for blindness and as males, they will not transmit the problem to their children because LHON is a maternally transmitted disorder.
“A great deal of research funding has been channelled into the centre that has developed MD. While this has generated fascinating scientific data and this treatment option is now available on the NHS, it hasn’t yet resulted in a dramatic clinical advance. Time will tell.”
Prof Dusko Ilic, Professor of Stem Cell Science, King’s College London, said:
“A remarkable accomplishment! State-of-the-art technology. Kudos to the team!”
Prof Dagan Wells, Professor of Reproductive Genetics, University of Oxford, and Director, Juno Genetics, Oxford, said:
“This is an important study which has been eagerly anticipated ever since the first license to carry out mitochondrial replacement therapy to avoid mitochondrial disease was granted eight years ago.
“The results indicate that established methods for avoiding mitochondrial DNA diseases, such as preimplantation genetic testing, perform well and will be suitable for most women at risk of having an affected child.
“A minority of patients are unable to produce any embryos free of mitochondrial disease, and for those women the study provides hope that they may be able to have healthy children in the future.
“The treatment has succeeded in producing 8 babies, and although mitochondrial DNA mutations can be detected in the cells of most of the children, the great majority of their mitochondria are functional, and consequently they do not have mitochondrial disease.
“The published results are very valuable, but some scientists will be a little disappointed that so much time and effort has, so far, only led to the birth of 8 children.
“Larger studies will be needed to truly understand the value of mitochondrial replacement therapy, and to understand whether there are any risks associated with the treatment.
“Three of the eight children born have some evidence of ‘reversal’, a phenomenon where the therapy initially succeeds in producing an embryo with very few defective mitochondria, but by the time the child is born the proportion of abnormal mitochondria in its cells has significantly increased.
“It is not understood why reversal sometimes occurs. Taking data from the new study as well as previous research, it seems that it may affect as many as one-third of embryos produced using mitochondrial replacement therapy. Importantly, all the children in the study have low levels of abnormal mitochondria in their cells, including those where a degree of reversal has occurred. However, the fact that reversal can happen suggests there is a chance that mitochondrial replacement therapy might occasionally fail, and consequently the procedure should be seen as a way of reducing the risk of mitochondrial disease inheritance, not guaranteeing it.”
Dr Andy Greenfield, Honorary Fellow at the Nuffield Department of Women’s & Reproductive Health, University of Oxford, said:
“Mitochondria are the energy-producing organelles of the body’s cells. They contain DNA (mitochondrial DNA, mtDNA) and as such are prone to changes to that DNA (mutations) that can disrupt mitochondrial function and cause disease. The paper by Hyslop et al describes the first clinical use in the UK of a technique – mitochondrial donation (MD) – aimed at reducing the risk of transmitting a class of mitochondrial diseases (mtDNA diseases) from mother to offspring. This is an often devastating and life-limiting group of diseases for which no curative treatments exist. The specific technique described, based on IVF, is pronuclear transfer (PNT), one of the two MD techniques made lawful in the UK in 2015. The last preclinical review of the safety and effectiveness of MD, commissioned by the HFEA and published in 2016, recommended its clinical use as a risk reduction strategy – to be used only in those women for whom preimplantation genetic testing (PGT, an established procedure that is used to detect genetic abnormalities, including the amount of disease-causing (pathogenic) mtDNA, in an embryo) followed by selection of an embryo with low levels of pathogenic mtDNA for transfer was unlikely to be a successful strategy i.e. only in those women with high levels of pathogenic mtDNA (elevated heteroplasmy) in all eggs or with exclusively pathogenic mtDNA in their eggs (homoplasmy). This cautious approach is at the heart of this new report, which, along with an accompanying paper by McFarland et al, assesses MD alongside PGT in an integrated programme performed at Newcastle Fertility Centre, UK, under the regulatory framework developed by the HFEA.
“Whilst PGT for mtDNA is an established procedure that acts as a useful comparator, the attention here will be rightly focused on the MD clinical data: 22 women at high risk of transmitting mitochondrial disease to their offspring were treated using PNT, resulting in 8 live births and one ongoing pregnancy. Firstly, this headline result alone is highly significant: PNT is compatible with embryo viability in humans. Secondly, levels of pathogenic mtDNA (in blood) from the infants varied from 0% to 16%. Whilst the last figure hints at a degree of reversion to the maternal mtDNA type, it is also sufficiently low to conclude that the procedure has successfully reduced the risk of mtDNA in all children born. The amount of maternal mtDNA could, however, vary from tissue to tissue and so follow-up of these children is vitally important. McFarland et al report that none of the children has any health condition that could be straightforwardly attributed to the presence of mtDNA disease. As the authors note, there are reasons to be optimistic about the outcome of this first MD treatment in the UK.
“The data in the last paragraph, whilst summarised very briefly, are the culmination of decades of work: from the earliest investigations in mice aimed at understanding the impacts of nuclear transfer, through to targeted experiments in human embryos to provide preclinical evidence of safety and effectiveness. But this is to focus only on some of the scientific/technical challenges that have been overcome. There were parallel activities over a similar time frame concerning ethical inquiry, public and patient engagement, law-making, drafting of regulations and execution of those regulations by committees. And last but not least: the careful establishment of a clinical pathway by which the health of the mothers and infants born could be monitored and they could be cared for (detailed in McFarland et al). This all represents a vast amount of work by a large number of people over a long period.
“The Hyslop et al paper itself is a treasure trove of data, which will likely to be the starting points of new avenues of research and opportunities for refinement. What is the explanation for the somewhat elevated maternal mtDNA levels (still beneath the clinical threshold for disease) detected in two babies born following PNT? Further studies of mitochondrial DNA replication, segregation and interaction with the nuclear DNA may provide clues. The reduction in normally fertilized eggs in the PNT group also requires explanation and may indicate that some mtDNA pathogenic variants can compromise fertilisation of the egg, which is an energy-demanding process. This observation opens up a whole area of research concerning the role of played by mitochondria in fertility. Of course, numbers analysed here are still low and a larger and more diverse cohort will be required to draw firm conclusions about efficacy and safety of MD at a population level. We can look forward to future assessments of maternal spindle transfer (the other lawful MD technique in the UK) and even, possibly, the use of targeted, enzymatic degradation of pathogenic mtDNA to eliminate the risk of carry-over and reversion.
“How do we summarise what this all means? It is a triumph of scientific innovation in the IVF clinic – a world-first that shows that the UK is an excellent environment in which to push boundaries in IVF; a tour de force by the embryologists who painstakingly developed and optimised the micromanipulation methods; an example of the value of clinical expertise, developed over decades of working with children and adults suffering from these devastating diseases, being used to support a new intervention and subsequent follow-up, potentially for many years. And it is so much more, depending on whether one’s perspective is that of an historian, sociologist, ethicist or philosopher. It is tempting to suggest that this report marks the end of a process – but it is actually the beginning, of a new era in which technologies that change how we think about human reproduction are introduced into a tightly regulated environment – the only way in which they should be introduced.
