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expert reaction to study looking at a technique to overcome a genetic cause of infertility in mice

In a new study published in Science, researchers report on a technique designed to remove one of the extra sex chromosomes in mice with a specific (trisomy) genetic cause of infertility.  These mice were then able to produce offspring.

 

Prof. Dagan Wells, Associate Professor at the NIHR Biomedical Research Centre, University of Oxford, said:

“This is an excellent piece of work that provides fascinating insights into biology and suggests exciting clinical possibilities for the future.  Dr Turner and his colleagues should be commended for the skilful way in which they have utilised a range of complex laboratory techniques during the course of this research.

“The findings are significant.  The elimination of an additional chromosome from abnormal cells, essentially allowing them to become genetically ‘normal’ is an interesting and important observation.  This is especially relevant at the current time, given the growing interest in the correction of inherited defects using new genetic technologies such as CRISPR.  The fact that Dr Turner and his team took their findings a step further and succeeded in harnessing the phenomenon to address, in mice, a previously intractable problem – similar in nature to a particular type of human infertility – is all the more remarkable.

“As the scientists involved were careful to acknowledge, any application of their findings to solve problems of human infertility are still a long way off.  The methods used to create the sperm, embryos and ultimately mouse pups, were complex and highly artificial.  It will be some time before it is clear whether there could be any negative impacts on the health of offspring born following the procedures.  Furthermore, the process involved injections of ‘corrected’ cells into the testis of another mouse, which would be unlikely to be an acceptable strategy for treatment of infertile men even if it were safe.  Consequently, the use of this strategy in humans will have to await the perfection of methods of growing sperm cells outside the body.  Such methods are under development, but are not ready for clinical use at this time.”

 

Prof. Azim Surani, Director of Germline and Epigenomics Research, The Gurdon Institute, University of Cambridge, said:

“This study shows that some adult mouse skin cells with extra sex chromosomes, lost the extra chromosome during reprogramming to pluripotent cells, which were then used to generate viable mouse sperm, partly in culture.  The resulting sperm were used to fertilise eggs that resulted in normal live offspring.  A similar procedure was applied in attempt to correct for the extra chromosomes in cells from mice with Down’s syndrome.

“To test if such a procedure for correcting the chromosome numbers could in theory work in humans, this study obtained human skin cells from Down’s syndrome patients which have an extra copy of chromosome 21.  Reprogramming resulted in some – but not all – cells with the normal number of chromosomes.  We also know from other recent work that it may be possible to eradicate other types of disease causing mutations in single genes in humans using recently developed precise gene editing techniques, such as the recent work from Mitalipov.

“However, the procedure for obtaining viable human gametes from skin cells itself is not yet possible, and will require overcoming considerable challenges, as well as ethical considerations well ahead of any such attempts in people.”

 

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

“This is a well performed study with a number of implications both in basic biology and in clinical medicine.

“The process shown in this study is far from clinical application and would, in any event raise safety and ethical concerns that would need to be addressed.

“The work supports existing evidence, particularly evidence early embryonic development derived from IVF.  The process (or something like it) has been various called ‘trisomy rescue’ or ‘embryo correction’ in the past.  It is particularly relevant in the IVF world where embryos are often screened for chromosome abnormalities.  Critics of this approach cite embryo correction as one reason why it should not be performed at all.

“A caveat is that it’s not clear which copy of the chromosome was eliminated and which were kept.  If imprinted genes are on the chromosome in question it could affect the functioning of the ‘rescued’ stem cells.  In natural conceptions this process has been known to lead to diseases such as Angelman syndrome and Prader-Willi syndrome.

“This method addresses specifically patients that have extra chromosomes, as mentioned above however it may have relevance in IVF in general.”

 

Dr Peter Ellis, Lecturer in Molecular Biology and Reproduction, University of Kent, said:

“The body of the press release accurately reflects the science, however the title should perhaps specify ‘male’ infertility as there is, as yet, no indication whether this applies to female patients.

“The authors show that the process of reprogramming adult cells into stem cells can sometimes correct chromosomal abnormalities and thereby allow the production of normal stem cells from a patient that has an extra chromosome in their cells.  They have tested this in both mouse cells and human cells, and show in the mouse model that these ‘rescued’ stem cells can be subsequently used to produce apparently healthy, fertile offspring.  The authors are quite clear however that this is not yet a ‘real-world’ treatment suitable for clinical application.  This is because the key advance reported in this paper – producing normal stem cells from a patient with the wrong number of chromosomes – is only the first step in the process.  Treating infertility also requires convincing the stem cells to divide and differentiate into mature sperm or eggs.

“One slight caveat is that when the extra chromosomes were eliminated they did not look at which copy of the chromosome was eliminated and which copies were kept.  If there are imprinted genes on the chromosome in question (these are genes that carry a specific mark to say which parent they are inherited from), then this might conceivably affect the functioning of the ‘rescued’ stem cells.”

