Mitochondrial replacement techniques (MRT), sometimes called “three-parent IVF,” were developed to reduce the chance that mothers pass serious mitochondrial diseases to their children. But findings from UK births and small studies elsewhere have raised concerns that the procedure may not reliably prevent the transmission of faulty mitochondrial DNA.
In MRT, an embryo receives nuclear DNA from its intended parents and mitochondria from a donor egg. One concern is “reversion”: a small amount of the mother’s mitochondria can remain after the procedure and increase as the embryo’s cells divide.
Researchers at Newcastle University reported last year that eight children born after pronuclear transfer showed no signs of mitochondrial disease. However, three had detectable reversion, with maternal mitochondrial levels between 5% and 16%. Separately, unpublished data from Ukraine’s Nadiya Clinic found reversion in two of six children tested, with maternal mitochondrial levels reaching 12% in one child and 72% in the other. In that clinic’s cases, the mothers were receiving MRT as a fertility treatment and did not have known disease-causing mitochondrial mutations.
Evidence of reversion has also emerged from research on maternal spindle transfer, another form of MRT. In a small study conducted in Greece, two of the seven children born had a mixture of maternal and donor mitochondria; maternal levels reached 51% in one child and 35% in the other. The study involved women under 40 who had experienced repeated IVF failures.
These findings have sharpened debate over whether MRT should continue to be used to prevent mitochondrial disease, and whether carefully controlled trials for infertility could help researchers understand the procedure. Some researchers argue that studies should pause until the risk of reversion is better understood. Others say infertility trials could help clarify how MRT works while avoiding exposure to the known risks faced by families carrying disease-associated mutations.
Bioethicist Guido Pennings has argued for developing MRT through controlled infertility trials. Researchers say this could also help investigate possible risks from combining a donor’s mitochondrial DNA with the mother’s nuclear DNA. Studies in mice have suggested that such mismatches could have unintended health effects, though their implications for people are not established in the material available.
Several proposals call for a staged approach: identify specific forms of infertility that MRT might plausibly address, study the technique in the lab, and then test it in small trials among patients with those conditions. At Ghent University in Belgium, researchers are seeking approval to study nuclear transfer in three groups: people with a history of mitochondrial disease, patients with a condition known as OZEMA, and women of advanced maternal age. Regulators have approved the first two groups, with an initial plan to treat seven patients in each. The team is still preparing evidence for a study involving older women.
The UK’s fertility regulator told STAT that, for now, MRT is available only to people at very high risk of passing a serious mitochondrial disease to their children. Researchers involved in the Newcastle program have reported a 75% to 100% reduction in transmission of disease-causing mutations, but former Newcastle researcher Mary Herbert said the technique cannot guarantee prevention. In cases where reversion was detected, she said, the mutated mitochondrial levels remained below the 50% threshold at which disease symptoms are expected to arise.
Australia, which has legalized MRT, is preparing a national trial. Herbert’s team at Monash University is training embryologists and plans to seek permission for a study involving women who carry mitochondrial mutations. The proposed follow-up would track any carried-over mutated DNA over time and across different organ systems. Researchers and ethicists have stressed that families considering MRT need clear information about both known and uncertain risks, as well as long-term monitoring of children born after the procedure.
Sources: STAT News.