November 30, 2016

expert reaction to fourth scientific review of the safety and efficacy of methods to avoid mitochondrial disease through assisted conception

An independent expert panel, convened by the Human Fertilisation and Embryology Authority (HFEA), have published their fourth scientific review into the latest evidence on the safety and efficacy of mitochondrial donation techniques, recommending that those techniques be approved for “cautious use” in “specific circumstances”. These comments accompanied a press briefing.

Prof Mary Herbert, Professor of Reproductive Biology, Newcastle University, said:

“We are delighted with the positive outcome of the Expert Panel’s latest review of mitochondrial donation techniques.

“Once we get the green light from the HFEA, we are ready to submit an application for a licence to offer mitochondrial donation treatments here at Newcastle Fertility Centre.  This will form part of a comprehensive programme of NHS-funded treatment for families affected by mitochondrial DNA disease.

“It is really gratifying for us to be able to extend the scope of reproductive technologies to help families affected by these dreadful diseases and it will be a great privilege to see our work over the past decade finally come to fruition.

“Our research efforts over the next five years will focus on refining the techniques to further reduce the risk of disease transmission.”

Dr Rob Buckle, Director of Science Programmes at the Medical Research Council, said:

“We welcome the findings of today’s HEFA scientific review into whether mitochondrial donation is ready for clinical practice. In proceeding to the next stage of this exciting research, it is still important to remain pragmatic and move cautiously in following the review’s thoughtful recommendations. The implementation of any new treatment in humans always presents some risks, but a strong regulatory and governance framework, overseen by the HFEA, will mean families and their doctors can decide whether the potential benefits outweigh these risks. Through carefully selecting patients and encouraging long-term follow up of both patients and their offspring, we will continue to add to what we know about how to best treat these devastating conditions.”

Prof Bert Smeets, Professor Clinical Genomics, Director Genome Center, Maastricht University, said:

“It is historic that the independent science review panel concludes that it is appropriate to offer mitochondrial donation techniques as clinical risk reduction treatment for carefully selected patients. I fully support their conclusions.

“There is an end to what can be done pre-clinically and the final proof of the pudding is in eating. Being from the Netherlands I admire how these decisions are being made in the UK. It is a very careful and thorough process, but also open to the general public, allowing a decision, which might not be supported by everybody, but certainly will be respected by everybody. It makes sense to limit the application of mitochondrial donation to patients, who do not have an alternative in prenatal diagnosis or preimplantation genetic diagnosis.

“This may seem obvious, but as shown by the recent report on a successful application of mitochondrial donation in Mexico, this is not always the case, as preimplantation genetic diagnosis could have been applied in that situation as well.

“With respect to the match between donor and acceptor I would have put less emphasis on haplotype matching, but more on replication differences between donor and acceptor mtDNA as this must be fully controlled to prevent that the carry-over mtDNA with the pathogenic mutation becomes the predominant fraction, possibly leading to an affected child.

“Another issue is that polar body transfer, which may be the best approach for mitochondrial donation is not allowed by the current regulations. As it is not fundamentally different from the strategies approved, there is no reason why it should not be included and I certainly would argue for this.

“The long-term follow-up in a controlled setting is another very important issues. No experimental technique should be implemented in the clinic without monitoring it on the long run. I am looking forward to the first healthy child being born after mitochondrial donation in a fully controlled setting.”

Prof. Doug Turnbull, Professor of Neurology, Newcastle University, said:

“This is obviously great news and I agree with the report conclusions. They have considered the evidence in great detail and their conclusion that that ”it is appropriate to offer mitochondrial donation techniques as clinical risk reduction treatment for carefully selected patients” is entirely appropriate given the evidence.  I also completely agree with importance that there is long term follow up of any children born.

“I think the report highlights the very careful way in which the UK has proceeded with this new IVF technique and hope the HFEA approve this at their meeting in December.

“This gives women who have mitochondrial DNA mutations reproductive choice and I am delighted for them.

“We have been working closely with NHS England to develop care pathways which ensure that women with mitochondrial DNA mutations will have access to advice about the available techniques, pathway for mitochondrial donation itself and the subsequent care of the mothers through pregnancy, pathway for mitochondrial donors, and pathway for the long-term follow up of children born.”

Robert Meadowcroft, CEO of Muscular Dystrophy UK, responds:

“We wholeheartedly support the positive recommendations for mitochondrial donation IVF to be cautiously implemented in clinical practice, for carefully selected patients. This recommendation, if approved by the HFEA, is a major step towards the reality of offering an effective treatment to the 2,500 eligible women in the UK.

“This pioneering technique could give women with mitochondrial disease the chance to have a healthy child, without the fear of passing on this condition which can lead to babies born with this condition having multiple disabilities and indeed life limiting impairments. As a major initial funder of this technique, more than ten years ago, we are thrilled to see how the procedure has advanced and look forward to the possibility that it may shortly be available to eligible women at specialist clinics.”

Dr David J Clancy, Lecturer, Lancaster University, said:

“The panel’s purpose in the fourth report was ‘to review the latest evidence of safety and efficacy for the two mitochondrial donation techniques – maternal spindle transfer (MST) and pronuclear transfer (PNT), with particular reference to whether the recommendations outlined in the 2014 scientific report have been met.’

““…the panel concluded both in 2011 and 2013 that the evidence available at those times did not suggest that the techniques are unsafe. The direction of travel remains the same, and the panel therefore come to the same conclusion in this report.”

“While the report covers well the scientific evidence, there can seem in the report a determination by the panel to stick to its direction of travel. This is of concern because what is almost entirely lacking in the considerations of safety is any sorts of clear definitions of what ‘safe’ is in this context.