 

Prof. Joyce Harper, Professor of Human Genetics and Embryology, Institute for Women’s Health, University College London, said:

“Humans should have 23 pairs of chromosomes.  There are some disorders that are caused by an additional chromosome, such as sex chromosome abnormalities and Down syndrome.  Usually a female has two X chromosomes (XX) and a male has one X and one Y chromosome (XY).  Abnormalities of sex chromosomes are the most common genetic cause of infertility and include conditions such as Turners syndrome, where a female has only one X chromosome (XO) and Klinefelter syndrome where a male has an extra X chromosome (XXY).

“In this paper the authors have used cell lines from mice with an additional sex chromosome (XXY and XYY) and developed a method that caused the extra sex chromosome to be lost thereby correcting the abnormality, which they called trisomy based chromosome loss (TCL).  They achieved this when the XXY and XYY cells were reprogrammed to produce induced pluripotent stem cells (iPS cells).  They went on to develop sperm from the corrected iPS cells and found that these sperm produced fertile live offspring.  They repeated the experiments using a mouse model for Down syndrome and found that in 62% of reprogrammed cells, the additional chromosome 21 had been loss, thereby correcting the abnormality in those cells.  Finally they tested the procedure on human cell lines containing chromosome abnormalities including Klinefelter and Down syndrome and found that the additional chromosome was lost from the cell lines after reprogramming, but not to the same efficiency as in the mouse.  Even though the authors have not worked out the mechanism of the chromosome loss, overall this is a well-designed set of experiments, which for the first time shows that it may be possible to alter the number of chromosomes in human cells.

“This technology has the potential of being a treatment for infertile men carrying an additional sex chromosome but before any technique that alters the genome is undertaken in a clinical setting, it will require robust evidence to ensure it is as safe as possible and a change in the regulatory/legal framework would be required.”

 

Dr Channa Jayasena, Clinical Senior Lecturer in Reproductive Endocrinology, Imperial College London, said:

“1% of all men have no sperm at all, and having an extra X chromosome (Klinefelter’s syndrome) is a major cause of this.  Affected couples have limited fertility options.  Although a mouse study, this research is exciting, since it raises the future possibility that sperm without the extra X chromosome could be made.  This could offer potential hope for affected couples.

“However, this work raises important ethical issues that the public should consider – under which circumstances, if any, is it okay to genetically engineer sperm, eggs or embryos?  There is a strong argument for UK to lead the way in responsible research helping couples with genetic disorders; however, the topic is clearly controversial and emotive.”

 

Prof. Gary Butler, Professor and Consultant in Paediatric & Adolescent Endocrinology, University College Hospital & UCL Institute of Child Health, said:

“This is still experimental in animals and it will be a long time before it can be done in humans.  XYY and XXX people don’t usually have major infertility problems.  It is mainly XXY where the germ cells which produce sperm are reduced.  It is not clear whether this process can work on the germ cells, which in any case have half the normal number of chromosomes including sex chromosomes.”

 

Prof. Adam Balen, Chair, British Fertility Society, said:

“This is fascinating science, but its application for the improvement of fertility in men with Klinefelter’s syndrome, which is a relatively common condition, is a long way off clinical practice.  Furthermore there are possible significant risks outlined in the paper which mean that any therapeutic application is far from certain.”

 

Prof. Chris Barratt, Professor of Reproductive Medicine, University of Dundee, said:

“For reasons that we don’t yet fully understand, although the extra X chromosome appears to have a relatively minimal impact on somatic tissue it has a profound negative effect on germ cells’ development, subsequent sperm production and fertility.  Men with Klinefelter’s syndrome have reduced testicular function and generally produce no or few sperm.  Prior to the advent of ICSI (Intracytoplasmic sperm injection) these men were sterile.  However, with the ability to recover very few sperm from the ejaculate or the testis and inject these into eggs there have been over 120 births (and these are just the ones that have been published in the scientific literature).  Now we don’t consider men with Klinefelter’s syndrome as sterile although they do require assisted conception.

“For a long time people have been wondering – can’t we just delete the extra sex chromosome and thus revert the cells (and man) back to normal sperm production?  Until recently this was a purely theoretical and frankly fanciful idea.  However, experiments reported here by Takayuki Hirota and colleagues have done pretty well much this – in mice.  Quite remarkable.

