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Science of Mitochondrial Donation and Related Matters Submission 23

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Science of Mitochondrial Donation and Related Matters Submission 23 11th May, 2018 Jeanette Radcliffe Secretary, Senate Community Affairs References Committee Parliament House PO Box 6100, Canberra 2600 Dear Ms Radcliffe, Re: Inquiry into the Science of mitochondrial donation and related matters Thank you for the invitation to provide a submission addressing the terms of reference. I have written this submission with the support and approval of Prof. Kathryn North, Director of the Murdoch Children's Research Institute (MCRI), and Prof. Martin Delatycki, Clinical Director of the Victorian Clinical Genetics Services (VCGS). To provide some personal context, I have been a close observer of progress in this area, with expertise based on: • leading the MCRI Mitochondrial Research Group and VCGS Mitochondrial Diagnostic Laboratory for over 25 years, with the latter long regarded as the Australasian referral laboratory for children suspected of mitochondrial disease; • being involved in diagnosis of over 600 children with mitochondrial disorders and over 150 relevant peer-reviewed publications; • publishing the first study on disease-causing mitochondrial DNA mutations in human oocytes1; • defining approaches to predict the likelihood of having a child with mitochondrial DNA disease and to predict outcomes of mitochondrial DNA mutations based on the amount of the mutation that a mother carries2-4; • writing one of the first comprehensive reviews on reproductive options for mitochondrial disease5, including defining circumstances where it was appropriate to offer prenatal diagnosis or pre- implantation genetic diagnosis; • professional involvement in human genetics and pathology via previous roles such as President of the Human Genetics Society of Australasia (HGSA), a member of the Royal College of Pathologists of Australasia (RCPA) Genetics Advisory Committee, Principal Examiner in Genetics for the RCPA Faculty of Science, and current roles including being a Director of the Australian Mitochondrial Disease Foundation (AMDF), Chair of the AMDF Scientific and Medical Advisory Committee and Co-Lead of the Australian Genomics Health Alliance Mitochondrial Diseases Flagship with Prof. John Christodoulou, who has put in a separate response. I should also acknowledge that I have collaborated for many years with the Newcastle, UK team who have pioneered the mitochondrial donation approach. This collaboration has focused on the genetics and prevention of mitochondrial disorders but I have not been directly involved in their research on mitochondrial donation. A brief summary of my Key Recommendations is provided below, followed by a detailed Response to the specific Terms of Reference. I have provided some background on the unique genetics of mitochondrial disease that are relevant to this inquiry in my responses but a useful 3-minute overview of mitochondrial disease and mitochondrial donation in lay language is provided as a video as part of a recent review I contributed to at www.nature.com/nrdp/animations/mito-dis-16. 2 Key Recommendations • The devastating outcomes caused by mitochondrial DNA disease and the lack of effective treatments provide a compelling case to enable families to access effective reproductive options to have healthy children. • Enormous progress has been made in the science of mitochondrial donation since previous reviews in 2010/2011 of relevant Australian legislation, namely the Prohibition of Human Cloning for Reproduction Act 2002 and Research Involving Human Embryos Act 2002. Research in Newcastle, UK and Oregon, USA suggests that mitochondrial donation is highly likely to be safe and effective. • The science and ethics of mitochondrial donation have been reviewed extensively in the UK over the last 10 years. Australia can incorporate most of the learnings and outcomes from that process rather than starting from scratch. • I recommend adopting the recommendations of the UK Human Fertilisation & Embryology Authority (HFEA), that: “The panel continues to see clinical value in maternal spindle transfer (MST) and pronuclear transfer (PNT) to mitigate or prevent the inheritance of mitochondrial disease. It recommends that, in specific circumstances, MST and PNT are cautiously adopted in clinical practice where inheritance of the disease is likely to cause death or serious disease and where there are no acceptable alternatives.” • Extensive preclinical studies justify that the potential benefits now outweigh the potential risks if mitochondrial donation is offered in a cautious and targeted manner. As with the introduction of any new medical procedure or treatment, some uncertainties remain about safety and efficacy. • It is thus timely to amend Australian legislation to