Introducing Mitochondrial Donation into Australia: The mitoHOPE (Healthy Outcomes Pilot and Evaluation) Program
Professor John Carroll, Doctor Deepak Adhikari, Doctor Meenakshi Choudhary, Professor John Christodoulou, Professor David Coman, Professor Martin Delatycki, Associate Professor Carolyn Ellaway, Professor Michael Fahey, Associate Professor Ilias Goranitis, Doctor Christopher Gyngell, Doctor Karin Hammarberg, Doctor Tristan Hardy, Professor Mary Herbert, Associate Professor Ryan Hodges, Associate Professor Lisa Hui, Doctor Louise Hyslop, Doctor Benjamin Kamien, Doctor Janet Long, Associate Professor Karinne Ludlow, Professor David Mackey, Professor Andrew Mallett, Professor Jeffrey Mann, Professor Catherine Mills, Professor Rebecca Robker, Professor Luk Rombauts, Professor Michael Ryan, Doctor Suzanne Sallevelt, Professor Christopher Semsarian, Professor Robert Sparrow, Doctor Michel Tchan, Professor David Thorburn, Doctor Meaghan Wall, Doctor Mathew Wallis, Doctor Narelle Warren, Doctor Wai Yan Yau, Professor Deirdre Zander-Fox, Professor Sophia Zoungas
Monash University, Monash IVF, Murdoch Children’s Research Institute, The University of Adelaide, Newcastle University, Mito Foundation
Every week in Australia, it’s estimated one child is born with a severe form of mitochondrial disease, which can lead to premature death or a lifetime of debilitating illness and disability.
There is no cure for mitochondrial disease. Current treatments aim to decrease the impact of symptoms but they do not change the course of the disease.
Monash IVF researchers, in collaboration with Monash University and Murdoch Children’s Research Institute, are establishing an Australian-first clinical program to investigate a lifesaving technique known as mitochondrial donation or ‘three-person IVF’.
Mitochondrial donation aims to ensure only healthy mitochondria, the powerhouses of our cells that are vital to our survival, are passed on to an embryo by minimising the risk of prospective mothers passing on devastating mitochondrial disease to their children.
Used in conjunction with IVF, mitochondrial donation techniques allow an embryo to be created that contains the nuclear DNA from a man and a woman (the prospective mother) and mitochondria in an egg donated by another woman (the mitochondrial donor).
The mitoHOPE Program is an mitochondrial pilot program to test the safety, efficacy and feasibility of mitochondrial donation to help determine whether mitochondrial donation could be introduced into clinical practice in Australia.
The mitoHOPE Program is funded by a $15 million Medical Research Future Fund (MRFF) grant as well as contributions from program partners.
Felix-Method for Separating DNA intact sperm to improve IVF Outcomes
A/Prof Hassan Bakos, A/Prof Deidre Zander-Fox, Prof John Aitken and Prof Rob McLachlan
Monash IVF Group and University of Newcastle. Sponsored by Memphasys Ltd
Current semen preparation methods in Assisted Reproductive Technology (ART) do not assess the molecular integrity of sperm. The selection of sperm for ICSI is usually based on morphological suitability which is determined by low magnification screening. Sperm with high levels of DNA damage are known to result in reduced fertilisation rates, poorer embryo development, reduced pregnancy rates and increased levels of miscarriage. The FelixTM System, manufactured by Memphasys Ltd, uses electrophoresis and size-exclusion membranes to separate DNA intact sperm. The Monash IVF Group has partnered with Memphasys to undertake a clinical study to evaluate this new technology.
ANZCTR Trial ID: ACTRN12622000439741
Incubating sperm in a new sperm washing media 'SpermFAST' to induce post ejaculation maturation prior to IVF result in fertilization.
Dr Nicole McPherson, Dr Hamish Hamilton, Kevin Lam, Marg Szemis, A/Prof Hassan Bakos, A/Prof Deirdre Zander-Fox, Dr. Leanne Pacella-Ince
Monash IVF Group and University of Adelaide
In the past 5-10 years fertilisation rates after IVF have stayed the same (~65%), with 10% chance of cycle cancellation due to failed fertilization after standard IVF insemination which is substantially higher than that of intracytoplasmic sperm injection (ICSI), which is usually ~ 1%. As our understanding of sperm biology has advanced we know that the female reproductive tract activates the sperm to improve the ability of the sperm to bind and fertilize an egg. Currently, the media that are used for IVF only result in less than 20% of sperm to undergo this activation process. We have developed a new sperm media (SpermFAST) which induces these naturally occurring changes in sperm to a much higher rate (approximately 60%). Based on our understanding of sperm biology these changes should make it easier for the sperm to bind to and fertilise an egg during IVF. This pilot study will determine if sperm incubated in our new sperm media (SpermFAST) will promote activation of sperm thereby improving their ability to bind and fertilise the egg.