“In time, there will no doubt be retrospective studies and assessments of how all this was done – some critical – and there will be much to learn. It is hoped that other papers will follow, detailing different aspects of the process by which these first UK children were born, because this whole exercise has been a steep learning curve for all involved and future progress relies on such learning being shared. Safety assessment should be at the heart of all these and future reports. Some may wonder about the time taken for these current reports to see the light of day – but that would be to underestimate what is required to transition from preclinical research activities in an academic setting to offering a bona fide clinical service on the NHS (with the spanner of COVID-19 thrown into the works for good measure). Others will wonder whether supporting the desire to have biological children merits all this time and effort, when ‘unmet clinical need’ is the focus and budgetary constraints are the norm. But this evaluation unnecessarily attempts to marginalise a human activity – ‘having children’ – that is actually central to the health and wellbeing of a significant proportion of the population. And those ordinary resemblances that parents and children often share also matter to them. Of course, the results of clinical follow-up of the children born using PNT will be a major determinant of the future prospects for mitochondrial donation in the IVF clinic, as this report acknowledges.
“There will be many responses to this work, but I see these reports, despite their matter-of-fact understatement, as an extraordinary reminder of what well intentioned science, collaborating with medicine, can do to improve the lives of human beings.”
Mr Stuart Lavery, Divisional Clinical Director Women’s Health and Consultant in Reproductive Medicine/Honorary Associate Professor, University College Hospitals NHS Foundation Trust, said:
“The concept of nuclear transfer has attracted much commentary and occasionally concern and anxiety.
“The Newcastle team have demonstrated that it can be used in a clinically effective and ethically acceptable way to prevent disease and suffering.
“The HFEA has shown that regulation need not always be restrictive, and that permissive regulation can lead to innovation at the highest level, allowing scientists to push boundaries, patients to be successfully treated and the public to be reassured.
“This truly represents the very best of British science and regulation.”
Prof Bert Smeets, Professor in Clinical Genomics with focus on Mitochondrial Diseases, said:
“These are papers, the scientific community has waited for, for a long time, as they describe the experience of the Newcastle team on pronuclear transfer to prevent the transmission of mtDNA disease, for which they got approval in 2017. The papers describe the current experience in PNT and PGT for preventing the transmission of mtDNA disease. It is good to present a reproductive care pathway, although it is not fully complete and some of the criteria might be reevaluated based on the presented data. The care pathway starts with carriers of mtDNA mutations. I would also include women who have affected children with de novo mtDNA mutations. This concerns about 25% of the mtDNA patients. The recurrence risk is low and generally prenatal diagnosis is offered for reassurance. Furthermore, women with a very low mtDNA mutation load, with skewing mtDNA mutations or large scale deletions could also opt for prenatal diagnosis. For a reproductive care pathway for mtDNA disease, these groups should be included as well. It is clear that for the remainder according to the HFEA guidelines PNT should only be offered if PGT is unsuitable. It is great that the PNT as an addition to the reproductive choices for mtDNA disease seems to deliver as 8 children without the mtDNA condition were born. However, there are still concerns, as 2 PNT children had a higher mutation load than the carry-over, which means that reversal can occur and could be a risk for having affected children in future treatments. Also, two children had rare medical complications, which according to the authors were not related to the treatment, as this would then be expected for all of them. I do not think that is true as technical variation occurs and donors will be different. It is good to carefully monitor this, as one of the aims of HFEA guided clinical application is to find-out if PNT by itself is safe, not only to prevent mtDNA disease. The discussion on this is not very strong. Finally, a key unanswered question is why it took so long to come out with these results. Eight births with no mtDNA disease in 7 years deviates largely from the expected150 yearly births, as described by the same group in NEJM in 2015, if all women would opt for this procedure. It seems that the children born are quite recent (only one >18 months), so one wonders if there is a learning curve, change in procedure or whatsoever, explaining the increasing success rate. It would be fair to discuss this in more detail as it would make it much clearer and more realistic which women of the target group will benefit from MD. And that is still a positive message.”
Comments on the broader story:
Kevin McEleny, Chair, British Fertility Society, said:
“These landmark papers provide compelling evidence that mitochondrial donation through pronuclear transfer can massively reduce the transmission of pathogenic mitochondrial DNA variants and are a terrific example of how a regulatory framework can be adapted to permit world-leading scientific discovery. Although the number of babies conceived through this novel treatment is small and their long-term follow-up will be required, the study provides hope to people affected by mitochondrial DNA disease and their loved ones.”
Sarah Norcross, Director of the Progress Educational Trust (PET), said:
“We could not be more delighted by the news that eight babies with donated mitochondria have been born in the UK, and that all of these children have made normal developmental progress.
“Our charity spent many years campaigning for UK law to be changed, to permit the use of mitochondrial donation in treatment. We salute the patients who had the courage to attempt these novel treatments, and we thank the team at Newcastle for justifying patients’ confidence in them.
“Mitochondrial donation will not necessarily be appropriate for every patient who carries disease-causing mitochondrial DNA mutations – rather, its appropriateness depends on various factors that are explored in detail in the new studies. Importantly, the studies place mitochondrial donation within the context of a broader NHS care pathway, that offers a variety of options for people carrying mitochondrial DNA mutations who wish to have children.
“Nonetheless, the studies demonstrate that mitochondrial donation is a feasible option – indeed, a positive reproductive choice – for some patients. An important consideration is that women considering mitochondrial donation are advised to start their fact-finding early, because of the decline of egg quality with age.
“The medical and scientific work at Newcastle, and the policy and legal work that preceded it, have set a high standard for introducing new reproductive technology in a careful and scrupulously regulated way. We are pleased to see that Australia is following a similarly responsible path, having recently introduced its own law that permits the use of mitochondrial donation for the purpose of avoiding mitochondrial disease.
“The work at Newcastle will no doubt inform – and in future, will perhaps also be informed by – the mitoHOPE pilot programme for mitochondrial donation in Australia.”
Nick Meade, Chief Executive Genetic Alliance, said:
“Most rare conditions do not yet have a cure or treatment, so for families affected, reproductive choice techniques are the only opportunities to take control of the impact of the condition. For serious conditions caused by nuclear DNA, these opportunities have existed for many years (through preimplantation genetic testing), with today’s news, we know more families have that opportunity now. These techniques have the potential to work for hundreds of conditions caused by mitochondrial DNA, and they are an example of how innovative research can be applied to take steps forward for multiple rare conditions in parallel. With more than 7,000 rare conditions affecting people in the UK, we need this kind of progress.”
Beth Thompson, Executive Director for Policy & Partnerships at Wellcome, said:
“This is a remarkable scientific achievement, which has been years in the making and we are overjoyed for the families of the eight children born so far.
“The pioneering work behind mitochondrial donation is a powerful example of how discovery research can change lives. The UK has led the way and has demonstrated the importance of science grounded in close and careful co-ordination between researchers, funders and regulators – and, very importantly, working closely with families affected.
“Wellcome has proudly supported this work since the earliest days, including advocating for legislation and licensing. As the science progresses, we will continue championing brave investment in science and for policy and regulation to keep pace. The success of this research should inspire us move forward on other updates, opening the way for further innovation. The groundwork for review of Human Fertilisation and Embryology Act, for example, has been done, it now needs to move forward. We must ensure the UK stays a world leader in life sciences.”
