The estimated prevalence of inherited mitochondrial diseases, due to mutations in mitochondrial DNA (mtDNA), is 1 in every 5,000-10,000. Recently, the first U.K. license was granted to researchers at Newcastle University to carry out mitochondrial donation IVF treatment for affected women to give them an option of having children unaffected by the disease.
The goal is to prevent the transfer of mutant mtDNA from the affected mothers to their children. There are four different techniques that are available. These are pronuclear transfer, maternal spindle transfer, nuclear genome transfer, and polar body nuclear transfer.
Pronuclear transfer (PNT)
This procedure uses a donor egg that harbors healthy mitochondria. Both the donor egg and the mother’s egg (with unhealthy mitochondria) are already fertilized. The donor embryo is enucleated (the nucleus is removed and destroyed) and the nucleus from the egg of the couple undergoing the treatment is incorporated into this un-nucleated egg. This results in an embryo with healthy mtDNA from the donor and nuclear DNA from the parents (see diagram here). Following maturation, the embryo is transferred into the mother’s uterus for the healthy baby to develop.
PNT has the potential to reduce mitochondrial disease in the offspring, but it cannot prevent the transfer of some mutant mitochondria from the mother together with the nucleus into the donor egg. These unhealthy mitochondria may take over the healthy mitochondria in the donor egg. To avoid such a situation, researchers proposed a new “early” PNT technique (where the parental nucleus is transferred earlier), which reduces the probability of unhealthy mitochondria being transferred to the donor egg.
Maternal spindle transfer (MST)
In this technique, the eggs are not yet fertilized. Nuclear spindle or DNA from the egg of the mother who has mitochondrial disease is taken out and transferred to the donor’s enucleated egg (see here). The resulting egg is then fertilized with the father’s sperm and develops in vitro. It is then implanted into the mother’s womb for a child with healthy mitochondria.
The technique, developed by researchers at Oregon Health and Science University, was originally tried in monkeys. However, it was unsuccessful in human embryos and resulted in early developmental abnormalities.
MST and PNT may result in several irreversible errors that may arise due to genetic material loss during transfer; transfer and replication of small amounts of mutant mtDNA; a mismatch between foreign mtDNA and nuclear DNA; and tissue-specific segregation of mtDNA leading to mutant DNA accumulation.
Nuclear genome transfer (NGT)
This technique is the same as MST except that the premature activation of the egg is prevented to reduce early developmental abnormalities. It is still being researched.
Polar body nuclear transfer (PBNT)
This is a recent technique, wherein polar bodies, which are small cells produced during oogenesis, or the formation of the egg cell, are transferred into the donor egg instead of the parental nuclei or nuclear spindle. Polar bodies contain only the genetic material and do not develop into eggs since they lack mitochondria. It is hypothesized that this would reduce the transfer of mutant mitochondria into the donor egg.
It is important to note that the safety and effectiveness of mitochondrial donation IVF are still being investigated and that there are still many risks and limitations associated with the technique.
The United Kingdom is the first country where the use of the technique has been approved, but it is under tight regulation and it can only be considered for patients who have a high risk of having a child affected by mitochondrial disease. In the U.S., the technique is prohibited by legislation.
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