Parental nuclear DNA (inside needle) being transferred into a donor egg. Credit: Newcastle Fertility Centre, Newcastle Hospitals NHS Foundation Trust
Eight children in the UK have been born from a pioneering IVF technique designed to reduce the risk of mitochondrial diseases – severe and often fatal conditions which affect about 1 in 5,000 births.
The 4 girls and 4 boys – including one set of identical twins – were born to 7 women at high risk of transmitting serious disease caused by mutations in mitochondrial DNA (mtDNA).
The reproductive and clinical outcomes of the “pronuclear transfer” (PNT) treatments are reported in 2 papers published in The New England Journal of Medicine a decade after the technique was first legalised in the UK in 2015.
Dr Julian Koplin, a lecturer in bioethics at Australia’s Monash University who was not involved in the research, says: “It is exciting to see early evidence that mitochondrial donation may be an effective way of increasing the reproductive options of those who are at risk of passing on mitochondrial disorders.
“These early results are encouraging, though it is important to note that they do not show that mitochondrial donation is risk free.
“Mitochondrial donation’s ability to broaden some women’s reproductive options should be celebrated. However, it is important that mitochondrial donation continues to be seen as just one option among many, including potentially safer pathways that eliminate maternal mitochondrial DNA risk altogether, like donor egg IVF.”
Mitochondrial DNA disease is a group of genetic conditions that disrupt how mitochondria – the energy producing organelles in cells – function. It particularly affects tissues with high energy demands, such as the heart, muscles and brain.
Mitochondria contain their own DNA which encodes the instructions required for energy production. This mtDNA is passed down from mother to offspring, so disease is maternally inherited.
Despite years of research there is still no cure for mtDNA disease, but the new research shows that PNT can be used reduce the risk by limiting the transmission of disease-causing mtDNA mutations from mother to child.
PNT involves transferring the nuclear genome of a fertilised egg into a donor egg, which has had its nuclear genome removed. The resulting embryo inherits its parents’ nuclear DNA but the mtDNA is inherited predominantly from the donated egg.
The technique was pioneered in human eggs by a team based in Newcastle in the UK.
Steps involved in pronuclear transfer (PNT). Credit: Monash University and MitoHOPE
Professor David Thorburn, co-group leader of brain and mitochondrial research at Murdoch Children’s Research Institute in Australia, who was not involved in the research, says: “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 3 quarters of couples participating in the PNT 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 mtDNA. 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.”
Three newborns had low levels of disease-causing mitochondrial DNA mutations: 5 and 9%, 12 and 13%, 16 and 20% in their blood and urine, respectively.
The levels are well below the 80% level required for clinical disease for these mutations. In the child with 5 and 9%, the level of the disease-causing mutation was undetectable at 18 months.
The presence of mtDNA mutations resulted from carryover of maternal mitochondria, which surrounded the nuclear DNA at the time of transplantation.
Study author Mary Herbert, professor of reproductive biology at Newcastle University and Monash University, says that while the findings give grounds for optimism “…research to better understand the limitations of mitochondrial donation technologies will be essential to further improve treatment outcomes”.
“In previous lab-based research,” she explains, “we found that carryover of even a small amount of maternal mitochondrial DNA during the pronuclear transfer procedure can increase to very high levels in embryonic cell lines.
“For this reason, mitochondrial donation technologies are regarded as risk reduction treatments. Our ongoing research seeks to bridge the gap between risk reduction and prevention of mitochondrial DNA disease.
“In the UK, mitochondrial donation treatment is performed within a strict regulatory framework under a licence granted by the Human Fertilisation and Embryology Authority. I hope that the successful outcomes reported today will help in navigating the rather complex regulatory system here in Australia.”
Dr Christopher Rudge, deputy director of the Sydney Health Law Centre at the University of Sydney who was not involved in the research, says the study emerges at a pivotal moment for Australia.
“In 2022, the Commonwealth Parliament passed the Mitochondrial Donation Law Reform (Maeve’s Law) Act. This legal change created a narrow exception to the broad prohibition on genome editing, specifically to allow mitochondrial donation to be researched and administered under strict licensing conditions.
“As reports of the Embryo Research Licensing Committee (ERLC) since 2022 show, no licence for the first clinical trial for mitochondrial donation has been issued in Australia. That is because the regulator is first building the detailed safety and ethical framework required to oversee the technology.
“This UK data is essential as both a proof-of-concept and direct evidence to inform the safety protocols and long-term monitoring for Australia’s eventual trial participants.”