We kicked off an exciting series of events dedicated to Mitochondrial Replacement Therapies (MRT), starting with Birol Aydin, Consultant at IFG, Scientific Director of Ovogene and Senior Clinical Embryologist.
In this first session, we discussed the science, clinical applications, and future possibilities of MRT in assisted reproduction, offering hope to many facing fertility challenges.
The event was hosted by: Walid Maalouf, Senior Scientific Director at Vitrolife Group, bringing his 25+ years of expertise in embryology and assisted reproductive technologies to the discussion.
First, we have one side recipient, which we will use for mitochondrial transfer. We are controlling their phenotypical information. Although the donor phenotype will not be shown after the reconstructed embryos or the child from the mitochondrial transfer, we still take care of the blood group, especially Rh factors. Additionally, the donor undergoes all necessary testing. Most donors also have carrier screening to avoid any potential risks. This is a key point for successful mitochondrial transfer.
Sometimes, we even give patients the chance to select the donor themselves. If they wish, they can choose the donor. However, more than phenotypical selection, we focus on the donor’s efficiency and genetic potential.
Patient eggs or zygotes can be frozen or fresh; it doesn’t matter, as we will not use the structure of the patient’s eggs. However, donor oocytes must be fresh. We do not use frozen donor eggs.
To synchronize the process, we ensure that the donor and the patient undergoing mitochondrial transfer are aligned. For example, if the patient has fresh egg retrieval, the donor’s egg retrieval is synchronized for the same day. In cases where the patient has frozen zygotes or eggs sent from different countries (to collect a larger number), we prepare the donor on the day of thawing and proceed with mitochondrial transfer on the fresh stage.
Yes, mitochondrial replacement could be a solution in such cases. When we see cycle arrest, it is mostly connected to mitochondrial energy, although not always. Detecting this issue is not easy.
For patients of advanced maternal age, we cannot be certain every failure is due to mitochondrial energy issues, but there are few alternatives available. That’s why the number of IVF trials becomes a critical factor.
If a patient has had 3 or more failed IVF cycles, with all ending on day 2 and producing highly fragmented embryos without reaching the day 5 blastocyst stage, they would be a candidate for mitochondrial replacement.
Mosaic embryos are still a topic of debate. Up to 50% mosaic rate is generally acceptable for embryo transfer, and we do transfer these embryos.
It’s important to consider the patient’s situation. These patients often have difficulty obtaining euploid embryos, so losing the potential of blastocysts with high morphogenetic scores would be unfortunate. We analyse only 3 cells from the trophectoderm during PGT-A, and these 3 cells may show 40% mosaicism. Assuming the entire embryo has the same potential would be a mistake.
This is the main concern with PGT because we are basing decisions on a localized cell sample. In our experience, even embryos with mosaicism rates of 50–60% have resulted in live births. However, if the percentage of aneuploidy is high or involves specific chromosomes, the chance of transfer and success is very low.
Mitochondria are present throughout the cell, and isolating them is not as straightforward as transferring nuclear DNA. Mitochondria cannot be easily identified or separated without electron microscopy, which is not widely available or practical for this purpose.
Currently, it is technically impossible to extract mitochondria and transfer them into another cell. The only feasible option is to transfer the nuclear DNA from the intended mother into the donor egg. If mitochondrial DNA transfer were possible, it would indeed be a much simpler process.
Mitochondria are present throughout the body, both extracellularly and intracellularly. Of course, your habits, genetics, diet, and lifestyle—like whether you smoke or drink—can influence mitochondrial function or dysfunction. Physical activity can help supply your body with more energy, making you feel better. However, at the intracellular level, these actions do not directly increase egg quality or the potential of mitochondria in eggs. While these habits may positively affect your endometrial receptivity, metabolism, or follicular development, they do not directly impact the intracellular mechanisms of eggs.
The first child born from this technology is now 14 years old, which provides a significant amount of time to observe outcomes. In my own experience, the first child I worked on is now seven years old. Out of 23 live births, I have not heard of any health issues.
It’s worth noting that with regular egg donation or IVF, there is no way to confirm whether the donor has mitochondrial issues. In contrast, mitochondrial transfer involves carefully selected donors with healthy children and proven results from previous IVF cycles. This approach is arguably more reliable for ensuring healthy outcomes compared to traditional egg donation or standard IVF.
There is no evidence, nor any publications, that suggest babies born from mitochondrial transfer have developed genetic diseases linked to mitochondrial mutations. Morphological issues unrelated to mitochondrial disease, however, may still occur during pregnancy, but these are not chromosomal and are not linked to mitochondrial transfer.
Most patients coming to us have issues with aneuploidy, but these cases often involve patients who are unable to develop blastocysts. Many of these patients have previously only produced aneuploid embryos. With mitochondrial transfer, while not all blastocysts will be euploid, we aim to give them at least one chance for embryo transfer with a euploid embryo.
For patients with no issues with implantation or pregnancy but difficulty finding healthy embryos, achieving even one euploid blastocyst can lead to pregnancy. We’ve also observed that mitochondrial transfer often results in higher-quality embryos (e.g., 4AA, 5AA) compared to previous attempts (e.g., 4BB, 4BC).
I suggest a minimum of 6 zygotes. This allows for at least 2 blastocysts for embryo transfer, increasing the chances of success. This also provides an option for a second attempt in case of implantation failure or, if successful, the possibility of a second child. The more eggs or zygotes collected, the higher the chance of obtaining euploid blastocysts.
The 1% of mitochondrial DNA transferred from the donor remains detectable. This is why the term “three-parent baby” is often used. In cases where a non-invasive prenatal test (NIPT) or real-time PCR is conducted, 3 different genetic components can be identified.
For example, after performing a mitochondrial transfer, a genetic lab may detect 3 distinct genetic profiles in a sample. This is normal in such cases, as the donor’s mitochondrial DNA contributes a small portion. This is, however, only detectable at the molecular level or with specific tests like microarrays and is not typically relevant to standard DNA fingerprinting.