Danielle Hamm, Director of the Nuffield Council on Bioethics, said:
“Today we have seen the first evidence that for a small number of UK families the use of pronuclear transfer (PNT) to prevent the transfer of maternally inherited mitochondrial DNA disorders has resulted in what everyone hoped it would: children who are thriving and appear free of the devastating symptoms of mitochondrial disease.
“The Nuffield Council on Bioethics’ landmark ethical review of techniques for the prevention of maternally inherited mitochondrial disorders has been instrumental in creating the right regulatory environment to allow this innovative treatment to reach the clinic and change lives for the better.
“The HFEA’s licensing conditions followed our recommendation and ensured that PNT is only available through a specialist centre. The establishment of the NHS Highly Specialised Mitochondrial Reproductive Care Pathway has ensured that families referred to the service are fully supported and have access to appropriate information, and that long term follow up of participants has been secured.
“We welcome this great progress, but continued follow-up is crucially important to inform our understanding of the long-term efficacy of the treatment.”
Peter Thompson, Chief Executive of the HFEA, said:
“Ten years ago, the UK was the first country in the world to licence mitochondrial donation treatment to avoid passing the condition to children. For the first time, families with severe inherited mitochondrial illness have the possibility of a healthy child. Although it’s still early days, it is wonderful news that mitochondrial donation treatment has led to eight babies being born.
“Only people who are at a very high risk of passing a serious mitochondrial disease onto their children are eligible for this treatment in the UK, and every application for mitochondrial donation treatment is individually assessed in accordance with the law. These robust but flexible regulatory processes allow the technique to be used safely for the purposes that Parliament agreed in 2015.”
Prof Frances Flinter, Chair of the HFEA’s Statutory Approvals Committee, said:
“We are pleased to see the peer-reviewed papers published in the New England Journal of Medicine that explain what has happened to those patients who the HFEA authorised to have mitochondrial donation treatment at the Newcastle Centre at Life. These are patients for whom there was no other option to have a healthy baby who is genetically related to them, and we are delighted for those families.
“The HFEA will continue to oversee the safe use of mitochondrial donation treatment and assess each application as families come through the programme. These results are testimony to how the UK continues to be a world leader in the use of new medical techniques to change lives.”
Comment from the editor of the journal the papers are published in (so NOT third party):
Eric Rubin, MD, PhD, Editor-in-Chief, The New England Journal of Medicine, said:
“These studies unite scientific rigor, clinical innovation, and deep ethical reflection to illustrate the full research continuum from bench to bedside. At the New England Journal of Medicine, we chose to publish this work in its full context, not only to highlight the outcomes, but also to surface the critical questions it raises about translating breakthroughs into patient care. Where allowed by government regulations, this research has the potential to prevent serious inherited disease and gives parents truly meaningful new options for their children. Its publication also reminds us that preserving the infrastructure and integrity of biomedical research in the U.S. and around the world is essential if we are to continue delivering such transformative treatments to patients.”
Comments via colleagues at other international SMCs:
Prof. Dr. Marcus Deschauer, Head of the Working Group on Rare Hereditary Neurological Diseases and Senior Physician at the Clinic and Polyclinic for Neurology, Klinikum rechts der Isar, Technical University of Munich (TUM), said:
“To my knowledge, this is the first publication of a larger cohort of families/mothers with mitochondrial DNA (mtDNA) disorders who have given birth to children after pre-implantation genetic diagnosis or mitochondrial donation. The work is therefore very important for assessing the effectiveness and risks of these methods in practice.”
“Per se, the study includes well-studied families with reliable data, but it was not possible to prevent the transmission of the disease-causing mtDNA variants in all families.””A certain carry-over of mtDNA with a disease-causing variant occurs during pre-cell nucleus transfer. It cannot be ruled out that the proportion of mutated mtDNA will continue to increase over the course of a lifetime after carry-over. However, this is unlikely: for example, in patients with the m.3243A>G variant, the degree of heteroplasmy in the blood decreases over the course of life.“
”The follow-up periods are not yet sufficient to assess the risks of later disease. Manifestation of an mtDNA disease at a later stage is conceivable in children.””A pathological mtDNA variant is identified in women who can pass it on by means of molecular genetic testing if the woman has symptoms of a mitochondriopathy. There are also cases in which molecular genetic diagnostics are performed for another indication – such as the search for another genetic disease – and a pathological mtDNA is detected. However, according to the ACMG recommendations, this should not be disclosed by genetic laboratories.“
”Until now, the lack of data has made it difficult to advise women with mitochondrial diseases on their desire to have children. The DGN guideline ‘Mitochondrial Diseases’ states: ‘Human genetic counselling is particularly complex when it comes to the desire to have children. Prenatal diagnosis can be routinely performed for nuclear mutations, but is more limited for mutations of mitochondrial DNA. The data on preimplantation diagnosis as a means of preventing or reducing the risk of inheritance of pathogenic mitochondrial DNA mutations is extremely limited, and the method is subject to the Preimplantation Diagnosis Ordinance in Germany. These two studies from Newcastle are helpful for counselling.“
”Whether a woman with mtDNA disease can expect an uncomplicated pregnancy also depends on the manifestation/severity of the woman’s disease. In cases of significant muscle weakness (including respiratory muscle weakness), this may increase during pregnancy. Natural childbirth may be difficult, making a caesarean section necessary.”
“If the mitochondrial donation procedure were also permitted in Germany, this would be an option for selected women with an mtDNA disease to significantly reduce the risk of passing on a disease-causing mtDNA variant with a heteroplasmy level above a disease-causing threshold. This would increase the chances of healthy children for families.”
“However, the data from Newcastle do not suggest that the methods used can guarantee that the disease will not be passed on. In some mtDNA variants, the severity of the disease clearly depends on the degree of heteroplasmy in the blood, so that a reduction in the degree of heteroplasmy in such cases could lead to a milder form of the disease in children.”
“In the short term, there are no good therapeutic methods for treating mtDNA diseases, so preventing the transmission of mtDNA diseases is the better option. I also consider it difficult to successfully treat children who have inherited an mtDNA variant in the medium term, as gene therapy must reach the DNA in the mitochondria. There is the example of 5q-associated spinal muscular atrophy, in which infants diagnosed in newborn screening can be treated very successfully. Unfortunately, this is not expected to be the case for mtDNA diseases in the near future.””I consider it unlikely that the two children who were symptomatic have a maternally inherited mitochondriopathy. In the case of the child with epilepsy, I would even classify this as very unlikely. I consider the authors’ assessment that the reproductive technology procedure itself or pregnancy complications or metabolic disorders in the mother may be responsible for the symptoms of the two children to be plausible.”
Nuno Costa-Borges, researcher and embryologist, scientific director and CEO of Embryotools, Barcelona Science Park, says:
“As a pioneering center in mitochondrial replacement therapies (MRT), Embryotools welcomes the recent publication by Hyslop et al. in The New England Journal of Medicine, reporting outcomes from pronuclear transfer (PNT) to prevent the transmission of mitochondrial DNA (mtDNA) disease. The study reports the birth of eight babies—four girls and four boys, including one set of identical twins—born to seven women at high risk of transmitting severe mtDNA disorders. Importantly, all infants are healthy and show no signs of mitochondrial disease. However, the detection of low-level postnatal mtDNA heteroplasmy (“reversal”) in 3 of the 8 infants (5%–16%) deserves particular discussion.
