Milestone in reproductive medicine: a pioneering technique that reduces the risk of mitochondrial diseases with DNA from three parents

A pioneering in vitro fertilization (IVF) technique that reduces the risk of mitochondrial diseases, approved in the United Kingdom in 2015, has led to the birth of eight healthy babies , according to research published in the New England Journal of Medicine.

The technique, known as pronuclear transfer , is performed after the egg is fertilized. It involves transplanting the nuclear genome (which contains all the genes essential for our individual characteristics, such as hair color and height) from an egg carrying a mitochondrial DNA mutation into an egg donated by a healthy woman, from whom the nuclear genome has been removed. The resulting embryo inherits nuclear DNA from both parents, but mitochondrial DNA is predominantly inherited from the donated egg. This is known as the ' three-parent technique '.

The first baby of three parents was born in 2016 thanks to Dr. John Zhang's team using a slightly different approach . Dr. Zhang did not use the procedure pioneered in the United Kingdom due to 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 to be fertilized) and transferred it to the egg of another woman (with healthy mitochondria), from whom he had also previously removed its own nucleus. Once the mother's nucleus was transferred to the second woman's egg, he used this resulting egg to perform in vitro fertilization with the father's sperm to obtain embryos. Dr. Zhang created five embryos in this way, of which only one developed normally, was implanted in the mother's uterus, and gave birth to a healthy baby. "It was the first newborn obtained using the 'three-parent technique': two mothers and one father," recalls Lluís Montoliu, a researcher at the National Center for Biotechnology (CNB-CSIC) and at CIBERER-ISCIII, in statements to SMC Spain .

The procedure approved in 2015 in the United Kingdom is technically distinct , but also known as the 'three-parent technique' to solve problems related to mitochondrial diseases. "In this procedure, methodologically somewhat more aggressive than the previous one, but less risky, one embryo is destroyed to create another, something that the Muslim couple who assisted Dr. Zhang considered unacceptable. The first baby in the United Kingdom obtained through the authorized British three-parent procedure was born in 2023 ," adds Montoliú.

Mutations in mitochondrial DNA can cause devastating diseases affecting organs such as the brain, heart, and muscles. These pathologies, transmitted exclusively through the maternal line, are often fatal.

The babies, four girls and four boys, including a pair of identical twins, were born to seven women at high risk of transmitting serious diseases caused by mitochondrial DNA mutations. The findings, published Wednesday by the Newcastle team, a pioneer in mitochondrial DNA donation using fertilized human eggs, indicate that the new treatment, known as pronuclear transfer , is effective in reducing the risk of otherwise incurable mitochondrial DNA diseases.

The findings describe the reproductive and clinical outcomes of pronuclear transfer treatments performed to date. All infants were born healthy and reached their developmental milestones , and disease-causing maternal mitochondrial DNA mutations were either undetectable or present at levels very unlikely to cause disease.

The technique was carried out on human eggs by a team based at Newcastle University, UK, and the Newcastle upon Tyne Hospitals NHS Foundation Trust in work funded by Wellcome and NHS England.

"As parents, we always wanted to give our daughter a healthy start in life. IVF with mitochondrial donation made that possible. After years of uncertainty, this treatment gave us hope and finally gave us our baby girl. Now we see them full of life and possibilities, and we are overwhelmed with gratitude. Science gave us a chance," explains the mother of one of the girls born after mitochondrial donation.

The mother of another baby says: "We are now the proud parents of a healthy baby boy—a true success of mitochondrial restoration. This breakthrough has dispelled the deep fear that haunted us. Thanks to this incredible progress and the support we've received, our little family is complete. The emotional burden of mitochondrial disease has been lifted, and in its place is hope, joy, and deep gratitude."

“Mitochondrial disease can have a devastating impact on families. Today’s news offers new hope to many more women at risk of passing on this condition, who now have the opportunity to have children who will grow up free of this terrible disease . Within a well-regulated NHS environment, we can offer mitochondrial donation as part of a research study to affected women in the UK,” said Professor Sir Doug Turnbull, a member of the team from Newcastle University.

Mitochondrial DNA is inherited through the maternal line, so these diseases are passed from mother to son. Males can be affected, but do not transmit the disease. Despite years of research, there is still no cure for people with mitochondrial DNA diseases .

In the absence of effective treatment for mitochondrial DNA diseases, attention has focused on IVF-based technologies to reduce risk by limiting the transmission of disease-causing mitochondrial DNA mutations from mother to child.

"The findings are cause for optimism. However, research to better understand the limitations of mitochondrial donation technologies will be essential to further improve treatment outcomes," says Professor Mary Herbert, lead author of the reproductive outcomes paper and who conducted the research at Newcastle University.

The team emphasizes that follow-up studies are essential to detect any patterns in childhood conditions and says they will continue to offer screenings until children turn 5.

"The results are encouraging: in six of the eight babies born, the presence of pathogenic mtDNA variants was reduced by more than 95%; in the other two, the reduction was from 77% to 88%. This demonstrates that the technique is effective in reducing the transmission of these serious hereditary diseases. However, the study also raises ethical and scientific questions. The combination of nuclear and mitochondrial DNA from different people could have as yet unknown long-term effects. Therefore, the researchers emphasize the need for rigorous monitoring of these children, which in this case will extend until they are five years old. Furthermore, they insist that this procedure should only be applied when there are no other viable reproductive alternatives," warns Rocío Núñez Calonge, scientific director of the UR International Group and coordinator of the Ethics Group of the Spanish Fertility Society, in statements to SMC Spain.

For his part, Lluis Montoliú points out that in Spain, 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 "strictly speaking, the procedure would not be expressly prohibited or explicitly authorized in our country. Essentially, it is not regulated. The legal and ethical doubts that remain have prevented, to date, the three-parent technique from being applied in Spain."

"However, this new study shows that the technique has a remarkable success rate (36%) and could be offered to couples whose mother carries affected mitochondria, so they can have offspring free of these terrible mitochondrial diseases. Personally, I believe we should allow this technique in our country in assisted reproduction clinics that have the appropriate training in this sophisticated embryonic intervention methodology," Montoliú concludes in a statement to SMC Spain.