Babies With DNA From Three People: The End Of Mitochondrial Disease?

A new technique, called pronuclear transfer, has been considered a breakthrough in assisted reproduction and is being used to prevent the transmission of inherited mitochondrial diseases from mother to child. The technique involves transferring the parents' nuclear DNA to a donor egg with healthy mitochondria, resulting in babies with the DNA of three people. In the United Kingdom, eight healthy children have already been born using this method, all without signs of the disease, offering hope to affected families and demonstrating that it is possible to significantly reduce the risk of these serious conditions.

Mitochondrial diseases are serious genetic conditions that affect energy production in cells. Mitochondria are small structures within cells responsible for generating the energy the body needs to function.

When there are mutations in mitochondrial DNA, which is inherited exclusively from the mother, problems can arise that affect organs and tissues with high energy demands, such as the heart, muscles, and brain. These diseases have no cure and, in severe cases, can be fatal even in childhood. It is estimated that one in 5,000 children is born with mutations of this type.

To reduce the risk of passing these mutations on to children, scientists have developed an innovative technique called pronuclear transfer.

It is performed after the egg is fertilized and works like this: first, the nucleus of the mother's fertilized egg, which contains almost all the genetic information responsible for the child's characteristics, such as eye color and height, is removed. This nucleus is then inserted into a fertilized egg from a healthy donor, whose nucleus has been removed but retains unmutated mitochondria.

This way, the baby inherits the nuclear DNA of the biological parents and the mitochondrial DNA of the donor, preventing the transmission of the disease.

This approach is part of an integrated program that also includes preimplantation genetic testing. This test analyzes embryos before pregnancy to identify whether they carry mitochondrial mutations and select only those at lower risk.

In general, women with mutations present in all copies of mitochondrial DNA, or at very high levels, receive pronuclear transfer. Those with lower levels may opt for preimplantation testing.

The results have been promising. In the United Kingdom, eight healthy babies were born using pronuclear transfer, the result of research conducted by Newcastle University and the NHS (National Health Service).

They are developing normally, with no signs of mitochondrial disease, and have very low or undetectable levels of the mutation in their blood and urine. All were born at normal birth weight and within the expected term, and were closely monitored until at least five years of age to monitor any potential long-term effects.

The program's success rates show that pronuclear transfer resulted in eight live births and one ongoing pregnancy, while preimplantation genetic testing resulted in 18 live births.

In pronuclear transfer cases, mitochondrial DNA mutation reduction reached 95–100% in some babies, ensuring that levels were well below the threshold for causing symptoms. Minor health problems appeared in three children, but all were successfully treated and are not directly related to the technique.

Legalized in the UK in 2015, this form of in vitro fertilization is strictly regulated and only available to women at high risk of transmitting serious mitochondrial diseases.

This achievement represents not only a scientific breakthrough, but also new hope for families who previously had no alternatives to break the cycle of these inherited diseases. As one mother reported: "After years of uncertainty, this treatment gave us hope, and then gave us our healthy baby. Science gave us a chance."

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Mitochondrial Donation and Preimplantation Genetic Testing for mtDNA Disease

Louise A. Hyslop, Emma L. Blakely, Magomet Aushev, Jordan Marley, Yuko Takeda, Angela Pyle, Eilis Moody, Catherine Feeney, Jan Dutton, Carol Shaw, Sarah J. Smith, Kate Craig, Charlotte L. Alston, Lisa Lister, Karina Endacott, Samantha Byerley, Helen McDermott, Kathryn Wilson, Lynne Botham, Beth Matthew, Nilendran Prathalingam, Matthew Prior, Alison Murdoch, Douglass M. Turnbull, Gavin Hudson, Meenakshi Choudhary, Robert W. Taylor, Rekha N. Pillai, Jane A. Stewart, Robert McFarland, and Mary Herbert

New England Journal of Medicine. 2025; 393 : 438-449. VOL. 393 NO. 5

DOI: 10.1056/NEJMoa2415539

Abstract: 

Children born to women who carry pathogenic variants in mitochondrial DNA (mtDNA) are at risk for a range of clinical syndromes collectively known as mtDNA disease. Mitochondrial donation by pronuclear transfer involves transplantation of nuclear genome from a fertilized egg from the affected woman to an enucleated fertilized egg donated by an unaffected woman. Thus, pronuclear transfer offers affected women the potential to have a genetically related child with a reduced risk of mtDNA disease. We offered mitochondrial donation (by pronuclear transfer) or preimplantation genetic testing (PGT) to a series of women with pathogenic mtDNA variants who sought to reduce the transmission of these variants to their children. Patients with heteroplasmy (variants present in a proportion of copies of mtDNA) were offered PGT, and patients with homoplasmy (variants present in all copies of mtDNA) or elevated heteroplasmy were offered pronuclear transfer. Clinical pregnancies were confirmed in 8 of 22 patients (36%) and 16 of 39 patients (41%) who underwent an intracytoplasmic sperm injection procedure for pronuclear transfer or for PGT, respectively. Pronuclear transfer resulted in 8 live births and 1 ongoing pregnancy. PGT resulted in 18 live births. Heteroplasmy levels in the blood of the 8 infants whose mothers underwent pronuclear transfer ranged from undetectable to 16%. Levels of the maternal pathogenic mtDNA variant were 95 to 100% lower in 6 newborns and 77 to 88% lower in 2 newborns than in the corresponding enucleated zygotes. Heteroplasmy levels were known for 10 of the 18 infants whose mothers underwent PGT and ranged from undetectable to 7%. We found that mitochondrial donation through pronuclear transfer was compatible with human embryo viability. An integrated program involving pronuclear transfer and PGT was effective in reducing the transmission of homoplasmic and heteroplasmic pathogenic mtDNA variants. (Funded by NHS England and others.)