Deadly Inherited Diseases

8 babies spared from potentially deadly inherited diseases through new IVF 'mitochondrial donation' trial

A groundbreaking trial in the U.K. has released data on eight babies born through a special IVF procedure to lower their risk of mitochondrial DNA disease. Mitochondria (pictured) carry unique DNA, but when that DNA is mutated, it can cause incurable diseases. A new trial looks at a way of lowering the risk of those conditions. (Image credit: MARK GARLICK/SCIENCE PHOTO LIBRARY via Getty Images). 

Mitochondria, the powerhouses of cells, contain their own special DNA that gets passed from mother to child - but that DNA can sometimes carry mutations, causing diseases for which there are currently no cures. Now, in a new clinical trial, eight babies who had a high risk of inheriting such diseases from their moms appear to have been spared, thanks to an emerging technique called "mitochondrial donation."

The approach used in the trial has been in development for many years and is only just making its way into human patients. Early attempts at mitochondrial donation were first described in mouse experiments published in the 1980s, said study co-author Mary Herbert, a professor of reproductive biology at Monash University in Melbourne.

After that came studies in human embryos that were fertilized through in vitro fertilization (IVF) but unfit for use, so they were instead donated for research. Then, world-first legislation passed in the United Kingdom in 2015 enabled research with good-quality human embryos, which was necessary to show the technique could actually result in a viable pregnancy. Since then, scientists have refined the approach for transferring healthy mitochondria into embryos, troubleshooting the many problems that arose along the way.

"There were hurdles at every stage," said Herbert, who also holds appointments at Newcastle University and the Newcastle Fertility Centre in the U.K. Now, the trial results, described in two reports published Wednesday (July 16) in The New England Journal of Medicine, may offer a solution to parents who otherwise have a very high likelihood of passing these diseases to their kids.

"It's just such a burden that goes down through the generations of women in these families," Herbert said. "It really is gratifying to be able to do something, to offer some kind of way out." "This has brought joy and relief to the parents". Inherited mitochondrial diseases, estimated to affect about 1 in 5,000 births, can cause a wide range of symptoms, including seizures, muscle weakness, fatigue, vision loss, heart disease, developmental delay and learning disabilities. These symptoms can range from mild and manageable to severe and life-threatening, with more serious presentations typically arising shortly after birth.

Although it's known that the mutations behind these diseases are inherited from mom, their transfer from parent to offspring is still somewhat unpredictable. That's because, in a given egg, the "mutational load" can vary - some eggs carry mitochondrial DNA with few to no harmful mutations, while others carry mitochondria with only mutated DNA.

If affected parents conceive without the help of reproductive technologies, "they might have a child who's perfectly healthy or a child who dies in the first few days of life, essentially," Herbert said. Moms-to-be who carry a mix of high-load and low-load eggs have the option to handpick eggs with low loads using preimplantation genetic testing (PGT), a technique paired with IVF. However, "the ones who are not suitable for PGT are people who have very high mutation loads in all their eggs - sometimes 100% mutation loads," Herbert explained.

These patients, who aren't necessarily super sick themselves but would likely pass on concerning mutations, are the ones who could benefit from mitochondrial donation. In the trial, researchers directly compared the PGT approach to mitochondrial donation. All the participants carried disease-causing mitochondrial DNA mutations, and they all underwent intracytoplasmic sperm injection (ICSI), a form of IVF in which a single sperm cell is injected straight into an egg to trigger fertilization. Patients with low enough mutational loads in some of their eggs were offered PGT, while those whose mutational loads were too high were offered mitochondrial donation.

The donation itself could be done a few different ways, but in the trial, the researchers used "pronuclear transfer," in which an egg is fertilized before having its nucleus removed and placed in a different, donated egg cell. The donated egg had been screened for known mitochondrial mutations and also had its own nucleus removed. As such, the resulting embryo carries the nuclear DNA from the egg and sperm used for fertilization, as well as mitochondrial DNA from the donor egg.

Ultimately, 16 of 39 patients given PGT became pregnant, resulting in 18 babies born (including some twins). By comparison, 8 of 22 patients who received mitochondrial donation got pregnant, resulting in the birth of eight babies, so far, as there's one pregnancy still ongoing. Both techniques resulted in a similar proportion of pregnancies out of the total people treated.

"This process has brought joy and relief to the parents of these children, who thought they were never going to be able to have children without the risk of mitochondrial disease," said study co-author Dr. Bobby McFarland, a professor of pediatric mitochondrial medicine and honorary consultant pediatric neurologist at Newcastle University.

"To be part of the team effort to make that happen has been very special indeed," he told Live Science in an email. Related: In a 1st, child treated for rare, often-fatal disorder while still in the womb
Refining the technique even further. All the babies conceived through mitochondrial donation were born healthy and are meeting their developmental milestones, the team reported.

"We are now proud parents to a healthy baby - a true mitochondrial replacement success," one mother to a baby boy said in a statement. "This breakthrough has lifted the heavy cloud of fear that once loomed over us." The children's health will continue to be monitored closely going forward. "We have cast a wide net for clinical health data reporting on these children and also included a detailed developmental assessment at 18 months," McFarland said. "We are in the process of amending the study to look for more subtle developmental problems at 5 years."

Notably, the pronuclear transfer procedure doesn't guarantee that every last scrap of mitochondrial DNA in the baby will be from the donor egg. That's because, in the process of moving the nucleus from one egg to another, some small amount of mom's mitochondrial DNA can be carried over with the nucleus, Herbert explained.

In the eight babies born so far, some had undetectable levels of maternal mitochondrial DNA in their blood cells while others have a detectable amount, but the concentration is below that which would be expected to cause disease. However, the team will need to watch to see if that mutation-carrying DNA becomes more plentiful over time, Herbert said.

"We have to view these technologies as risk reduction; we cannot guarantee prevention," she said, emphasizing that parents are informed of this limitation prior to the procedure and counseled about all their options. Looking forward, the scientists hope to refine the technique to reduce the risk of that carry-over as much as possible, while also making the process more efficient and easy to reproduce.

"Long-term monitoring of the children is essential," said Dr. Paula Amato, a professor of obstetrics and gynecology at Oregon Health & Science University (OHSU) and past president American Society for Reproductive Medicine. "But it is reassuring that they appear healthy at the time of birth," she told Live Science in an email. She added that she'll be interested to see how the risk of maternal DNA carry-over could be mitigated in the future.

Genetic disorders, Inherited diseases, Autosomal dominant, Autosomal recessive, X-linked disorders, Cystic fibrosis, Huntington’s disease, Sickle cell anemia, Tay-Sachs disease, Hemophilia, Thalassemia, Muscular dystrophy, Marfan syndrome, Phenylketonuria, Neurofibromatosis, BRCA mutations, Familial hypercholesterolemia, Wilson's disease, Mitochondrial disorders, Genetic screening,

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