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expert reaction to new findings on the safety and feasibility of mitochondrial DNA replacement

A study published in Nature reported that mitochondrial DNA had been successfully replaced in human oocytes by the maternal spindle transfer process, and that a significant proportion of those oocytes developed into blastocysts.

 

Professor Robin Lovell-Badge, of the MRC National Institute for Medical Research, said:

“This is an excellent set of experiments that provides some reassurance that at least one of the proposed methods to avoid the transmission of mitochondrial disease, which have so far been considered by expert committees at the level of both science and ethics, and which are now the subject of an HFEA Public Consultation (see: http://mitochondria.hfea.gov.uk/mitochondria/), are likely to be feasible. The work should give further, but I am sorry to say still cautious, hope to families affected by these diseases that a practical solution to having an unaffected child may not be so far away. 

“Mitochondria are small structures (organelles) within cells that have a vital role in the generation of energy used for living processes in all animals. They each have a small amount of DNA (mtDNA), carrying a few genes essential for this process. However, if one of these is mutated, it can lead to devastating diseases affecting many tissues, particularly those with a high demand for energy, such as muscles and the brain. Unlike the vast majority of genes that are contained within the cell’s nucleus that are inherited from both parents, mitochondria (of which there are usually many in a cell) are uniquely passed on from the mother via her eggs. Mothers with a mix of abnormal and normal mitochondria can themselves be free of the disease, yet pass it on to many or all of her offspring.

“This latest study from the lab of Shoukrat Mitalopov and colleagues, provides important data that are relevant to the question of the safety and efficiency of one of the key methods currently being explored to avoid transmission of mitochondrial disease, namely maternal spindle transfer (MST). The method involves moving the nuclear genetic material from one egg (or oocyte) to another, at a stage when this is in the form of chromosomes lined up in preparation for cell division on a structure termed the spindle. The rationale with affected mothers (not used in this study) will be to move the spindle from an egg with defective mitochondria into one with normal mitochondria that has been supplied by a donor.

“The same lab had shown previously (with some additional data reported in the current work) that MST was an efficient and safe technique in Macaque monkeys. These were chosen as an animal model for being much closer to humans in their reproductive biology than more commonly used laboratory species such as mice.  In the current study the authors show that the techniques are also possible to perform with human eggs and that, after fertilization, a significant proportion develop to blastocysts, an early stage of embryo (with about 100 cells). Most of these appeared to be normal, and could with high efficiency give embryonic stem cells lines, which could then be further tested to verify that chromosome numbers were good, that the cells were pluripotent (they could form many specialized cell types), and critically that there must have been very little carryover of mitochondria with the spindle to the new egg with the MST techniques. The latter is essential if the methods are to avoid passing on the disease not just to any resulting child, but if a girl, to her children, and so on. Avoiding both the psychological and physical threats of passing on the disease to subsequent generations are important additional potential  benefits of the methods, although this aspect is considered contentious by some because it constitutes a form of germ-line genetic modification.

“This set of experiments was one requested by the HFEA’s Review of scientific methods to avoid mitochondrial disease (http://www.hfea.gov.uk/6372.html). While the results appear very promising and they do not challenge the main conclusion of this Review, that there is no evidence to suggest that the methods are unsafe, there are still outstanding questions. In the current study, about half the manipulated eggs failed to fertilise properly, and consequently these gave abnormal embryos. While these are clearly recognisable, and could be discarded, this substantially lowers the efficiency of the procedure. The same problems were not evident with the macaque studies, suggesting to the authors that human eggs are more sensitive to manipulation at this stage. It is therefore conceivable that the other proposed method, that of pronuclear transfer (PNT), where the nuclear genetic material is transferred after fertilisation, will be more robust. This is an approach being actively pursued by Doug Turnbull and his collaborators in Newcastle.

“Although the results in the current paper appear convincing, it would be good to see the MST methods repeated by other scientists. Perhaps a slight tweaking of the methods would overcome the problems of abnormal fertilisation and development. If not, then this might suggest that extrapolating from monkeys to humans in the field of reproductive biology is not always ideal, especially when we know that this is a rapidly evolving system, and that humans are quite unique in showing such a high rate of early embryo failure, even under normal circumstances.”

 

Professor Mary Herbert, on behalf of the mitochondrial team at Newcastle University, said:

“We welcome the publication of this paper.

“This study is encouraging because it confirms our previous work published in Nature, showing that, in principle, it is possible to use IVF-based techniques to reduce the risk of transmitting mitochondrial DNA disease from a mother to her child. The manipulations required to do this can be performed either before (Spindle Transfer) or after (Pronuclear Transfer) fertilisation. This study published in Nature today represents an important step towards understanding the likely efficacy of Spindle Transfer as a treatment to prevent transmission of mitochondrial DNA disease.

“Overall the findings are encouraging. However, a striking result is that, in contrast to their previous findings using monkey oocytes, these researchers found that a high proportion of human eggs did not fertilise normally following Spindle Transfer. The data indicate that this is caused by failure of the Spindle Transfer eggs to properly halve their DNA content during subsequent fertilisation. 

“This finding is not altogether surprising.  The unfertilized egg has the complex task of remaining poised in readiness to halve its DNA content upon sperm entry.   Given the biological complexities associated with maintaining this state, we have always held the view that manipulation of the egg at this stage would be rather precarious.  In fact, the more surprising thing to us is that Spindle Transfer worked so well in monkey eggs.    

“The alternative technique of Pronuclear Transfer, allows the egg to halve its DNA content and become packaged into a large clearly visible pronucleus before being transplanted.   This means that the risk of inducing abnormal fertilisation is minimal.  The work here in Newcastle is focused on continuing to develop and test the efficacy of this technique.

“The study from the Oregon group also reports that those eggs that fertilised normally following Spindle Transfer were capable of developing under laboratory conditions. While, the researchers were able to grow some embryonic stem cell lines, the likelihood of pregnancy remains to be established.  This is largely dependent on embryo quality, which, in humans is highly variable.  While the recent paper does not report specifically on the quality of the embryos, the limited information provided is encouraging.  

“The study confirms that human eggs are more challenging to work with than those of the rhesus monkey.  The important thing now is to optimise procedures in human eggs and to perform detailed comparison with embryos created by conventional IVF.”

 

Professor Peter Braude, Emeritus Professor of Obstetrics and Gynaecology, King’s College London, said:

“This is excellent and important work that continues to examine the safety of one of the methods proposed to avoid transmission of mitochondrial diseases, namely maternal spindle transfer (MST). It is exactly the sort of science that the HFEA expert committee recommended needed doing, and demonstrates further the feasibility of this technique. However it is still a long way off ready for human use.

“Although the team was able to reconstruct eggs with new spindles using donated eggs, when they were fertilised more than half of them showed significant abnormalities that would make them unsuitable for use. Only one in five of the original eggs obtained fertilised normally and made it through to the implantation stage. This would mean that in order to be certain of getting embryos that might be suitable for transfer, around 12 eggs might be needed, not always possible in an IVF procedure. The authors agree that this information is important and further work is needed to understand the reasons for the fertilisation abnormalities.

“The other technique, pronuclear transfer (PNT), which is being pursued by the Newcastle team supported by Wellcome Trust funding, holds the advantage that any manipulation takes place after fertilisation – so the sorts of abnormalities seen in this paper are less likely. Similar laboratory experiments using human eggs for the PNT technique are essential, emphasising how necessary it is for willing women to come forward to donate eggs in pursuance of this research.”

 

 

‘Towards germline gene therapy of inherited mitochondrial diseases’ by Masahito Tachibana et al, published in Nature on Wednesday 24th October. 

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