A new reproductive method called mitochondrial donation has reached a milestone. The goal of this approach is to prevent mitochondrial diseases in children whose mothers have disease-associated mitochondrial DNA.
Two linked NEJM papers on report encouraging results in humans from the innovative approach. The first small paper reported on this first-of-its-kind mitochondrial donation study, focusing on the details of the work. The second paper is more clinical and gave a bigger picture, reproductive care perspective on the work.
Panel A shows the pronuclear-transfer procedure. The images in Panel B show the enucleation of patient karyoplasts and the fusion of
patient karyoplasts with the donor egg cytoplast (scale bar, 20 μm). Arrows in the first image indicate the pronuclei, and arrows in the
fourth image indicate the karyoplasts.” Fig. 3A, Hyslop, et al. NEJM, 2025.
I might have been the most outspoken biologist raising concerns about this area of research over the years. Especially 5-10 years ago. Despite that, reading this pioneering study left me feeling cautiously optimistic. It’s about as successful a first step as I could have imagined given the complexity here.
Why have I been concerned about this technology?
One of the extraordinary things about this kind of research is that it produces actual human babies. We’re not talking about just studying cells in a dish. Or doing research on rodents. So, the stakes are extremely high should something go catastrophically wrong. The good news here is that so far that reportedly hasn’t happened, and there are clear indications it might prevent mitochondrial disease.
Mitochondrial donation: some brief history
To prevent disease, the specific goal here with this research involves trying to avoid inheritance of disease-associated mitochondrial DNA during the reproductive process. Certain mitochondrial genome variants can cause catastrophic mitochondrial diseases. For that reason, minimizing the presence of such DNA during very early reproduction might give the resulting kids greatly reduced odds of getting sick. Some may never get mitochondrial disease at all.
The key method involves combining the maternal or one-cell embryo nuclear genome of the intended parents-to-be (again, the maternal familial line has that history of mitochondrial disease in these cases) with a new cytoplasm from a donor egg that does not bear disease-associated mitochondrial DNA. Recall that mitochondrial DNA is in the cytoplasm.
To achieve this, the team in the new study used something called pronuclear transfer. Other methods are also possible.
No matter how you approach this, some of the mitochondrial disease-associated DNA can come along with the nuclear DNA that is being moved to the donor cell/embryo. If it’s minimal enough, perhaps disease risk will be quite low.
The new, early but mostly encouraging study
Overall, on first glance the new pronuclear transfer method might seem not quite as effective as a more standard approach, called preimplantation genetic testing or PGT. The readout here is the extent of heteroplasmy. However, the study data comparing the methods wasn’t apples-to-apples and the new approach was actually very successful.
Out of an abundance of caution, in this study the new method was only used in severe cases where PGT was unlikely to be usable at all, so I see the pronuclear transfer results as impressive.
In PGT researchers screen IVF embryos for how much disease-related mitochondrial DNA is present and select the ones with the lowest amount. So they aren’t trying to actively lower the amount somehow as with mitochondrial donation. Note that PGT appears to be a great method for avoiding disease-associated mitochondrial DNA, but again it’s not always usable.
It’s appropriate that this initial study was relatively small because caution was warranted, but now with a foundation of these encouraging early results, it likely will be tested in a larger study.
Of the eight births, two infants subsequently developed transitory health issues that should be kept in mind:
“Hyperlipidemia and cardiac arrhythmia developed in a child whose mother had hyperlipidemia during pregnancy; both of the child’s conditions responded to treatment. Infant myoclonic epilepsy developed in another child, with spontaneous remission.”
Are these outcomes somehow related to pronuclear transfer? It’s hard to know at this point.
What’s in a name and why “mitochondrial donation”?
On another level, one of the challenging things about this area of research has been how to even name it.
Early on in this line of research, the monikers “three-parent baby” or “three-parent IVF” were popular in the media, but those didn’t seem like ideal choices. I sometimes used them here on The Niche for lack of better terminology. They are still sometimes used.
Then along came the name “mitochondrial transfer”, which was even more problematic in a sense because mitochondria aren’t being transferred with this technology. It’s nuclear DNA that is most often moved from one cell to another.