enable provision of mitochondrial donation in Australia to prevent severe mitochondrial diseases under appropriate regulatory oversight. • Australia should adopt the UK practice of issuing licenses to centres that wish to offer mitochondrial donation subject to “a requirement for appropriate levels of skill being demonstrated by named practitioners within a named clinic, and relevant key performance indicators being met”. The legislation should provide the capacity for centres seeking to offer mitochondrial donation to perform the preliminary experiments required to demonstrate competence in the licensing process, including that they can achieve carry-over of less than 2% of maternal mitochondrial DNA, as recommended by the HFEA panel. Licensing should also ensure that the proposed clinical pathway will ensure appropriate counselling and follow-up during pregnancy and in childhood. • Australia should adopt the UK practice of issuing licenses only to couples “for whom preimplantation genetic diagnosis (PGD) or other methods would be inappropriate or unlikely to succeed”. • Regulation is potentially more complex in Australia and requires careful thought. In the UK, licensing is the responsibility of the HFEA. Given the level of expertise required and likely patient numbers, it would be desirable if there were no more than one or two Australian centres approved to offer mitochondrial donation. • To ensure community confidence in the licensing of centres and couples, a body independent of the IVF industry should oversee the licensing process. • It is imperative that prospective parents receive counselling about potential alternative approaches (both reproductive options and for concepts such as haplogroup matching), risks and benefits. • Appropriate legislative changes and a strong regulatory regime should ensure the community has confidence that this novel procedure will only be used for prevention of serious diseases caused by mitochondrial DNA disease and allay any concerns about slippery slope arguments. 3 Response to Terms of Reference (a) the science of mitochondrial donation and its ability to prevent transmission of mitochondrial disease; Mitochondrial diseases are basically problems in converting the energy in food into a small molecule called ATP, which all our cells and organs use to go about their normal business. The magnitude of this energy demand is shown by the estimate that we each have to make and degrade about 70 kilograms of ATP each day! Mitochondria are the powerplants in virtually all our cells that do this and are composed of more than 1200 different proteins that are encoded by an equivalent number of genes. The vast majority of these genes are among the roughly 20,000 regular (nuclear) genes in the 23 pairs of chromosomes, half of which are inherited from our mother and half from our father. We currently know of more than 250 different nuclear genes in which mutations cause severe mitochondrial disease in children or adults. However, mitochondria are unique in that they also contain a tiny chromosome (the mitochondrial DNA) containing just 37 genes, which is often regarded as an evolutionary relic. Mitochondrial DNA is absolutely essential to energy generation and thus to our health and survival but does not contribute to characteristics such as appearance or intelligence, other than via mutations causing ill health. Mitochondrial DNA has unique genetics in that it is inherited only from our mothers. This is largely because mature human eggs have about 200,000 copies of mitochondrial DNA, which vastly outnumber the approximately 50 copies present in sperm. Sperm mitochondria also degrade soon after fertilising the egg. In thinking about patients with mitochondrial disease, in about half the patients the genetic problem is in a nuclear gene, while in the other half it is in a mitochondrial DNA gene. Mitochondrial donation is only relevant to families affected by mitochondrial DNA disease. It has no role in prevention of any genetic disorder caused by any nuclear gene problem. The aim of mitochondrial donation is to allow parents to have a healthy child by replacing the mother's mitochondrial DNA (some of which carries a disease-causing mutation) with healthy mitochondrial DNA from a donor. The results of international research into mitochondrial donation The science of mitochondrial donation has been largely pioneered by one centre in Newcastle, UK and another in Oregon, USA. The Oregon group developed a method called Maternal Spindle Transfer that involved removing the nuclear genes from mature eggs of Macaque monkeys. They then transferred the nuclear genes from one egg into another egg from which the nucleus had been removed. This led to carry- over of less than 3% of the mitochondrial DNA from the original egg, meaning the new egg had the mother’s nuclear genes but that over 97% of
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