“Due to UK regulations that prohibit testing for heteroplasmy in embryos, the timing of this reversal could not be pinpointed. Their analysis relied on arrested embryos and blood samples from newborns, which limits interpretation. In contrast, our recent pilot trial using maternal spindle transfer (MST)—a form of MRT where mitochondrial replacement occurs in the oocyte before fertilization—in infertile patients led to seven live births, two of which also showed reversal, a comparable frequency. However, our approach included direct assessment of heteroplasmy in blastocysts and, longitudinally, in multiple tissues including amniotic fluid. This allowed us to accurately define that reversal occurred between the blastocyst stage and mid-gestation (~15 weeks), reinforcing the importance of prenatal testing to detect reversal early and guide clinical decision-making. In our study, all infants are also healthy and have been followed up showing no adverse events.
“This phenomenon—mtDNA ‘reversal’—has previously been described in human cells in vitro but not in MRT-derived children. Minimal levels of maternal mtDNA carryover can expand substantially, potentially compromising the efficacy of MRTs to prevent mitochondrial disease. The biological mechanisms underlying this selective amplification remain unclear but appear to occur early in development, and instances may therefore be detectable using prenatal testing. It is worth noting that the impact of mtDNA reversal in infertility treatments is likely less concerning, as maternal mtDNA in these cases does not carry pathogenic mutations. Moreover, with appropriate matching of mtDNA haplotypes between the mother and donor, the biological consequences of low-level heteroplasmy could be further minimized or even rendered clinically irrelevant.
“Currently, only the UK and Australia have regulated the use of MRT to prevent transmission of mtDNA mutations. We believe that other countries should adopt similar regulatory models. In particular, MRT should also be contemplated for infertility treatment. Infertility is a disease recognized by the WHO, and MRT can offer a genetic link to the mother for patients who would otherwise rely on egg donation. This justification aligns with the ethical principles underpinning MRT for disease prevention. As a pioneer group in this technology, Spain should lead in regulating these applications to ensure patient safety and prevent reproductive tourism to countries where such techniques may be offered without appropriate oversight.
“In light of these findings, we reaffirm the urgent need to continue performing well-regulated, larger, long-term studies to fully evaluate the safety, efficacy, and clinical implications of MRTs. Ongoing research under appropriate oversight is essential to ensure the responsible development of these technologies, improve genetic counseling, and support informed decision-making by patients and clinicians alike.
“We also advocate for thoughtful regulatory evolution that upholds patient autonomy, scientific excellence, and the principle of reproductive justice.”
Dr. Dunja M. Baston-Büst, Deputy Head of the IVF Laboratory, UniCareD Cryobank, and UniKiD Research, University Hospital Düsseldorf, Germany, said:
“Since there are currently no curative therapies for mitochondrial diseases, advances in assisted reproductive technology open up new possibilities for reducing the transmission of such variants. Preimplantation genetic diagnosis, which is commonly used to detect defects in nuclear DNA, can also be used to identify embryos with a low proportion of maternal pathogenic mitochondrial DNA variants, thereby reducing the risk of disease.
“The replacement of the donor’s zygote pronuclei with the patient’s pronuclei was successful in 127 of 160 cases (79.4 per cent). Of the 127 embryos resulting from this, 122 (96.1 per cent) were still intact on the following day (day 1). The number of intact zygotes per pre-nuclear transfer performed (33 procedures in total) ranged from zero to seven.
“In 37 of the 39 patients (95 per cent) in the preimplantation diagnosis group, the embryos were assessed on the third day after intracytoplasmic sperm injection (ICSI). For preimplantation diagnosis, a blastomere was biopsied on day three of embryonic development and transfer was usually performed in the fresh cycle after analysis of the mitochondrial DNA from the blastomere.
“Implementation in Germany is not possible under the current legal requirements (Embryo Protection Act), as egg donation is prohibited.
“The earlier and more severe a mitochondrial disease occurs, the earlier patients can be identified. Patients in Germany receive comprehensive human genetic or interdisciplinary counselling in accordance with the current S1 guideline ‘Mitochondrial Diseases’. A decision regarding the options for reproductive measures and possible preimplantation diagnosis is made in consultation with the patients and depending on the degree of heteroplasmy. Pre-implantation genetic screening is not possible in Germany due to the ban on egg donation. The alternatives are egg donation abroad or adoption.
“A patient registry for mitochondrial diseases was established in Germany in 2009. It would be beneficial for reproductive medicine if reproductive outcomes were also collected there, or analysis results if preimplantation diagnosis was performed. Unfortunately, there is no cross-linking between the registries.
“Furthermore, the search for biomarkers is generally supported in Germany in order to increase the diagnostic accuracy for mitochondrial diseases.
“For reproductive medicine, I currently see no application of the technology presented in the study in Germany without a comprehensive revision of the Embryo Protection Act and the legalization of egg donation.
“The new EU SOHO Regulation will come into force in the next few years. Its main purpose is to provide greater protection for the genetic background of children born from egg and sperm donation (in addition to the amendments to the sperm donation register), so that many questions will still arise in the case of three-parent constellations.
“In mitochondrial donation using pre-nucleation transfer, the nuclear genome is transferred from a fertilized egg cell of the affected woman to an enucleated, fertilized egg cell from a healthy donor. The pronuclei are removed individually from the patients’ zygotes and, after brief treatment with a fusion agent (haemagglutinating virus from the Japanese shell), are placed together under the zona pellucida (protective shell around the egg cell; editor’s note) of the enucleated donor egg cell. Based on findings from preclinical studies, it is standard practice to freeze (vitrify) the eggs of patients for whom pre-nuclear transfer is planned, as donor eggs are not always available at the same time and in sufficient quantities.
“Pathological variants of mitochondrial DNA can be either homoplasmic (present in all mitochondrial DNA copies) or heteroplasmic (present in only some of the copies). Homoplasmic variants are passed on completely to all offspring, but their expression (penetrance) can vary from individual to individual.
“Clinical pregnancies were confirmed in eight of 22 patients (36 per cent) who underwent intracytoplasmic sperm injection (ICSI) as part of preimplantation genetic testing, and in 16 of 39 patients (41 per cent) who underwent ICSI as part of preimplantation genetic diagnosis (PGD). Pronuclear transfer resulted in eight live births and one ongoing pregnancy. PGD resulted in 18 live births.
“Heteroplasmy levels in the blood of the eight infants after pronuclear transfer ranged from undetectable to 16 per cent. Compared to the enucleated zygotes, the proportion of diseased maternal mitochondrial DNA was reduced by 95 to 100 percent in six newborns and by 77 to 88 per cent in two newborns. Heteroplasmy data were also available for ten of the 18 infants after preimplantation genetic diagnosis, with values ranging from undetectable to seven percent.
