What is Mitochondrial Replacement Therapy?

Children inherit their mitochondrial DNA (mDNA) from their mothers. When a mother carries a mDNA mutation, it can be passed on to her children. Mitochondrial replacement therapy (MRT) is an in vitro fertilization (IVF) technique (a medical procedure where an egg is fertilized by sperm in a test tube) that allows women carrying a mDNA mutation to have children without passing on the mutation.

MRT is a relatively new therapy option that could be a great opportunity for individuals and families affected by mito. MRT isn’t currently available in Canada, but it is available in some countries, like the UK, Ukraine and Australia.

MRT is performed using one of two methods: maternal spindle transfer or pronuclear transfer.

Maternal Spindle Transfer

Maternal Spindle Transfer (MST) involves transplanting the nuclear DNA (nDNA) from a mother, confirmed to be carrying a mDNA mutation, into an unfertilized egg from a donor. Here are the steps:

  1. Donor eggs are screened and confirmed to be free of any mDNA mutations.
  2. The nDNA from the donor egg is removed, leaving a donor egg with healthy mDNA but no donor nDNA.
  3. The nDNA from the mother is then transplanted into the donor egg containing the healthy mitochondria.
  4. The donor egg with the biological mother’s nDNA is then fertilized and implanted into the mother’s uterus using IVF. 

Pronuclear Transfer

Pronuclear Transfer (PNT) is similar to MST but instead involves using the mother’s lab-fertilized egg. The steps are:

  1. A lab-fertilized egg is created using the biological mother’s egg and the biological father’s sperm.
  2. A donor egg, which has been screened and confirmed to be free of any mDNA mutations, is selected.
  3. The nDNA from the donor egg is removed, leaving a donor egg with healthy mDNA and no donor nDNA.
  4. The nDNA from the lab-fertilized egg is removed and transplanted into the donor egg.
  5. The donor egg is then implanted into the mother’s uterus using IVF.

Once isolated, the mitochondria can be evaluated in several ways, for example, using a combination of fluorescent dye and probes that help illuminate mitochondria microscopically. An ATP assay (ATP is the energy-carrying molecule that fuels cells) can identify and assess viable mitochondria in a transfer batch. Once evaluated, the viable mitochondria are then ready to be transferred, by injection or infusion, into the bloodstream or into impaired or damaged cells, tissues or organs (3).

Because MRT is a relatively new technique, donor criteria can vary, but generally, donor eggs are received from women who do not carry a disease associated with mDNA mutations. Often, clinics will manage MRT recipients and donors using similar medical and consent processes as those used for other fertility treatments (gov.uk., 2014). There have also been discussions about mitochondrial donors being treated similarly to organ donors, regarding donor information being collected and made available if a child born using MRT wanted to communicate with a donor (gov.uk., 2014).

In a 2016 study published in the Journal of Human Reproduction, out of 112 women from a local IVF clinic, 87% said they were willing to donate to MRT if a viable embryo was created (Mitochondrial replacement therapy. MitoAction, 2023). This is very optimistic for future patients seeking donors.

MRT has been used before, and babies have successfully been born. The first baby born from MRT was in 2016 when a US doctor treated a Jordanian woman at a clinic in Mexico. The mother had a mitochondrial mutation for Leigh syndrome and had previously had two children and four miscarriages (Sample, 2023). Of the two children born, one child died at age six and the other at eight months. Using MRT, doctors provided the family the opportunity to have a healthy baby.

In 2017, another baby was born using MRT (Pronuclear transfer) in Ukraine (Concept Fertility Clinic, 2017). After a mother had been trying to have a child for a decade without success. MRT is legal and practiced in clinics in Ukraine (Dockrill, 2017).

Currently, MRT is practiced in United Kingdom (UK) fertility clinics. MRT is reviewed on a case-by-case basis, and approval is obtained from the Human Fertilization and Embryology Authority (HFEA) (Wellcome Trust). Due to patient confidentiality, UK authorities cannot release specific numbers or details related to MRT births. Still, in early 2023, regulators said the number of births from MRT was less than five (Sample, 2023).

In March 2022, the Australian Senate passed the Mitochondrial Donation Law Reform (Maeve’s Law) Act 2021. Named after an Australian girl with Leigh syndrome, Maeve’s Law permits the use of mitochondrial replacement therapy (MRT) to assist families and mothers at risk of passing on mitochondrial mutations. The Australian government is funding a project called mitoHOP to support MRT research and clinical trials, with the aim of beginning MRT participant recruitment in 2025 (MitoFoundation, Maeve’s Law).

MRT is not currently legal in Canada due to the Assisted Human Reproduction Act (AHRA). When the AHRA law was written, Parliament had the goal of preventing the full cloning of humans (creating an exact genetic copy) even though this technology was not available at the time.

Unfortunately, the way the law was written makes MRT illegal, even though this was not the intention of the Act, as MRT had not been developed at the time the AHRA was created. A similar situation occurred in Australia, but family and physician input and advocacy campaigns led by the Mito Foundation of Australia led to amendments to laws, legalizing MRT.

Approximately 1 in 5,000 individuals are estimated to be affected by a mitochondrial disease caused by mutations in mitochondrial DNA (mtDNA) or nuclear DNA (Schaefer AM). Given the current global population of around 8 billion, this equates to roughly 1.6 million people globally affected by mitochondrial diseases. However, the actual number may be higher due to underdiagnosis and misdiagnosis.

In Canada, with a population of around 38 million people, the estimated 1 in 5,000 individuals affected by a mitochondrial disease equates to roughly 7,600. This estimate may vary due to factors such as diagnostic criteria, access to healthcare, and awareness of mitochondrial diseases.

Mitochondrial disease caused by mDNA mutations impacts approximately 1:8000 live births (Mitochondrial Disease | Boston Children’s Hospital). MRT is most likely to be used in future pregnancies in families that have already been affected.  This suggests that 10-20 children per year could be born with the assistance of MRT.

Currently, there isn’t enough research to know what the risks of MRT are, but understanding the benefits of accessing this reproductive technique can be life-changing for parents who are worried about passing on an inherited mitochondrial DNA mutation to a child. Mothers carrying a mitochondrial mutation typically have a few options:

  • Choose not to have children
  • Normal reproduction with the chances of the baby developing mito
  • Choose IVF with a donor egg
  • Through IVF, it is sometimes possible to screen the mother’s eggs for mito mutations
  • Adopt a child

In the UK, MRT techniques have been reviewed multiple times by HFEA with an expert scientific review panel (gov.uk., 2014). They found no evidence that the MRT techniques are unsafe for clinical use in mothers carrying mDNA mutations (NYSCF). In Australia, Maeve’s Law and the research conducted thus far suggest that the seriousness of mito surpasses any risks associated with MRT and would improve many patients’ and families’ quality of life.

Because few reported cases of MRT have been performed, research is needed to fully understand the benefits and risks of MRT, the techniques used, and its safety and efficacy. With the results so far, MRT provides the opportunity to minimize the risk of passing mDNA mutations on to future children.

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