ANZCTR Trial ID: ACTRN12619000370101
NuLIFE: A prospective placebo-controlled trial investigating the ability of uterine application of a copper chloride containing gel to modulate endometrial cytokine production in healthy women.
Prof Kelton Tremellen, Dr Erin Morton
Monash IVF Group, Flinders University and NuLIFE B.V., Netherlands
Implantation failure is an important cause of unexplained infertility and a common reason for failure of IVF treatment. Even when a high quality genetically normal embryo is transferred to the uterus, only 50% of these embryos successfully implant. As such, inefficient implantation rates are the “Achilles’ heel” of IVF treatment, resulting in significant psychological distress to patients and costs. Therefore, new therapies that augment successful implantation are urgently required. Successful implantation of the embryo requires appropriate development of the adjacent endometrium to assist embryo cell division, attachment and invasion. Several cytokines and growth factors have been identified whose expression in the endometrium occurs at the time of implantation and have been suggested as biomarkers for uterine receptivity. Two of these growth factors, Leukaemia Inhibitory Factor (LIF) and Vascular Endothelial Growth Factor (VEGF) have been consistently reported to be essential to implantation, with endometrial and uterine fluid levels of LIF and VEGF being significantly higher in fertile woman compared to those experiencing recurrent IVF implantation failure. We propose a proof-of-concept study in which we will investigate the possibility that application of an investigational gel to the endometrium will also up-regulate endometrial LIF and VEGF production in vivo, similar to our in vitro results.
ANZCTR Trial ID: ACTRN12621001666819p
Establishment and validation of the ‘exposome’ as a prognostic predictor of female fertility
A/Prof Mark Green, Dr Bradley Clarke, A/Prof Deidre Zander-Fox, Prof Luk Rombauts
Monash IVF Group and University of Melbourne
There is now an increasing reliance on ART in order to reproduce. It is postulated that rising infertility can be partially attributed to exposure to man-made environmental toxicants, such as endocrine disrupting chemicals (EDCs), found in many everyday household items and personal care products. The aims of this project are to establish and validate methodologies to quantify the ‘exposome’, the harmful substances, and to provide preliminary data to determine whether the exposome can be used as a reliable prognostic marker for egg quality and thus fertility. The project outcomes have substantial scope for understanding how exposure to chemicals can influence clinical success rates.
Which factors are associated with repeated implantation failure in couples undergoing IVF/ICSI?
Prof Beverley Vollenhoven, Dr Fabrizzio Horta, Prof Ben W Mol, Dr Sarah Hunt, A/Prof Mark Green, A/Prof Deirdre Zander Fox, A/Prof Peter Temple-Smith, Dr Sally Catt
Monash IVF Group and Monash University
Recurrent implantation failure (RIF) refers to the non-occurrence of pregnancy after transfer of at least four good-quality embryos in a minimum of three fresh or frozen cycles. RIF can be the consequence of male contribution/sperm or embryonic/uterine factors, including disrupted endometrial receptivity. Sperm DNA damage, blood clotting, immunological issues and factors affecting endometrial receptivity, have been suggested as important to consider in couples with RIF. While many infertile couples with RIF currently are undergoing such testing and subsequent treatment, the scientific knowledge underpinning these tests is lacking. The aim of this study is to assess whether the presence of hereditary and acquired blood clotting factors and/or sperm DNA damage are related to RIF in couples with unknown infertility.
Oocyte DNA repair capacity as a novel marker for female ageing in IVF/ICSI cycles
Prof Beverley Vollenhoven, Dr Fabrizzio Horta, A/Prof Peter Temple-Smith, Dr Sally Catt, A/Prof Mark Green, A/Prof Deirdre Zander-Fox
Monash IVF Group and Monash University
Female ageing and egg quality have been associated with genetic abnormalities, however, the factors determining egg quality remain unclear. Damage to sperm DNA has been considered a negative predictive factor for the clinical outcomes of patients undergoing assisted reproductive technologies (ART) such as in vitro fertilisation and intra-cytoplasmatic sperm injection. Studies have shown that eggs fertilised by sperm with DNA damage may still have developmental potential due to the egg’s ability to repair DNA, but little is known about this mechanism and how ageing may affect this DNA damage response. This study will identify the biological markers involved in DNA repair, assess the capacity of the ageing female egg to repair DNA, and investigate the consequences of sperm DNA damage in the presence of decreased egg DNA repair capacity.