“For reasons that are still unclear, the small amount of transferred maternal mitochondrial DNA can rise to homoplasmic levels in about 20 per cent of embryonic stem cell lines derived from embryos after mitochondrial donation. In addition, one in six infants born after maternal spindle transfer for the treatment of infertility had elevated heteroplasmy levels (40 to 60 per cent) of maternal mtDNA. These observations raise the question of whether mitochondrial donation can reliably prevent the transmission of diseased mitochondrial DNA in all cases, especially in homoplasmic variants.
“Approximately one in 5,000 people develop a mitochondrial disease, making it one of the most common hereditary diseases, although the symptoms can often vary greatly. The symptoms of mitochondrial diseases are very diverse and can affect various organs, for example the muscles with muscle weakness and pain, the nervous system with encephalopathy, epilepsy and neurological disorders, the heart with heart muscle disease, the eyes with blindness and visual impairment, the ears with hearing loss and the endocrine system with diabetes mellitus.
“Other examples of mitochondriopathies with named syndromes include: autosomal dominant optic atrophy (ADOA) with slowly progressive, usually bilateral, central vision loss; Kearns-Sayre syndrome with cardiac conduction disorders, degenerative changes in the retina, and external ophthalmoplegia; chronic progressive external ophthalmoplegia, which is an incomplete form of Kearns-Sayre syndrome and is characterized by external ophthalmoplegia; MERRF syndrome with cerebellar ataxia, myoclonus, generalized seizures, short stature, and dementia; MELAS syndrome with seizures, dementia, and headaches.
“In addition to the disease entities listed here, there are a number of other, sometimes very rare syndromes that can be classified as mitochondriopathies but have often been little researched or not yet described.”
Dr Holger Prokisch, Head of the Mitochondrial Genetics Research Group, Helmholtz Centre Munich – German Research Centre for Health and Environment, Munich, said:“The field of mitochondrial medicine has been eagerly awaiting the results of this study. The robust data describe a real breakthrough for women with a (nearly) homoplasmic pathogenic mitochondrial DNA (mtDNA) variant in terms of their ability to probably have healthy genetically related children. The risk of the children to develop the disease after preimplantation genetic testing is minimal. All gene variants tested require very high heteroplasmy for the disease to manifest, or are typically homoplasmic.“”There is an observation in the literature that in a few cases, the mother’s mutated DNA is revised. Interestingly, this also involves an LHON mutation (Leber’s hereditary optic neuropathy) [3] [4], which is almost always homoplasmic in the population and, according to recent data, has a low penetrance of less than five percent for LHON disease [5] (only five percent of gene carriers also develop the disease; editor’s note). In this respect, the selection of mutation carriers for this study with four LHON mutations is not entirely fortunate. The homoplasmy of the LHON variants suggests that they may offer a selective advantage [6]. Since mitochondrial transfer does not eliminate the mutation, there is a risk that the mutation will be passed on to the next generation. This often leads to significant shifts in heteroplasmy, sometimes to the detriment of patients. However, disease-causing variants tend to have a selection pressure [6].“Human studies show no risk of incompatibility between the donor mtDNA and the parents’ nuclear DNA.””There is no newborn screening for mitochondrial DNA mutations. Women are identified as mutation carriers when they or one of their children develop the disease. Prediction or risk assessment for the next generation is difficult for mtDNA mutations in the mother. Many centers for mitochondrial diseases work with the group in Newcastle to provide information about the options available there or to offer preimplantation genetic diagnosis.”[3] Hudson G et al. (2019): Reversion after replacement of mitochondrial DNA. Nature. DOI: 10.1038/s41586-019-1623-3.
[4] Kang E et al. (2016): Mitochondrial replacement in human oocytes carrying pathogenic mitochondrial DNA mutations. Nature. DOI: 10.1038/nature20592.
[5] Mackey DA et al. (2022): Is the disease risk and penetrance in Leber hereditary optic neuropathy actually low?. The American Journal of Human Genetics. DOI: 10.1016/j.ajhg.2022.11.014.
[6] Kotrys AV et al. (2024): Single-cell analysis reveals context-dependent, cell-level selection of mtDNA. Nature. DOI: 10.1038/s41586-024-07332-0.
Prof. Dr. Nils-Göran Larsson, Group Leader “Maintenance and expression of mtDNA in disease and ageing”, Department of Medical Biochemistry and Biophysics, Karolinska-Institut, Stockholm, Schweden, said:
“The study in NEJM is very important and represents a breakthrough in mitochondrial medicine. It should be remembered mitochondrial diseases can be devastating and cause substantial suffering in affected children, sometimes leading to an early death. Families are profoundly affected and the paper in NEJM describe how birth of affected children can be prevented by mitochondrial donation.
“This advanced procedure is not a disease-treatment but rather an intervention that minimizes the transmission of mutated mtDNA from mother to child. For affected families this is a very important reproductive option. The paper describes a relatively small series of 8 babies born after mitochondrial donation by pronuclear transfer. The paper is carefully done and of very high quality but as always in science the results need to be confirmed by independent studies. Also, long-term clinical follow-up studies of born babies will give additional information about the safety and efficacy of mitochondrial donation.”
“Before this procedure was applied to human reproduction there was a very long development and evaluation process. There has been a lot of constructive discussion in the scientific community, and the UK Parliament approved legislation allowing mitochondrial donation in 2015.”
“Mitochondrial donation by the pronuclear transfer procedure always leads to carry-over of some mitochondria from the mother and mutant mtDNA can be transferred. The data presented in the NEJM paper shows that mutant mtDNA was not detected in blood of 5 of the born children. However, in three children, low levels of mutant mtDNA were detected in blood. These low levels of mutant mtDNA are unlikely to cause mitochondrial disease but additional follow-up studies are needed. As pointed out by the authors, the mitochondrial donation by pronuclear transfer should be regarded as a risk-reduction strategy. As always, when it comes to new medical procedures there is a need for validation by independent studies. Also, additional long-term follow-up studies of children born after mitochondrial donation will be needed.”
“The authors report that the transferred mtDNA has no mutations and the donor mtDNA is therefore unlikely to cause disease or impact ageing. During normal ageing, mtDNA acquires mutations (somatic mutations), e.g., during the massive cell division when the embryo is formed and develops. These mutations are typically present at low levels but accumulate to high levels in a subset of cells in many different ageing tissues. The mitochondrial donation involves transfer of mtDNA without mutations and there is no reason to believe that the donor mtDNA will additionally impact the ageing process.”
“When it comes disease-causing mtDNA mutations that are present in all copies (i.e., homoplasmic mtDNA mutations) there is currently no alternative to mitochondrial donation to prevent transmission of mutated mtDNA from mother to child. It is possible that alternate methods will be available in the future, e.g., correction of mutant mtDNA by gene editing techniques. There are currently a few promising pharmacological therapies for mitochondrial disease, e.g., nucleoside therapy for mtDNA depletion disorders. It is likely that more treatments will be available in the near future because this field is rapidly developing.”