“We know that the technique is currently imperfect. One of the experiments deemed critical in the 2013 report has been done now by a team led by Shoukrat Milatipov of Oregon Health & Science University. Although numbers were low, their results suggest that reversion to the original mtDNA type could occur as often as 1 in 6 times, which might be able to be reduced to 1 in 18 using genetic screening. To quote: “reversal to the mutant mtDNA may occur in some MRT (mitochondrial replacement therapy) children”.  It would not be unreasonable to suppose that, if approval were granted today, 1 in 30 MRT-assisted pregnancies could result in a child with inherited mitochondrial disease.

“What proportion of children who inherit mitochondrial disease as a result of the therapy is considered a safe number? How severe? What happens if a child is born with disease so severe it dies before age 5? Or even how many failed conceptions, and at what monetary cost? It is unclear what it would take for the panel to recommend that treatment of humans not go ahead at this time, as the US has done.

“It may be in light of this new knowledge of risk that there is a subtle shift by the panel from the 2013 report in attitude toward MRT. It refers to a study which suggests that “it might even be acceptable to replace an embryo with a higher-than-threshold level of mutant heteroplasmy, recognising that, even at such levels, this would nevertheless represent a risk reduction from the high levels that would probably be present should the couple have decided to reproduce naturally.” As a result, “…. the panel recommends that it is appropriate to offer mitochondrial donation techniques as clinical risk reduction treatment for carefully selected patients.” The ethical basis for this decision is unclear and should be argued and clarified.

“The panel notes a US “report recommended limiting clinical research to the transfer of MRT XY (male) embryos, so as to avoid heritable genetic modification, with no transfer of female embryos until there “”is clear evidence of safety and efficacy from male cohorts, using identical MRT procedures, regardless of how long it took to collect this evidence.”” However the” panel had difficulty in supporting this view due to the requirement for additional manipulation of the embryo, the reduction in embryos available for transfer, the deliberate exclusion of normal XX (female) embryos and the impracticalities of attempting to deliver absolute safety.”

“It is surprising that this additional manipulation of the embryo is considered significant next to the magnitude of the manipulation that constitutes MRT. And at least one study of patients and carriers of disease-causing mitochondrial mutations indicates that many are keen to provide embryos to aid research in this area.

“Why is the Panel so ready to move to the clinic? The aim ‘to do no harm’ is violated sometimes in medicine. Cytotoxic therapy is harmful and can sometimes kill, but without it patients face certain or near-certain death from cancer in the short to medium term. Let us, once again, be very clear about MRT. Its sole benefit is to allow affected women to have healthy children who bear half their genes. The best alternative is IVF by donor egg. By the intervention that is MRT, the evidence now suggests that, at some point, producing a child who will suffer from mitochondrial disease is a certainty. Are we, as a society, OK with that?

Prof Darren Griffin, Professor of Genetics, University of Kent, said:

“In the current climate where it seems that hype and hyperbole appear to outweigh measured decision making based on the facts, it’s pleasing to see a victory of common sense. The report is good news for families at risk of transmitting these disorders and infinitely better than the alternative of children suffering with horrible diseases.”

Prof Alison Murdoch, Head of Newcastle Fertility Centre at Life, Newcastle University, said:

“No other IVF technique has undergone such rigorous scientific and ethical evaluation before implementation. During the 15 years that mitochondrial transfer has been developed at Newcastle Fertility Centre, a generation of children with mitochondria disease have been born. We hope that the prospects for their children will be better.”

Sarah Norcross, Director of the Progress Educational Trust said:

“We welcome this thoroughgoing report and its recommendations. The judicious selection of the first patients to be treated with these techniques is a sensible measure, and one which can be reviewed in future as the techniques become better established.  Due to the high standards of regulatory scrutiny which have been required throughout this process, there are still a number of steps which need to be taken before these treatments can be used by women wishing to avoid passing on mitochondrial disease.”

Dr Beth Thompson, Senior Policy Advisor at Wellcome said:

“This latest scientific review finds that recent research adds further evidence of the safety and efficacy of mitochondrial replacement, a technique with the potential to transform the lives of couples affected by mitochondrial disease. The next stage will be for the UK’s robust regulatory system to make a decision as to whether this technique is safe enough to move into the clinic, and be made available to affected families. We’re delighted that, following the legislative change Wellcome has helped to drive, we are now closer than ever to this technique being an option for families.”

Prof Sian Harding, Professor of Cardiac Pharmacology and Director of the British Heart Foundation Cardiovascular Regenerative Medicine Centre, Imperial College London, said:

“This is a landmark document, not only for the decision itself but for the careful and transparent process which has led to it and the recommendations going forward around both treatment and further research.”

* ‘Scientific review of the safety and efficacy of methods to avoid mitochondrial disease through assisted conception: 2016 update, Report to the Human Fertilisation and Embryology Authority (HFEA) November 2016’ chaired by Dr Andy Greenfield was published at 18:00 UK time on Wednesday 30th November.

All our previous output on this subject can be seen at this weblink: http://www.sciencemediacentre.org/tag/mitochondrial-dna/

Declared interests

Prof Mary Herbert: M.Herbert is employed by Newcastle University as Professor of Reproductive Medicine based at Newcastle Fertility and Wellcome Trust Centre for Mitochondrial Research.

Prof Bert Smeets: No conflicts of interest.

Prof Doug Turnbull: Prof Doug Turnbull receives funding from the Wellcome Trust for research into mitochondrial donation techniques and other research into mitochondrial disease. His other research is supported by MRC, BBSRC and NHIR.

Dr David Clancy: No COIs.

Prof Alison Murdoch: No conflicts of interest

Sarah Norcross: No conflicts of Interest

None others received