Mitochondrial Replacement Therapy (MRT) is a specialized form of in vitro fertilization (IVF) designed to prevent the transmission of severe inherited diseases. This technique focuses on mitochondria, the cellular components that generate chemical energy. The therapy replaces the defective mitochondrial DNA (mtDNA) of an intending mother with healthy mtDNA from a donor. This intervention allows a woman who carries a mitochondrial disease mutation to have a child who is genetically related to her but free from the disease.
The Diseases MRT Aims to Prevent
Mitochondrial diseases are inherited disorders that occur when mitochondria fail to produce enough energy for the body to function properly. These conditions are caused by mutations in either nuclear DNA (nDNA) or, in cases relevant to MRT, mitochondrial DNA (mtDNA). Unlike nDNA, which is inherited from both parents, mtDNA is inherited exclusively from the mother through the egg cell.
A mother who carries a pathogenic mtDNA mutation can pass it down to all of her children, though the severity of the disease can vary widely. Because mitochondrial dysfunction reduces the energy supply, these diseases tend to affect high-energy-demand organs and tissues. Symptoms often involve the brain, heart, skeletal muscles, eyes, and liver, leading to issues like developmental delays, muscle weakness, seizures, and heart problems. MRT is intended for women who have a high risk of transmitting serious, life-limiting mtDNA-related disorders, such as MELAS syndrome or Leigh syndrome.
How Mitochondrial Replacement Therapy Works
Mitochondrial Replacement Therapy involves a microscopic manipulation of the egg or embryo to swap the mother’s faulty mitochondria for a donor’s healthy ones. The core goal is to ensure the resulting embryo contains the nuclear DNA from the intending parents and the healthy mtDNA from the donor. This process is carried out using two primary techniques, which differ mainly by the stage at which the transfer occurs: before or after fertilization.
Maternal Spindle Transfer (MST)
Maternal Spindle Transfer is performed on unfertilized egg cells. The procedure begins with the intending mother’s egg, which contains her nuclear DNA and mutated mitochondrial DNA. Scientists remove the mother’s nuclear DNA, which is contained within a structure called the spindle, and preserve it for transfer.
A donor egg with healthy mitochondria is selected, and its own nucleus is removed, leaving behind the healthy cytoplasm. The mother’s nuclear DNA is then inserted into this enucleated donor egg. This reconstructed egg now contains the intending mother’s nuclear DNA and the donor’s healthy mitochondrial DNA. The egg is then fertilized in vitro with the father’s sperm and implanted into the mother’s uterus.
Pronuclear Transfer (PNT)
Pronuclear Transfer is carried out after the egg has been fertilized. The intended mother’s egg is fertilized with the father’s sperm, creating a zygote with parental nuclear DNA but the mother’s unhealthy mitochondria. Simultaneously, a donor egg is fertilized, creating a donor zygote that contains healthy mitochondria but the donor’s nuclear DNA.
The step involves removing the two pronuclei—the separate nuclei containing the maternal and paternal DNA—from the mother’s fertilized egg. These pronuclei are then transferred into the donor zygote, which has had its own pronuclei removed. This swap results in a reconstructed zygote that has the intending parents’ nuclear DNA and the donor’s healthy mitochondrial DNA. The embryo is then cultured and transferred to the mother’s womb for implantation.
Regulatory and Ethical Status Globally
The implementation of Mitochondrial Replacement Therapy has been accompanied by ethical and regulatory discussions worldwide. A point of discussion is that the resulting child has genetic material derived from three individuals. The child inherits over 99.9% of their DNA from the two intending parents, but receives the small fraction of mitochondrial DNA from the third-party donor. This has led to the procedure being colloquially referred to as “three-parent baby” technology.
Another ethical concern is whether MRT constitutes germline modification or gene therapy. Since the genetic change is made to the egg or zygote, it is heritable and would be passed down to future generations if the resulting child is female. Regulators have debated this distinction, as germline modifications are generally prohibited in many jurisdictions.
The global regulatory landscape is varied, with few countries having explicitly legalized the procedure for clinical use. The United Kingdom was the first nation to approve MRT in 2015, allowing for its use to prevent the transmission of severe mitochondrial disease. Australia followed suit, legalizing the therapy under specific conditions with the passing of Maeve’s Law in 2022. In contrast, the United States has not approved the procedure for clinical use, largely due to a legislative rider that prevents the Food and Drug Administration (FDA) from reviewing applications for heritable genetic modification. This difference in regulation has led to “fertility tourism,” where people travel to countries with more permissive laws to access the treatment.