Prof. Dr. Heidi Mertes, Associate Professor in Medical Ethics, Department of Philosophy and Moral Sciences, Ghent University, Belgien, said:
“I am happy to see that the first results from the Newcastle University group are now finally published, after being granted a license by the HFEA in 2017, and that the eight resulting children are in good health. However, while the results show that the technique is feasible and can lead to a substantial reduction of the mutation load in the resulting children, it also shows that we need to tread very carefully.”
“In line with previous research by the group of Nuno Costa-Borges [1], this research confirms the possibility of reversal (meaning that although there is only a small fraction of the intended mother’s mitochondrial DNA (mtDNA) in the embryo, this fraction sometimes increases substantially as the foetus develops), which could still result in mitochondrial diseases in the resulting children. Fortunately, preliminary research does indicate that while the mutation loads appear to increase between the embryonic phase and birth, they appear to remain stable after birth.”
“These are very important results as there was a lot of uncertainty over the safety of MRT. Using PGT when possible and reserving MRT for those cases in which PGT cannot offer a solution was a prudent approach given the experimental nature of MRT. It will be interesting to see more data in the future on whether reversal is more frequent in MRT or PGT, so that the safest procedure can be selected.”
“Although the heteroplasmy-levels are limited in this study, it does show that reversal is a real danger for the offspring, which can have serious health implications. At least three things follow from this.”
“First, people entering into this and future clinical trials will need to be extensively counselled that this is not a risk-elimination treatment, but a risk-reduction treatment.”
“Second, we need more research into the mechanisms that trigger reversal, so that it can be prevented before this technique is implemented in routine care + We need follow-up research in the children born after MRT.”
“Third, it is important to keep in mind that by framing this as a risk-reduction strategy, we are ignoring the possibility of conceiving through a traditional egg donation procedure. While genetic parenthood is evidently important to many people, the trade-off that we are making here is that between a genetically related child with a high risk of mitochondrial disease (natural conception), a genetically related child with a reduced risk of mitochondrial disease (PGT or MRT) and a non-genetically related child with the near-absence of a risk of mitochondrial disease (through donor conception). If people who would have chosen for donor conception now opt for MRT, this is actually a risk-increasing technology, rather than a risk-reducing one.”
“This strategy lowers the risk of mitochondrial disorders in the children when the point of comparison is natural reproduction by the parents, but the safest option is still donor conception, which eliminates the risk of passing on the mitochondrial condition, rather than reducing it.”
“While the donor plays an essential role in the birth of the child, attributing them a parenthood-status based on a small genetic contribution appears unwarranted. At the same time it would be correct to call them a ‘genetic progenitor’ or ‘genetic contributor’.”
“While the group of Nuno Costa-Borges ([1] [2]) received a lot of backlash for performing their MRT clinical trial in people with repeated IVF failure, rather than people with mitochondrial diseases, we must acknowledge in hindsight that given the phenomenon of reversal, their approach might have been the more prudent one. In their study they observed reversal in one infant going from <1% of maternal mtDNA at the blastocyst stage to 30-60% (depending on the tissue type) at birth. This was fortunately not a problem as the maternal mtDNA was not disease-causing, but a similar level of reversal may have devastating consequences in a clinical trial in women with mitochondrial disorders, such as the one reported on in the NEJM today.”
[1] Costa-Borges N et al. (2023): First pilot study of maternal spindle transfer for the treatment of repeated in vitro fertilization failures in couples with idiopathic infertility. Fertility and Sterility. DOI: 10.1016/j.fertnstert.2023.02.008.
[2] Savash M et al. (2025): Mitochondrial DNA ‘reversal’ is common in children born following meiotic spindle transfer, potentially reducing the efficacy of mitochondrial replacement therapies. Konferenzabstract.
Prof David Thorburn, co-Group Leader of Brain & Mitochondrial Research at Murdoch Children’s Research Institute and the University of Melbourne, said:
“Mitochondrial donation was legalised in the UK in 2015 and in Australia in 2022. It was clearly a complex process in the UK to develop the approvals processes, the clinical and lab pathways, cope with delays from COVID and accumulate sufficient outcomes to publish them without impinging on the privacy of the families involved.So it is very exciting to see the first publications describing results for the first 8 babies born in the UK program. The initial results demonstrate that the approach is effective in reducing the risk of having a child with mitochondrial DNA disease for women who are at high risk. For about three quarters of couples participating in the pronuclear transfer method, at least one suitable embryo was generated. About 40% of these couples had a baby and all were healthy and had undetectable or low levels of the abnormal mitochondrial DNA. Three babies had short-term symptoms that resolved and did not appear to relate to mitochondrial disease. All babies are developing normally to date, with the oldest 5 years of age.The studies emphasise that longer-term followup needs to be performed, and the efficiency of the method could be further improved to achieve higher pregnancy rates. They demonstrate the value of offering the program in conjunction with other reproductive options, such as pre-implantation genetic testing, which can be effective in women with lower risk. I regard these results as very encouraging and supporting the ongoing development and use of mitochondrial donation in the UK and Australia.
Dr Santiago Restrepo Castillo, biomedical engineer and postdoctoral researcher at the University of Texas at Austin (USA), said:
“Mitochondrial diseases are a group of chronic metabolic disorders that can be fatal. These diseases are caused by mutations in the human genome, which consists of nuclear DNA and mitochondrial DNA. In particular, metabolic disorders caused by mutations in mitochondrial DNA, which affect one in five thousand people, are maternally inherited and currently incurable. In recent years, there have been major advancements in the development of strategies for the treatment or prevention of genetic disorders caused by mutations in nuclear DNA. In contrast, similar strategies for diseases caused by alterations in mitochondrial DNA have remained largely understudied. Aiming to establish a preventive strategy for metabolic diseases caused by mitochondrial DNA mutations, the authors of this pair of studies published in the New England Journal of Medicine developed an integrated program of preimplantation genetic testing and pronuclear transfer (PGT and PNT, respectively). In this program, female patients carrying mitochondrial mutations underwent PGT to identify embryos with low levels of mitochondrial DNA mutations. In cases where an embryo with these characteristics was identified, the embryo was implanted in the patient and the course of the pregnancy was monitored. In addition, in cases where it was not possible to identify embryos with low levels of genetic alterations, the patients underwent PNT, a procedure in which mitochondrial DNA without mutations is obtained from a donor. Encouragingly, through this integrated PGT and PNT program, at the time of publication, the authors have already demonstrated a significant reduction in the maternal transmission of mitochondrial mutations in eight cases. Furthermore, the children born from these cases have shown normal development. In conclusion, this study represents a major advancement in the field of medical genetics and genomics. Understanding the current limitations of mitochondrial gene editing, which would allow genetic alterations to be corrected in different contexts, the authors chose to explore a procedure that cuts the problem off at the root by preventing the transmission of the mutated genetic material. Furthermore, this pair of studies demonstrates clinical benefits in children who, without the integrated PGT and PNT program, would likely have been born with debilitating or fatal genetic mutations. It will be exciting to see if the benefits are maintained over time, and it will be critical to further develop this integrated process to increase its success rates”.
