Healthy Infant Born After 'Three-Parent' Mitochondrial Intervention

Ricki Lewis, PhD

September 28, 2016

A healthy baby boy was born free of the mitochondrial disease that his mother carries, after the nucleus from her oocyte was transferred to an enucleated donor oocyte that was then fertilized with his father's sperm.

The infant was born on April 6 and appears to be healthy, with few of his mitochondria showing evidence of the disease his mother carries, called Leigh syndrome. Previously, the parents had two children who died from Leigh syndrome at 6 years of age and 8 months of age and four spontaneous abortions.

The mitochondrial manipulation technology (MMT) that led to the birth is controversial, as reported previously by Medscape Medical News. Whereas a US Food and Drug Administration panel concluded in February 2014 that more data were needed to assess MMT, an Institute of Medicine panel concluded in Feburary 2016 that MMT was "ethically permissible" and should be allowed under limited conditions.

John Zhang, MD, PhD, medical director and founder of New Hope Fertility, led the team that performed the nuclear transfer intervention in Mexico. They will present the work at the annual meeting of the American Society for Reproductive Medicine on October 19 in Salt Lake City and have published an abstract in Fertility and Sterility. The magazine New Scientist was the first to report the birth, describing it as involving a "three-parent technique."

The Mitochondrial Genome

The infant's mother carries a mutation in her mitochondrial DNA (mtDNA) that causes Leigh syndrome. Inheritance of mtDNA is unpredictable because each cell contains hundreds of mitochondria and each mitochondrion has several copies of the 16,569-nucleotide, 37-gene mitochondrial genome. As oocytes develop, the number of mitochondria decreases from approximately 150,000 to about 100. Mitochondria are not transmitted in sperm.

If a woman is a heterozygote for a mitochondrial mutation, some mitochondria receive the normal gene variant and some the mutant one. When an oocyte by chance receives many copies of the mutation and is fertilized, a child with the associated mitochondrial disease is conceived.

Because of the mtDNA inheritance pattern, "the mutation load and the clinical phenotype may vary widely between a mother and each of her children," Isabelle Thiffault, PhD, assistant director of the clinical laboratory at the Center for Pediatric Genomic Medicine, Children's Mercy Hospital, Kansas City, Missouri, told Medscape Medical News.

In the current case, the mother has the mutation in 24.5% of mitochondria in tested cells, but the two deceased children had the mutation in >95% of their mitochondria.

After MMT, fewer than 2% of the newborn's mitochondria have his mother's mutation.

Leigh Syndrome

Leigh syndrome is severe and untreatable, said Richard Kelley, MD, who has worked with children with mitochondrial diseases at the Kennedy Krieger Institute and at Children's Hospital of Philadelphia and is currently affiliated with the Department of Genetics and Genomics, Children's Hospital of Boston.

"Typical age of onset is 18 months to 2 years, and most die before 5," he told Medscape Medical News. "The damage is to the basal ganglia and brainstem. Symptoms are the fatigue and weakness typical of mitochondrial diseases, plus double vision, drooping eyelids, trouble swallowing, dystonia of the upper arms, and gradual motor deterioration."

Although mutations in several nuclear genes can cause Leigh syndrome by affecting mitochondrial function, the classic cause is a single-base mutation in a mitochondrial gene that encodes subunit 6 of the ATPase gene. The newborn's mother carries that mutation.

Two Routes to Substituting Healthy Mitochondria

MMT produces an infant who carries "the nuclear DNA of both parents, as well as mitochondrial DNA from a healthy donor," said Dr Thiffault. Two approaches for MMT are possible.

In pronuclear transfer, the father's sperm is used to fertilize two oocytes in vitro, one from the mother and one from a donor. The medical team then removes the nucleus from the donor's fertilized ovum and replaces it with the nucleus from the mother's fertilized ovum. This technique produces two fertilized ova, one of which is typically destroyed. In this case, the couple objected to destruction of the ova, on religious grounds.

Therefore, Dr Zhang's team used the second approach, called spindle nuclear transfer (SNT). They removed the mother's oocyte nucleus at metaphase of the second meiotic division, when it is clinging to the spindle fibers that separate the two sets of chromosomes during division. They then transferred it to an enucleated donor oocyte, fusing the manipulated cell with a jolt of electricity. Then intracytoplasmic sperm injection introduced the father's sperm, resulting in a fertilized ovum.

Four of five fertilized ova developed to the blastocyst stage, when preimplantation genetic diagnosis revealed that only one had a normal chromosome count. A sampled cell from that embryo showed about 95% of the mtDNA came from the donor.

A Normal Pregnancy

Transfer of the embryo to the mother's uterus led to an uneventful 37-week pregnancy. Sampling of neonatal tissues demonstrated that the mitochondrial mutational load was 1.60 (standard deviation, 0.92%, according to data in the meeting abstract).

"Human oocytes reconstituted by SNT are capable of producing a healthy live birth. SNT may provide a novel treatment option in minimizing pathogenic mtDNA transmission from mothers to their babies," the researchers write.

However, Dr Thiffault points out that a de novo mutation in mtDNA can arise in a mitochondrial donor, and that "a healthy baby is not a guarantee that eventually, tissue-specific expansion of mutated mitochondrial DNA won't occur, and [the individual] might eventually develop mitochondrial disease."

Dr Zhang told New Scientist that he performed the procedure in Mexico to avoid regulations, but his intent was to save lives. The New Hope Fertility Center website includes a "message from Dr. John Zhang: Every woman is unique and therefore customized treatments will give each couple the highest chance of success ― a more tailored approach in combination with the latest IVF technology will give you the family you hope for."

Concerns Remain

Additional cases are needed to assess safety and efficacy, experts caution.

Couples have other ways to avoid transmitting mitochondrial disease. Prenatal diagnosis using chorionic villus sampling or amniocentesis is available, Dr Thiffault pointed out. Additionally, Marcy Darnovsky, PhD, executive director of the Center for Genetics and Society, notes that preimplantation genetic diagnosis can be used to select blastocysts that are relatively free of maternal mutant mtDNA.

In a news release, Dr Darnovsky called the performance of SNT in Mexico "an irresponsible and unethical act" that "sets a dangerous precedent" of evading regulations.

"Mitochondrial transfer is not medically necessary ― it doesn't cure, treat, or prevent any existing person's disease. Nor is it necessary to have a child unaffected by mtDNA disease, since all people at risk of transmitting this condition can opt to use another person's egg," she told Medscape Medical News.

Medscape Medical News tried to contact Dr Zhang for comment, but he did not respond to the request.

The website for New Hope Fertility Center, New York City, where Dr Zhang works, includes links to two companies, Genesis Genetics and ReproGenetics, a CooperSurgical Company. Dr Kelley, Dr Darnovsky, and Dr Thiffault have disclosed no relevant financial relationships.

Fertil Steril. 2016;106(Suppl):e375–e376. Abstract

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