Another challenge for this arena has been that perhaps the first ever human instance of the use of mitochondrial disease-related reproductive methods was done in Mexico outside the bounds of standard research.
Monitoring of risks
Returning to the new study, there’s a long way to go here. Researchers will have to carefully monitor the research subjects for the rest of their lives.
One of the reasons that caution is still needed and longer-term research on these babies is required is that while the pronuclear transfer procedure seemed very effective at reducing mutated mitochondrial DNA that could potentially cause disease, there is a risk that the amount of such DNA could increase over time. In the past in a few other cases such so-called reversion, disease-associated mitochondrial DNA has shot way back up over time.
Three of the eight infants have some detectable mutant mitochondrial DNA and the amounts could increase over time. There may be traces in the other 5 kids that could increase too.
Other health issues could emerge too for these kids.
Why?
Marathon research should include life-long follow-up
Moving the nuclear DNA from one embryo to another is an elegant but somewhat harsh procedure that likely changes many things including the epigenetic state of the resulting new embryo. Possible unwanted effects of such changes could take years or decades to manifest. Even generations.
STAT also has a piece on this mitochondrial disease research with a similar note on long-term follow-up:
“Collecting long-term data, including ideally in the future, multi-generational data, is really important here,” said I. Glenn Cohen, a Harvard Law School professor of health law and bioethics. Such monitoring would be required to detect effects that might appear later in life or in any offspring born to these children many decades down the line.”
Glenn is right about this.
Yet the STAT piece also mentioned that the researchers will follow the children until age 5, which seems way too short a time period.
This is a marathon clinical research endeavor requiring decades of monitoring and data analysis.
A novel, heritable genetic therapy to prevent mitochondrial diseases
As I’ve been following this line of research, my main concern has been potential safety issues. It’s way too soon to be sure about those, but the initial findings from this study are generally encouraging. If safety can be clearly established over coming decades, I don’t see inherent ethical issues with the actual procedure. Things like cost and access are likely to be complicated, though.
Some may disagree, but I also feel like it’s important to keep in mind that these infants do have a form of heritable genetic change.
This isn’t CRISPR or other forms of gene editing. It’s not changing the nuclear genome. However, it’s still changing the genetic state of people in a heritable way.
I don’t see that as problematic, but it’s still important to think about and discuss. The changes (mitochondrial DNA mostly from the donor instead of the mother) are positive. They are what seem likely to help these kids not get mitochondrial diseases or have much milder cases.
Finally, it’s also notable that some clinics in other countries are offering similar procedures to parents-to-be outside the scope of responsible research. I see that as problematic and even potentially unethical in some cases.
Restrictions in the US
In contrast, while I haven’t always agreed with the UK regulators in the past as this technology emerged, the newly published research seems rigorous and ethically done.
This kind of human clinical research on mitochondrial donation is not allowed here in the US.
It’s restricted here despite some of the key early work on this kind of technology having been done in Shoukhrat Mitalipov’s lab at OHSU.
Yes, MRT was initially pioneered here at OHSU in Portland by Dr. Shoukhrat Mitalipov. And yes, we are looking at doing international trials. Dr. Mitalipov was part of the study done in Greece a few years ago. And yes, it remains to be seen whether MRT will be an effective treatment for age-related infertility.
As far as follow-up of the MRT children, I agree that it should continue into adulthood and also include transgenerational studies ideally.
Too bad we can’t do the clinical trials here in the U.S. where the technology was actually pioneered! The FDA rider forces us to do research outside the U.S. (not talking about the UK) where the regulation and human subject protections are far less robust.
Reversion might be less of an issue when MRT is used to treat female age-related infertility (still unproven) instead of for prevention of mitochondrial disease because in that situation both mtDNA haplotypes are wild type (non-pathogenic).
@Paula, I will add a note about the US restrictions to the post as an update. Good point. Are you all doing research on this in Portland? Some clinical research outside the US?
I’m less convinced that this kind of approach would definitely be an advisable way to go for infertility, but let’s see how safety looks in coming years and decades.
I saw in one place that the UK team will follow these 8 kids for just 5 years. Do you know if that’s right? It seems way too short. Maybe that’s just phase one of follow up.