Prof Lluís Montoliu, Research Professor at the National Biotechnology Centre (CNB-CSIC) and at the CIBERER-ISCIII, Spain, says:
“In 2016, John Zhang, a specialist doctor at an assisted reproduction clinic in New York called the New Hope Fertility Center, crossed the border into Mexico to perform a procedure that was banned in the US and not yet regulated in Mexico. A couple from Jordan had come to this clinic hoping to have viable offspring. The couple had already had two children who had died from Leigh syndrome, one of several mitochondrial diseases that are often devastating and untreatable. Mitochondria (our energy factories) are usually inherited from the mother, from the egg. The mother had approximately 25% of her mitochondria affected, and these were the ones she had passed on to her two deceased children. Dr. Zhang did not use the procedure pioneered in the UK because of the couple’s Muslim faith, which opposed the destruction of human embryos. Instead, he chose to extract the nucleus from the mother’s egg (actually the metaphase plate, an incomplete nuclear division, which is the stage at which all eggs are ready for fertilization) and transferred it to the egg of another woman (with healthy mitochondria), from which he had also previously removed the nucleus. Once the nucleus from the mother had been transferred to the egg of the second woman, he used this resulting egg to perform in vitro fertilization with sperm from the father to obtain embryos. Dr. Zhang created five embryos in this way, only one of which developed normally, was implanted in the mother’s uterus, and resulted in the birth of a healthy baby. It was the first newborn obtained using the “three-parent technique”: two mothers and one father.
“In the United Kingdom, the Human Fertilisation and Embryology Authority (HFEA) had approved another procedure in 2015, technically different but also called the “three-parent technique,” to solve problems related to mitochondrial diseases. In this case, the father’s sperm is used to fertilize (through intracytoplasmic sperm injection, ICSI) two eggs, one from the mother carrying the affected mitochondria and one from another woman with healthy mitochondria. After fertilization begins, the two pronuclei (paternal and maternal) that appear temporarily are destined to fuse and form the first nucleus of the zygote. Before this happens, researchers can extract the two pronuclei from the in vitro fertilization between the mother’s egg and the father’s sperm and transfer them to the egg of the woman fertilized by the same sperm from the father, from which the pronuclei will have been previously removed. The result is that the egg with the woman’s healthy mitochondria hosts the two pronuclei of the couple, whose baby will be born without the mitochondrial genetic disease and will be genetically from both the father and the mother. The healthy mitochondria will come from the female donor. In this procedure, which is methodologically somewhat more aggressive than the previous one but less risky, one embryo is destroyed to create another, something that the Muslim couple assisted by Dr. Zhang considered unacceptable. The first baby in the United Kingdom obtained through the authorized British three-parent procedure was born in 2023.
“Ten years later [after the approval of this technique in the UK], a team of British and Australian doctors and researchers published the results of applying the British “three-parent” technique to 22 women carrying pathogenic mutations in their mitochondria (and therefore at high risk of having children born with these incurable diseases) in the prestigious New England Journal of Medicine (NEJM). Of the 22 women treated, only 8 gave birth (36%), and one more pregnancy is still in progress. The eight babies born are healthy, with no signs or very low levels of affected mitochondria, which are not sufficient to cause the disease. So far, all eight children are doing well. Only a couple of them developed minor clinical problems, initially unrelated to the procedure, which were resolved with treatment or spontaneously. In addition, the researchers applied a second technique (preimplantation genetic testing, or PGT) to women with heteroplasmy (a mixture of healthy and affected mitochondria) to assess the percentage of affected mitochondria in babies obtained through in vitro fertilization and select those with lower values of affected mitochondria. In this case, they obtained 16 pregnancies from 39 women (41%) with the result of 18 babies born with a percentage of affected mitochondria of less than 7%.
“In Spain, our Law 14/2006 of May 26 on assisted human reproduction techniques does not explicitly refer to this technique (which did not exist when this legislation was passed), so sensu stricto the procedure is neither expressly prohibited nor explicitly authorized in our country. Essentially, it is not regulated. The legal and ethical doubts that remain have so far prevented the three-parent technique from being applied in Spain.However, this new study shows that the technique has a remarkable success rate (36%) that could well be offered to couples in which the mother is a carrier of affected mitochondria to have offspring free from terrible mitochondrial diseases. Personally, I believe that we should allow this technique in our country in assisted reproduction clinics that have adequate training in this sophisticated method of embryo intervention.”
Dr Paul Wuh-Liang Hwu, Professor, College of Medicine, Pediatrics, National Taiwan University, Taipei, Taiwan / Distinguished Research Fellow, China Medical University Hospital, Taichung, Taiwan, said:
“In this week’s New England Journal of Medicine, two research articles published by groups of researchers from the UK describe the success of mitochondrial donation treatments for mitochondrial DNA (mtDNA) diseases. Each human cell contains a few hundred mitochondria. The mitochondrion is a double membrane-bound organelle, and each mitochondrion contains a few copies of double-stranded, circular DNA molecules of around 16,500 genetic units (base pairs).
“Mitochondria are responsible for energy (ATP) production, fatty acid oxidation, and some other functions for the cells. Pathological variations or deletions of mitochondrial DNA can impair mitochondrial function, and when the proportion of defective mitochondria (heteroplasmy level) is high, cause serious symptoms involving the brain, muscle, and metabolism. During reproduction, all mitochondria are inherited from the mother (the egg). However, the level of defected mitochondria in offspring can be very different from their mothers, leaving reproduction planning almost impossible.
“In the two studies, mitochondrial donation by pronuclear transfer (PNT) was conducted to reduce the reproductive risk of women with mitochondrial diseases. Both the mitochondrial donor and patient eggs were fertilized first.
The nucleus of the donor’s fertilised egg was removed and discarded, leaving behind a fertilised egg without a nucleus but with healthy mitochondria. The nucleus from the patient’s fertilised egg was then transferred into this enucleated donor egg.
“The PNT zygote was then cultured and implanted to continue pregnancy. All live births were in good health and with low levels of defective mitochondria. PNT has been widely used in animal research and now proved to be safe and efficient in humans. This breakthrough gives a reproductive choice for women affected with mitochondrial diseases, which is very important for the patients and their families. However, this study also broke the ban for continuing pregnancy of genetically manipulated human embryos. One argument is that PNT does not really touch the genetic materials but only provides normal mitochondria. The excellent outcome of this study also eases the concerns of nuclear/mitochondrial genome compatibility and other safety issues. Nevertheless, one may still worry if this technology will be abused to improve human physiological quality, for example, creating a body with more efficient energy production. Then, how about adding a little bit of normal, or good, DNA to the nuclear genome, if we can do that safely?
“As doctors and researchers who take care of patients with genetic disease, we welcome inventions, including reproduction medicine, that can help patients. Certainly, before the safety of new treatments can be confirmed, they should be used in patients with no other choices, or with a favorable benefit over risk. Recently, gene therapies, including gene editing treatments, are rapidly developing, offering hope to patients who previously have no option for treatment. However, we need to ask people to restrain themselves, not to apply PNT or gene therapy to improve the health of people without a medical condition, but to let these new treatments be developed to rescue lives of patients.”