Post-thaw viability and function of ovarian tissue cryopreserved by slow-freezing or vitrification
Dr Sally Catt, A/Prof Deirdre Zander-Fox, A/Prof Peter Temple-Smith, Dr Fabrizzio Horta, Dr Kiri Beilby, Prof Beverley Vollenhoven
Monash IVF Group and Monash University
While ovarian tissue has been collected and stored from many patients (predominantly cancer patients) over the years, there is little indication as to whether this tissue will survive the freeze-thaw process, or if the tissue has the right complement of immature eggs to be useful if transferred as an ovarian graft. Pregnancies from in vivo transplantation are very rare around the world, and to date, no pregnancies have arisen from in vitro developed eggs, although it has been demonstrated in animal studies. The aims of this study are to thaw frozen ovarian tissue, consented for research, from a range of patient ages and analyse its viability, using histology, immunofluorescence and in vitro growth measures, and to compare traditional slow cooling ovarian tissue freezing methods with vitrification using similar in vivo and in vitro techniques, and egg maturation as an end point.
Genetic studies on male infertility and the trans-generational health of children conceived through ART
Prof Moira O’Bryan, Dr Sarah Catford, Prof Robert McLachlan, Dr Gideon Blecher, Dr Ie-Wen Sim, Dr Darren Katz, Prof Luk Rombauts
Monash IVF Group, University of Melbourne and Hudson Institute of Medical Research
Infertility affects 1 in 20 Australian men and male factors are involved in about half of all assisted reproductive technology (ART) treatments. Most often there is an unexplained failure of the testicular sperm tubules to produce adequate numbers of motile sperm capable of fertilisation. Genetic factors are suspected to be causal in many cases. Understanding such genetic factors may result in new diagnostic tests and ultimately specific treatments. Such research may also address uncertainties around the possible transmission of infertility to ART-conceived offspring. This ongoing complex study uses samples from the Monash Male Infertility data set, and in collaboration with the leading overseas investigators, as a part of the International Male Infertility Genetics consortium ( ), will forge ahead until the extent and impact of genetic variants in male factor infertility, including for the general and reproductive health of the man and his offspring is resolved.
Podocalyxin identified as a key negative regulator of human endometrial epithelial receptivity
Prof Guiying Nie, Prof Luk Rombauts
Monash IVF Group and RMIT University
Assisted Reproductive Technologies have become important medical interventions to help overcome infertility. However, despite significant advancements in embryo culture, selection and transfer techniques, implantation failure still poses a crucial limiting factor; it is believed that a contributing factor lies in the ‘soil for the seeds’, the endometrium. For implantation to occur, the endometrium must transform into a receptive state. As the embryo first contacts the surface of the endometrial epithelium, this surface must become adhesive for embryo attachment. Although it is known that the endometrial epithelium remodels structurally and functionally to gain receptivity, the exact molecular changes are not well understood. Our studies have discovered a membrane protein called podocalyxin, which is expressed in all endometrial epithelial cells and inhibits embryo implantation. During the establishment of receptivity, podocalyxin is down-regulated in the luminal epithelial cells, selectively converting the endometrial surface from a non-receptive to an implantation-permitting state. Further studies will evaluate the important role of podocalyxin in optimising endometrial receptivity, so that in future this may be used as tool to help determine the optimal time for embryo transfer and thus improve pregnancy success rates.
Australian Male Infertility Exposure study (AMIE)
Prof Jane Halliday, Dr Sarah Biggs, Prof Robert McLachlan and Prof Luk Rombauts
Monash IVF Group and Murdoch Children’s Research Institute
The aim of the study is to develop a better understanding of the impact of lifestyle and environmental factors on male infertility. Male reproductive health issues contribute to infertility in about half of all couples seeking help to have a baby. Unfortunately, not much is known about the causes of male infertility which is why we are supporting this important study. We know that smoking, diet or environmental pollutants can lead to diseases like diabetes or cancer, but we do not know whether they can also impact fertility. This study is being conducted by an expert team of scientists and clinicians, led by the Reproductive Epidemiology group at the Murdoch Children’s Research Institute. The Monash IVF Group is participating with several other fertility organisations across Australia to help find ways of improving reproductive health in men.