‘3 person IVF’ closer to reality as cure for mitochondrial diseases

IVF and DNA injection via Shutterstock x

A technique—popularly dubbed ‘3 person IVF’—for helping mothers with faulty mitochondria have healthy babies is a step closer to reality. Scientists in the UK report positive results from tweaking the technique’s protocol on human embryos.

The technique—called pronuclear transfer by scientistsinvolves removing the genome from a fertilized embryo and transferring it to a healthy donor embryo that has had its nuclear DNA removed. The hope is that during the transfer very few—or ideally none at all—mitochondria will carry over to the donor embryo in the process.

Mitochondria are the parts of a cell that turn food into energy, and they possess their own genetic instructions—although some genes for mitochondrial function are contained in the nuclear genome too. The concern with inheritance only pertains to maternal mitochondria because sperm exclusively contribute DNA to a fertilized embryo—all other cellular machinery of an embryo are directly passed from mother to fetus. Genetic diseases of the mitochondria can be very debilitating and even fatal, with symptoms including extreme fatigue, muscle pains, neurological issues, and stunted growth and development. 

Form MLB All Star Rocco Baldelli's career was cut tragically short most likely due to a mitochondrial disorder
Form MLB All Star Rocco Baldelli’s career was cut tragically short most likely due to a mitochondrial disorder

The team of scientists, led by those working at Newcastle University in the UK, published their results in the journal Nature. In contrast to attempts by other scientists at pronuclear transfer, this team performed the extraction at a much earlier time in development: just eight hours after fertilization. Generally it is done at 24 hours. They also made other adjustments like working with frozen—as opposed to fresh eggs—and withheld sucrose.

The study was performed on 500 embryos, from 64 women and the researchers found that while some diseased mitochondria were transferred, in the vast majority of donor embryos the unhealthy mitochondria were kept at levels that are not clinically relevant.

Scientists commenting to the Genetic Expert News Service (GENeS), a sister site of GLP, noted the success of the project, while also expressing some caution. Carlos Moraes a professor at the University of Miami Miller School of Medicine echoed said the study also brings the technique closer to the clinic:

Pronuclear transfer to prevent transmission of mitochondrial DNA (mtDNA) with disease-causing mutations has become a proxy for a new era, when genetic manipulation of human embryos is not only possible but allowed. The approach is relatively simple and the benefits obvious.

Moraes has some reservations, stating, “this relatively simple approach, even if already performed in several mammals (e.g. mouse, monkeys, and to a lesser extent in human embryos) is fraught with technical issues that have major consequences on the final outcome.”

The key worry is that a recent study found that even small amounts of diseased mitochondria can cause issues, as Moraes explains:

These improvements suggest that early pronuclear transfer (ePNT) has the potential to reduce risk of mitochondrial disease in a child born through this procedure. However, it cannot exclude the possibility that a few reconstituted embryos will carry some levels of the mutant mtDNA. This word of caution has also been given in a recent paper in Cell Stem Cell by the group of Dieter Egli.

The paper he is referencing found that the proportion of diseased mitochondria can occasionally increase over time which could mean a person could develop the mitochondrial disorder over time. Dr. Marni Falk a professor of pediatrics at the Children’s Hospital of Philadelphia explained the Dieter Egli paper:

I think papers like this speak to the fact that if you really are trying to remove mutated mitochondria altogether you may need to do more technical manipulations, because just relying on low-carryover may not be enough to reliably reduce the risk of mtDNA disease developing in the child born following this procedure.

The Newcastle team was able to keep their initial transfer rate of diseased mitochondria under 2 percent, which is promising—Falk says under 5 is the goal to ensure a child won’t show symptoms of the disorder—but as the Dieter Egli paper found any amount carries risks. Gerald Shadel, a professor at Yale School of Medicine, explained to GENeS that this isn’t an indictment of the technology and is merely similar to other genetic diseases:

Based on the results of the current study, it does seem the carryover can routinely be reduced to less than 2%, making the chances of disease occurring substantially less, but unfortunately still not zero.  However, with the risk being very low, I would liken the situation to a potential parent carrying a rare recessive nuclear disease gene who has to be counseled that there is a higher risk that their child could inherit the disease if the other parent is also a carrier.

Nicholas Staropoli is the associate director of GLP and director of the Epigenetics Literacy Project. He has an M.A. in biology from DePaul University and a B.S. in biomedical sciences from Marist College. Follow him on twitter @NickfrmBoston.

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