April 14, 2010

expert reaction to research on preventing the transmission of mitochondrial mutations in human embryos, to be published in Nature

The research from Newcastle University used a DNA transfer technique to prevent mutations affecting the DNA of mitochondria (the energy-generating components of cells) from being passed on to the next generation, thereby providing a potential means of preventing the transmission of diseases that result from such mutations.

Prof Peter Braude, Head of Department of Women’s Health, King’s College London, said:

“This is promising work and shows the benefits that can be accrued from properly targeted and regulated embryo research. The difficult task now will be the experiments to demonstrate pronuclear transfer to be safe for first-in-human trials of what is effectively germ line therapy.”

Mr Tony Rutherford, Chairman of the British Fertility Society, said:

“Mitochondrial diseases are a relatively rare but important group of conditions with an incidence varying between 1 in 4,000 to 1 in 10,000. They are caused by mutations in the DNA that code for mitochondria, the energy producing organelles in a cell. An example is a condition known as MELAS (Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) which presents in childhood, and is associated with muscle weakness and discomfort, headaches, vomiting and seizures. Most sufferers will have stroke-like episodes before middle age, which on a repeated basis can lead to loss of vision, issues with movement and dementia. Mitochondrial disorders are inherited through the maternal cell line, and they usually occur when the majority of the mitochondrial DNA is abnormal. Unfortunately at present, there are no cures for mitochondrial diseases, and the only treatment option is supportive therapy.

“This preliminary study outlines a possible method to prevent the transmission of mitochondrial disorders. The female pronucleus, which carries the genetic message from the mother to the next generation, is removed from an egg that is known to carry a high percentage of mutated mitochondrial disease and transferred to a healthy donor egg, after its own genetic material has been removed. This proof of concept study shows that transferring a pronucleus appears to be possible in human eggs, but more importantly it shows that this technique leaves the abnormal mitochondrial DNA behind, so that when the newly constructed fertilised egg cleaves to form an embryo, it uses the normal mitochondria from the donor egg. Of course this study was performed on abnormally fertilised eggs and needs to be repeated in controlled conditions using healthy eggs to establish whether the technique is indeed viable in conditions closer to those employed in a clinical setting, and to demonstrate that the procedure is safe. It is important to put this work into context, as it is only the first step on the long road to potentially developing a treatment to prevent the transmission of these dreadfully debilitating disorders. The British Fertility Society supports such research and we look forward to seeing the results of more extensive studies in due course.”

Prof Justin St. John, Professor and Director, Centre for Reproduction & Development, Monash Institute of Medical Research, Monash University, Australia, said:

“Finding effective assisted reproductive technologies for women who are carriers of mitochondrial disorders is a priority for these patients. Although this work and previous work have addressed some of the issues and provide some promising preliminary outcomes, we do not believe embryos carrying even very low levels of mutant mitochondrial DNA will not give rise to mitochondrial disorders. This is especially as mitochondrial DNA segregates randomly during fetal development. During fetal development mitochondrial DNA is also extensively replicated and selection of mutant and non-mutant mitochondrial DNA for replication is again random. We know from one clinical case that mutant mitochondrial DNA that contributed less than 0.01% of the total mitochondrial DNA population at fertilisation was found in a male patient suffering from a mitochondrial myopathy. Consequently, it is really necessary to eliminate all mutant mitochondrial DNA in any assisted reproductive technology aimed at helping patients with mitochondrial disorders who wish to have children that would not be affected or be subsequent carriers of such severe metabolic disorders.”

Sarah Norcross, Director of the UK assisted conception/genetics charity the Progress Educational Trust, said:

“Many mitochondrial disorders are not inherited in the usual sense of there being a defective gene (‘mutation’) in the regular human genome. Mitochondria carry their own DNA that is only 0.0005% the length of the nuclear human genome. It contains just 37 coding genes (0.15% of human genes), but harmful mutations can occur within them. Evolutionarily, mitochondria are enslaved primitive bacteria with their own genetic code. They replicate independently of the nucleus and carry no information that defines any human attribute. Mitochondrial disorders are a cruel class of inherited disease, because serious, even life-threatening conditions are coupled with great unpredictability about how future children will be affected. The options of prenatal diagnosis or PGD are not available or appropriate for many women and ovum donation can be unacceptable to couples since it does not permit them to have genetic children of their own.

“There is a clear need for this research to progress to therapeutic application, unfortunately this is currently illegal in the UK. We therefore urge the new government, whatever its political persuasion, to pass Regulations to allow this possible life-saving treatment to be used in a clinical setting.”