“This is a robust study done by an experienced group.  However, there are a number of substantial challenges to overcome for this to be realised.  The primary limitation will be translation as there is a world of difference to doing this in humans.  Primarily amongst these limitations is the ability in humans to produce functional germ cells in vitro – we are still very much at the early stages of understanding these processes and the fidelity of the in vitro process will need to be fully ascertained.  Additionally there will be the challenges of determining if and when to start human experiments.  We are undoubtedly a long way from achieving this but there is truly breath-taking progress in the arena of stem cell-germ cell biology.  Coupled with a highly efficient reproductive medicine discipline and potential permissive regulatory arena we are well placed to address the challenges of translating this exciting research into humans.”

 

Prof. Allan Pacey, Professor of Andrology, University of Sheffield, said:

“Men born with extra sex chromosomes in their cells can have many health problems, including infertility.  However, we know that in some men with Klinefelter (XXY) syndrome, for example, that small numbers of sperm can sometimes be recovered from their testicles and that those sperm are genetically normal (and give rise to healthy offspring if used in IVF).

“Therefore, it should come as no surprise that if we can reprogram adult cells from mice with an extra sex chromosome to make pluripotent stem cells (iPSC) and these can in turn be encouraged to produce functional sperm in the lab, that the sperm produced stand a good change of being genetically normal.  This is what this paper has demonstrated in a mouse model and the data seems very robust and encouraging.

“The study, therefore, gives a further example about a potential application of lab-derived sperm to help another group of infertile men.  This is very encouraging.  The only fly in the ointment is that currently the use of such sperm in the UK is not lawful and it would take a change of primary legislation to allow us to use such sperm in infertility treatment.

“Men with Klinefelter syndrome (or other medical conditions where there is an extra sex chromosome) should be encouraged by this development, but be realistic about the timescale that might be involved in getting this approach to the clinic.  In the meantime, such men should seek an early referral to a fertility specialist if they have concerns about their fertility.”

 

Prof. Richard Anderson, Elsie Inglis Professor of Clinical Reproductive Sciences, and Head of Section of Obstetrics and Gynaecology, University of Edinburgh, said:

“Men and women with chromosome abnormalities are often infertile, so this report offers some hope that this can be addressed.  However it seems a long way from clinical application: this is based on making mouse sperm from cells from a non-gonadal source (mouse ear, though it could be any mouse tissue), and the loss of the extra chromosome seems uncontrolled.

“Thus while very intriguing, making sperm (or eggs) from even normal cells that are first transformed into becoming stem cells and then into sperm/eggs (which has only been done here with mouse sperm) raises a lot of safety concerns, which are then increased when the source is cells with abnormal chromosomes.”

 

Prof. Simon Fishel, Founder and President, CARE Fertility, said:

“A fascinating and scientifically well-conducted biological study in the mouse.  The implications for human fertility are evident in theory but many years of research are necessary to understand if the complex processes involved could ever be regarded as safe for a medical therapy. Cells with the extra chromosome have to be harvested and reprogrammed into a different type of cell – the fibroblast. This process can be induced to ensure the fibroblast loses the offending extra chromosome – it is as yet unknown if this first element of the study is reproducible in humans.  The fibroblast then needs to be reprogrammed into a sperm cell, and in this mouse model the completion of this process needed to be undertaken inside the testes of the mouse.  This final stage, although producing viable sperm also caused tumours in the testes, so any human studies would require in vitro spermatogenesis (completion of the sperm development process totally outside the body).  Even if the complex laboratory technology could produce ‘safe sperm’, these would be considered ‘non-permissible gametes’ under current UK regulations (the HFE Act, 1990 and 2008).”

 

* ‘Fertile offspring from sterile sex chromosome trisomic mice’ by Takayuki Hirota et al. published in Science on Thursday 17 August 2017.

 

Declared interests

Prof. Dagan Wells: “I have no conflict of interest relevant to this work. I am an Associate Professor at the NIHR Biomedical Research Centre at the University of Oxford.”

Prof. Darren Griffin: “I declare no financial conflicts of interest except to say that I know the group leader (James Turner) well, both professionally and socially.”

Dr Peter Ellis: “I declare no financial conflicts of interest except to say that I know the group leader (James Turner) well, both professionally and socially.”

Prof. Joyce Harper: “Joyce Harper has not conflict of interest.”

Prof. Adam Balen: “No COI.”

Prof. Allan Pacey: “Chairman of the advisory committee of the UK National External Quality Assurance Schemes in Andrology, Editor in Chief of Human Fertility and Trustee of the Progress Educational Trust (all unpaid). Also, recent work for the World Health Organisation, British Broadcasting Corporation, Purple Orchid Pharma (paid consultancy with all monies going to University of Sheffield). Co-applicant on a research grant from the Medical Research Council (ref: MR/M010473/1).”

Prof. Richard Anderson: “I have no conflict of interest.”

Prof. Simon Fishel: “Minority shareholder in CARE Fertility.  Unpaid member of the Advisory Board of several journals and scientific reviewer (unpaid) for journals in the reproductive biology and fertility.”

None others received.

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