Prof Lee Chung-His Professor, Graduate Institute of Health and Biotechnology Law, Taipei Medical University, Taipei, Taiwan, said:
“Pronuclear Transfer Technology: Advancing with Cautious Innovation and International Consensus. While early clinical results show promise in reducing the level of pathogenic mitochondrial DNA in newborns, the application of Pronuclear transfer (PNT) raises significant ethical and regulatory questions that must be addressed through both national oversight and international dialogue. From a bioethical standpoint, germline modification—defined as altering genetic material in a way that affects future generations—has long been met with caution. This is because it involves irreversible changes to the human genome, with potential consequences not only for the individuals born from such interventions but also for society’s understanding of what it means to be human.
“Pronuclear transfer, however, occupies a unique space in this debate. It targets mitochondrial DNA, which, although essential for cellular energy production, contributes relatively little to traits traditionally associated with identity, such as physical appearance, personality, or intelligence. Because of this limited influence on key phenotypic characteristics, PNT is viewed by some as an acceptable “ethical testing ground” for germline-level intervention. Rather than resorting to high-risk gene therapy after the onset of a hereditary disease, using PNT technology to reduce the likelihood of disease is a more ethically acceptable option. It provides a possible pathway to explore the responsible use of reproductive technologies without crossing the bright-line boundaries typically drawn around nuclear DNA modification.
“Nonetheless, mitochondrial DNA modification is not without ethical complexity. Even if its direct functional role is narrower, it still involves heritable changes and the creation of embryos with genetic contributions from three individuals—the intended mother and father, and a mitochondrial donor. This raises questions about identity, kinship, and the rights of the resulting child, especially regarding disclosure and autonomy. Moreover, the long-term health effects of such interventions remain unknown. To prevent a gradual erosion of ethical boundaries, transparent ethical review processes and long-term clinical monitoring must be established as foundational requirements for any country considering the use of PNT.
“From a clinical perspective, preimplantation genetic testing (PGT) should remain the first-line option for reducing the risk of mitochondrial disease transmission. PGT is a more established and less invasive method that allows for the selection of embryos with minimal or undetectable levels of pathogenic mitochondrial DNA. In many cases, this approach has proven effective and carries fewer biological and ethical uncertainties than PNT. In contrast, PNT is a more complex and experimental procedure that combines nuclear DNA from the parents with mitochondrial DNA from a donor egg, and it may result in lower fertilization rates or higher embryonic loss. Therefore, in keeping with the precautionary principle in bioethics, PNT should be considered only when PGT is not feasible or has been shown to be ineffective.
“The United Kingdom currently leads in the clinical implementation of PNT, having established a strict licensing and regulatory regime through the Human Fertilisation and Embryology Authority (HFEA). The UK’s model reflects a commitment to enabling scientific advancement while maintaining ethical vigilance. However, reproductive technologies such as PNT are inherently transnational. If only a few countries offer access to such procedures, it may prompt “reproductive tourism”, whereby patients travel abroad to seek unregulated or less strictly governed treatments, potentially undermining safety standards and ethical norms.
“For this reason, a coordinated international approach is urgently needed. The World Health Organization (WHO) and the World Medical Association (WMA) are well-positioned to initiate global discussions and help formulate shared ethical guidelines and governance frameworks. These discussions should encompass not only scientific and medical dimensions but also social, cultural, and legal implications. Establishing minimum ethical standards and oversight mechanisms will help ensure that the benefits of PNT are pursued responsibly and that global health equity and ethical integrity are preserved.”
‘Mitochondrial Donation and Preimplantation Genetic Testing for mtDNA Disease’ by Louise A. Hyslop et al. and ‘Mitochondrial Donation in a Reproductive Care Pathway for mtDNA Disease’ by Robert McFarland et al. was published in The New England Journal of Medicine at 22:00 UK time on Wednesday 16th July.
DOI: 10.1056/NEJMoa2415539
DOI: 10.1056/NEJMoa2503658
Declared interests
Dr David J Clancy: No interests to declare
Prof Joanna Poulton: Nothing to declare
Prof Dusko Ilic: No conflicts of interest
Prof Dagan Wells: I don’t think I have any declarations relevant to this.
Dr Andy Greenfield: Andy was a member of the board of the Human Fertilisation & Embryology Authority (HFEA) from 2009 to 2018; he was a member of its Scientific & Clinical Advances Advisory Committee (SCAAC) and Chair of its Licence Committee. He chaired the 3rd and 4th preclinical scientific reviews of the safety and efficacy of mitochondrial donation, in 2014 and 2016. Andy chairs the Independent Advisory Committee of the MitoHOPE Program in Australia. He is also a member of the board of the Human Tissue Authority (HTA), the Regulatory Horizons Council (RHC), the Advisory Committee on Novel Foods and Processes (ACNFP) and Singapore’s Ministry of Health Regulatory Advisory Panel. Andy’s programme of research in developmental genetics was funded by the Medical Research Council at its Harwell Unit from 1996 to 2021. All opinions expressed are his own and not necessarily shared by any organisations with which he is associated.
Mr Stuart Lavery: No DOIs
Prof Bert Smeets: I am scientific advisor for the HFEA on PNT applications.
Sarah Norcross: PET – https://www.progress.org.uk/ – is a charity that improves choices for people affected by infertility and genetic conditions, and that campaigned for the introduction of the Human Fertilisation and Embryology (Mitochondrial Donation) Regulations 2015 into UK law.
Beth Thompson: Wellcome funded research into mitochondrial donation and co-funded the clinical trial to assess the safety and effectiveness of the treatment.
Danielle Hamm: The Nuffield Council on Bioethics conducted an ethical review of new techniques that aim to prevent the transmission of maternally-inherited mitochondrial DNA disorders in 2012. The report and key findings of the review are available here.
HFEA: As of 1 July 2025, 35 patients have been given approval for mitochondrial donation treatment by the HFEA Statutory Approvals Committee. These decisions are made on an individual case by case basis where there are no other options for the families involved and in strict accordance with the law. The published papers set out that 25 of those patients have undergone pronuclear transfer (mitochondrial donation treatment.)
Prof. Dr. Marcus Deschauer: “Apart from the fact that I spent six months as a researcher in the Mitochondrial Research Group over 20 years ago and subsequently collaborated with the group on scientific projects, and that I am of course well acquainted with some of the co-authors of the two papers, I have no conflicts of interest.”
Dr. Dunja M. Baston-Büst: “I have no conflict of interest.”
Dr Holger Prokisch: “I have no conflicts of interest.”
Prof. Dr. Nils-Göran Larsson: “I have no conflicts of interest with this work.”
Prof. Dr. Heidi Mertes: “I have no conflicts of interest.”
Prof David Thorburn: David has declared he has no financial conflicts of interest and has the following unpaid positions:
Board Member of the Mito Foundation (the major relevant mito advocacy group) and he played a prominent role in their advocacy for legalising mitochondrial donation in Australia.
He is also a Member of the MitoHOPE Executive, funded by the Medical Research Future Fund to deliver an Australian clinical trial of mitochondrial donation.
Dr Santiago Restrepo Castillo: No conflicts of interest
Prof Lluís Montoliu: He declares that he has no conflicts of interest
For all other experts, no reply to our request for DOIs was received.