Researchers have attempted to fix errors in mitochondrial DNA, which lead to a range of disorders, by using genome editing techniques. Publishing in the journal Cell, they report the use of the techniques in mice and suggest that they might in future be used as a therapeutic alternative to mitochondrial donation.
Dr Marita Pohlschmidt, Director of Research, Muscular Dystrophy UK, said:
“We welcome this exciting new technique, which could benefit thousands of women worldwide who risk passing on mitochondrial disease to their children. There are no effective ways to treat people with these devastating and unpredictable conditions, and currently, our best option is to prevent their inheritance. This approach of selectively eliminating mutated mitochondria in an egg or embryo is still at an early stage. However, the results seen in mice are promising. Initial evidence suggests that the technique may also be used for mutated human mitochondrial DNA. It does not require egg donation, and could eventually be an important alternative to mitochondrial donation IVF. We are keen to see results of further research into the technique’s safety and efficacy.”
Prof. Robert Lightowlers, Director of Institute for Cell and Molecular Biosciences and Professor of Molecular Neuroscience, Newcastle University, said:
“The work by Moraes, Izpisua Belmonte and colleagues elegantly illustrates how relatively simple methods can be used to deplete levels of disease-causing mutations in the mitochondrial genome. The work provides encouragement that at least for women who have eggs that harbour both normal and disease-causing populations of mitochondrial DNA, it may be possible to use these methods to lessen the load of defective mitochondrial DNA and prevent transmission of mitochondrial disease. The authors rightly point out a couple of important caveats associated with this method, but it is early days and it will be very interesting to follow the evolution of this approach.”
Prof. Doug Turnbull, Professor of Neurology, Newcastle University, said:
“It is very important that there are an increasing number of options that may be available for women who carry disease causing mitochondrial DNA mutations. These are very elegant and exciting studies which use gene editing techniques to remove the abnormal mitochondrial DNA whilst leaving the normal mitochondrial DNA. This technique, however, maybe be of limited value for those women whose oocytes have either large amounts of mutated mitochondrial DNA or all mutated mitochondrial DNA. It is these women who are most likely to benefit from mitochondrial donation.”
Prof. Bruce Whitelaw, Professor of Animal Biotechnology at the Roslin Institute, University of Edinburgh, said:
“The paper from the Belmonte lab is an example of how the genome editing technology world is expanding. Genome editors are capable of site-specific introduction or correction of mutations. In this paper, genome editing is successfully used to reduce mitochondrial mutations in mice, with the implication that a similar strategy could be used in humans.
“The authors present this as an alternative to the much debated mitochondrial replacement method. It would be technically simpler and not require donor mitochondria, thereby circumventing the ‘three parent’ aspect, but how specific and efficient are the genome editing tools – indeed how specific and efficient do we need them to be.
“Genome editing technology has been embraced by both the academic and commercial sectors worldwide with technological advances emerging on a continuous basis, ever broadening the range of potential applications. Today genome editor technology is not robust enough for all applications – tomorrow they may well be. This paper reinforces the call for society to engage with the very rapid advance of the genome editing ‘revolution’. This is a new era for biology; an era offering many benefits to medicine, agriculture and the environment. It is not that genome editing technology will necessarily open up new areas for debate (using technology to mitigate mitochondria disease is not new), rather there will be both more diverse and many more applications, with the potential to reach through to most people on our planet. There is an urgent need for transparent dialogue between the kaleidoscope of societal stakeholders to ensure the beneficial development of genome editing technology can follow a prudent path.”
Prof. Frances Flinter, Consultant in Clinical Genetics, Guy’s & St Thomas Hospital said:
“The suggestion that there might be an alternative way to prevent the transmission of maternally inherited mitochondrial disorders is interesting. Scientists in many institutions are studying technology that will allow editing of the genome to remove unwanted deleterious mutations for a number of inherited disorders, but there are still many unanswered questions. To date there are considerably more safety data available for mitochondrial replacement therapies than for genome editing, which has only been described more recently. The biggest question to address will be the possibility that DNA cutting enzymes may disrupt adjacent genes that are important, leading to unintended adverse consequences. As the authors acknowledge, there will need to be much more work done to establish the safety and efficacy of this technique before any clinical trials can begin.”
Dr Dusko Ilic, Reader in Stem Cell Science, King’s College London, said:
“Although this clever alternative approach for correcting genetic errors in mitochondria is a technical masterpiece, it is unlikely to make to clinic in the near future. Replacing faulty genes in human preimplantation embryos, germ cells or gametes poses serious risks and, with all ethical and especially safety implication, the therapeutic benefits are questionable.”
Dr David Clancy, Lecturer researching genetics and biology of ageing, Lancaster University, said:
“There was concern over mitochondrial replacement therapy. As an advance over current offerings (pre-implantation genetic diagnosis and donor IVF), it allowed affected women the chance to have offspring bearing their own chromosomes. Nothing more. In that light, the chance, however small, that unfavourable genetic combinations could be created, conflicts with the aspiration that we ‘do no harm’.
“Therefore the current development of targeted mitochondrial gene therapy is a major advance. In cases where women have some genetically healthy as well as some disease-causing mitochondria, the technique should perform well. However if the woman carries little or no genetically healthy mitochondria, it cannot be used, and perhaps her choice might be for mitochondrial replacement therapy.”
‘Selective elimination of mitochondrial mutations in the germline by genome editing’ by Reddy et al. published in Cell on Thursday 23rd April.
All our previous output on this subject can be seen at this weblink: http://www.sciencemediacentre.org/mitochondrial-dna-2/
Dr Marita Pohlschmidt: I have no conflicts of interest. We have not funded this work in any way. However we have funded work in Doug Turnbull’s lab for the research into mitochondrial donation IVF, however that grant has now ended.
Prof. Robert Lightowlers: I am a member of the Wellcome Trust Centre for Mitochondrial Research and so we are sponsored by them to perform research in this area. I have no financial conflicts of interest.
Prof. Doug Turnbull: I receive funding from the Wellcome Trust and Muscular Dystrophy Campaign for research into mitochondrial donation techniques.
Prof. Bruce Whitelaw: I am a consultant for and joint research grant holder with Genus plc, on the Scientific Advisory Board of Recombinetics Inc and ImmunoGenes AG, and Editor-in-chief of Transgenic Research.
Prof. Frances Flinter: I was a member of the Nuffield Council on Bioethics working party on ‘Novel techniques for the prevention of mitochondrial DNA disorders.’
No other conflicts of interest declared.