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Scientists in the US have created monkeys whose mitochondrial DNA (DNA in the ‘powerhouses’ of the cells, separate from nuclear DNA) was swapped, replacing the mDNA from the mother with that of a donor cell. This technique raises the potential of treatments for genetic diseases caused by damage to mDNA.
Prof Peter Braude, Head of the Dept of Women’s Health, King’s College London & Director of the Centre for Preimplantation Genetic Diagnosis, Guy’s Hospital, said:
“This is a meticulously executed series of technically difficult experiments undertaken in the prestigious Oregon primate centre in the USA. For the first time, proof of principle has been demonstrated that transmission of mitochondrial disease might be avoided. It is a first step toward preimplantation correction of the serious medical disorders caused by defective DNA inherited maternally in the mitochondria.
“Mitochondrial disorders may manifest with sudden blindness, severe heart disease in children, muscle weakness, some forms of epilepsy and profound mental and physical disability. In these diseases the genetic material involved is not passed on the usual way in the nucleus of the mother’s egg or father’s sperm, but wholly from the mother, in the DNA that resides in the mitochondria which are in the cytoplasm of the egg. For this reason these genetic diseases are not amenable to preimplantation genetic diagnosis in the same way as for dominant or recessive genetic disorders such as cystic fibrosis or Huntington’s disease.
“In the experiments described, the eggs of macaque monkeys had their genetic material, in the form of chromosomes lying on the spindle, removed with a small amount of cell membrane which reformed producing tiny chromosome containing spheres – karyoplasts. The enucleated eggs which had their spindle extracted were used in crossover experiments using a different karyoplast which was fused to the egg using extracts from Sendai virus. The remarkable finding was that over 90% of the reconstructed eggs were fertilised using ICSI, and 60% formed blastocysts suitable for transfer back the uterus. 3 monkeys (one twin and one singleton) were born and contained the mitochondrial DNA from the egg into which the spindle had been replaced. Remarkably, the authors were unable to find any mitochondrial DNA which could have contaminated the spindle and been brought over from the defective egg, as had been shown when similar experiments were tried on mice using pronuclear transfer.
“These are just the sort of procedures that were anticipated when parliament left the door open for transfer of genetic material to avoid mitochondrial disease in the latest revision of the Human Fertilisation and Embryology Act. The transfer of the normal genetic material from a mother who has defective mitochondria, to a clean donated oocyte (with normal mitochondria) would allow it to be fertilised with her partner’s sperm and for them to have a child free of the mitochondrial disease with the genetic material of the couple. However, as the authors state there is still much more work to be done before human application; not so much for the technology but for safety. It will be important to know that small amounts of mitochondrial DNA have not been passed to the offspring which will then multiply in the next generation. So far the data are promising.”
Prof Sir Ian Wilmut, Director MRC Centre for Regenerative Medicine, University of Edinburgh, said:
“”This paper demonstrates an exciting new route to therapy for diseases such as myopathy, a disease of muscles in which muscle fibres do not function properly. It also seems likely that mitochondrial malfunction predisposes patients to diseases such as osteoporosis, Alzheimer’s disease, Parkinsons’s disease and stroke.
“The authors are to be congratulated for being the first to demonstrate in primates a new route to therapy. This brings us an important step nearer to being able to prevent the birth of children with a particular type of inherited disease.
“The authors have used eggs from two female primates to assess the feasibility of preventing inheritance of mitochondrial diseases. Their results suggest that one day it may be possible to transfer the chromosomes from the eggs of a female who has diseased mitochondria to those from another female who had healthy mitochondria. By leaving the damaged mitochondria behind this makes it possible to produce embryos and then babies with healthy mitochondria and so avoid the very damaging mitochondrial diseases.”
More background from Prof Wilmut: “In addition to the genetic information carried in our chromosomes there is a small amount of critical information in our mitochondria. These are the essential power houses in our cells. Errors in the genetic information in mitochondria cause a range of diseases in many different organs including muscle and nerves. At present there is no means of preventing these diseases. “We inherit our mitochondria from our mothers. There are a large number of mitochondria in the egg when it is shed from the ovary before fertilisation. It is these mitochondria that multiply and become established in all of our cells. Transfer of chromosomes from the egg with damaged mitochondria to an egg with healthy mitochondria prevents inheritance of the mitochondrial disease. “Almost all of the characteristics of children resulting from this treatment would be carried by the chromosomes. “In the UK the HFEA has approved a study at Newcastle to develop a similar treatment for human disease.”