Nuclear transfer to prevent maternal transmission of mitochondrial DNA disease

Two new techniques to prevent diseases of maternally transmitted mitochondrial DNA—maternal spindle transfer and pronuclear transfer—have prompted a public consultation by the Human Fertilisation and Embryology Authority (HFEA) in the United Kingdom.1 2 3 After the announcement of the consultation, much of the comment in the press focused on “three parent embryos” as if they were a novelty.4 They are not, and such red herrings serve only to cloud the debate.

About one in 400 people have a maternally inherited pathogenic mutation of mitochondrial DNA. Mutations may cause no symptoms or may present at any age with problems such as developmental regression, deafness, blindness, neuropathy, diabetes, or cardiomyopathy. Mitochondrial DNA is maternally inherited because mitochondria are located in the cytoplasm, and the sperm contributes almost no cytoplasm to the fertilised egg. Many of these diseases are heteroplasmic—that is, mitochondria with mutant and normal DNA coexist in the same patient; low doses of mutant DNA cause mild symptoms and high doses cause severe symptoms. If heteroplasmic women transmit high doses of mutant mitochondrial DNA to their children,5 these children are severely affected. Homoplasmic women, whose mitochondria all have identical DNA, transmit 100% mutant mitochondrial DNA to all their children and additional, largely unknown, factors influence the severity of illness.

Maternal spindle transfer and pronuclear transfer are in vitro fertilisation based techniques for reducing the dose of mutant mitochondrial DNA in preimplantation embryos6; mutant mitochondrial DNA is replaced by mitochondrial DNA from a healthy donor. The difference between the two techniques is that maternal spindle transfer uses unfertilised eggs and pronuclear transfer uses very early single cell embryos (zygotes). The nucleus from the affected woman’s oocyte (or the zygote produced from her oocyte), containing her chromosomes, is removed. Most pathogenic mitochondrial DNA is left behind. The nucleus is then introduced into an enucleated oocyte (or zygote) from a healthy donor.

Because good alternative solutions such as egg donation and preimplantation genetic diagnosis are already available and licensed,5 some may query whether this new treatment is ethically sound or clinically safe (or both). In egg donation, healthy eggs are donated to women with a high risk of transmitting mitochondrial disease. The mother, who has the mutant mitochondrial DNA, carries a baby with none of her own genes, so she is the biological, but not the genetic, mother of the child. Egg donation is a robust way of eliminating the risk of transmission if it is acceptable to the couple. Egg donation already involves three people to produce a child and is a licensed procedure. Although it is limited by the supply of donor eggs, nuclear transfer requires even more eggs.

With preimplantation genetic diagnosis, the healthiest of the affected woman’s embryos—generated by in vitro fertilisation—is selected. The first birth after preimplantation genetic diagnosis for mitochondrial DNA diseases was as recent as 2006. It is still early days—by 2010 there were only three children live born after this technique.7 For most maternally inherited mitochondrial DNA diseases preimplantation genetic diagnosis will reduce the risk of later disease. For example, in Leber’s hereditary optic neuropathy, which affects many more boys than girls,8 the mitochondrial DNA is usually the same in each embryo. Most patients go blind in both eyes although some recover partially. However, because boys are two to five times more likely to go blind than girls,8 preimplantation genetic diagnosis may be used to reduce the risk of a child going blind just by selecting female embryos.9 This is a safer way to reduce the risk of transmitting this disease than nuclear transfer.

The concerns around the new techniques are more subtle than the ethics of children having “three parents.”10 The nuclear transfer technique has been described as “like changing a laptop battery.”11 Such a simplified description is misleading for two reasons. Firstly, nuclear transfer techniques constitute germline gene therapy and therefore have ethical implications.12 Secondly, as with many medical advances, it is not possible to prove the safety of nuclear transfer in advance of the first clinical trial. We will not be sure that the children have no health problems until they reach adult life or whether their children have the mitochondrial mutations until the girls have their own families a generation later. Assessing safety by preclinical experiments on animals is restricted by the scientific understanding available. There are numerous examples of surprises in science. Similarly, systems of which we know little may regulate mitochondrial function in early embryos. The only way to find out about safety is to license the first treatment.

Who are the most suitable candidate participants for the first trial of nuclear transfer? In homoplasmic diseases, preimplantation genetic diagnosis cannot be used to select embryos with a low load of mutant mitochondrial DNA because the load is identical in all embryos. If such families do not want to use donated eggs they might request nuclear transfer. However, homoplasmic mitochondrial DNA disease with a highly probable severe outcome and compelling evidence implicating mitochondrial DNA is exceptionally rare. Hence an extremely small number of families might be the first to try nuclear transfer.

The Nuffield Council on Bioethics concluded that nuclear transfer might be appropriate in a highly regulated research trial with expert genetic counselling. We recommend that the UK, rather than China, Russia, or Korea, hosts the first clinical trial of spindle transfer or pronuclear transfer because frameworks exist to ensure that it will be properly regulated. The risk of generating abnormal babies is unknowable until such a trial is done. Meanwhile egg donation and preimplantation genetic diagnosis remain safe alternatives available for most families affected by potentially devastating maternally inherited mitochondrial DNA disease.