Mitochondrial replacement therapy


Mitochondrial replacement ( MRT , sometimes called mitochondrial donation ) is a special form of in vitro fertilization in which the future baby’s mitochondrial DNA comes from a third party. This technique is used when mothers carry genes for mitochondrial diseases . The two most common techniques in mitochondrial donation are pronuclear transfer and maternal spindle transfer .

In 2015 MRT was made legal in the United Kingdom [1] and in 2016 the first regulations were issued there, clearing the way for procedures to begin. [2] In February 2016, the US National Academy of Sciences issued a report describing technologies and current ethical issues. [3]

Medical uses

Mitochondrial replacement therapy performed via pronuclear transfer or maternal spindle transfer was approved for use in the UK in December 2016 to prevent the transmission of mitochondrial diseases from mother to child; It may only be performed in clinics licensed by the UK’s Human Fertilization and Embryology Authority (HFEA), only for people who are approved by the HFEA, for whom preimplantation genetic diagnosis is unlikely to be helpful. not well understood. [4]

Relevant mutations are found in about 5000 individuals (0.02%) – the percentage of people affected is much smaller, compared to the number of mutations, and the number of mutated mutations. mitochondria need to reach a threshold in order to affect the entire cell, and many cells need to be affected for the person to show disease. [5]

The average number of births per year among women at risk for transmission is estimated at approximately 150 in the United Kingdom and 800 in the United States . [6]

The development of MRT, where it is not possible or not possible, which is at risk for transmitting and transmitting disease. [3] : 45

Techniques

Is a form of in vitro fertilization and involves removing eggs from a woman, removing sperm from a man, fertilizing the egg with the sperm, allowing the fertilized egg to form a blastocyst, and then implanting the blastocyst. MRT involves an additional egg from a third person, and manipulating both the recipient egg and the donor egg.

As of 2016 there have been three MRT techniques: maternal spindle transfer (MST), pronuclear transfer (PNT), and more recently, polar body transfer (PBT). [3] : 46-47

Diagram of the meiotic phases, showing how the chromosomes look in metaphase II

In MST, an oocyte is removed from the recipient, and when it is in the metaphase II stage of cell division, the spindle-chromosome complex is removed; Some of the cytoplasm comes with it, so some mitochondria are likely included. The spindle-chromosome complex is inserted into a donor from which the nucleus has already been removed. This paper is being fertilized with sperm, and allowed to form a blastocyst, which can be investigated with preimplantation genetic diagnosis to check for mitochondrial mutations, prior to being implanted in the recipient’s uterus. [3] : 47-48

In pronuclear transfer, an oocyte is removed from the recipient, and fertilized with sperm. The oocyte is fertilized with sperm from the same person. The male and female pronuclei are removed from each fertilizer prior to their fusing, and the pronuclei from the recipient’s fertilized egg is inserted into the fertilized egg from the donor. As with MST, a small amount of cytoplasm can be transferred to MST, the fertilized egg is allowed to form a blastocyst, which can then be investigated with preimplantation genetic diagnosis to check for mitochondrial mutations, prior to being implanted in the recipient’s uterus. [3] : 50

The process of fertilization in the ovum of a mouse, showing pronuclei.

Inorganic body transfer, a polar body (a small cell with a small cytoplasm that is created when an egg cell divides) from the container is used in its entirety, instead of using a nuclear material extracted from the recipient’s normal egg; this can be used in either MST or PNT. This technique was first published in 2014 and as of 2015 it has not been consistently replicated, but it is expected to be reduced significantly for mitochondrial mitochondria, and it does not involve extracting material. from the recipient’s egg. [7]

Diagram showing the creation of polar bodies.

Cytoplasmic transfer

Cytoplasmic transfer was originally developed in the 1980s in the course of the study of embryonic development. [5] In this technique, cytoplasmincluding proteins, mRNA, mitochondria and other organelles, is taken from a donor egg, and injected into the recipient egg, resulting in a mixture of mitochondrial genetic material. [5] This technique started to be used in the late 1990s to “boost” the eggs of older women. [5] Concerns were raised that the mixture of genetic materials and proteins causes problems with respect to epigeneticclashes, or differences in the ability of the donor and donor materials to the development process, or to the injection of the donor material. [5] After three children born through the technology were found to-have developmental disorders (2 cases of Turner’s syndrome and one case of pervasive developmental disorder (an autism spectrum disorder), the FDA banned the procedure up to a clinical trial Could Prove ict safety. [5] As of 2015 That study HAD beens Conducted not, the goal still being white procedure Was used in other countries. [5]

Risks

MRT is a form of assisted reproductive technology that involves preimplantation genetic screening of the mother, preimplantation genetic diagnosis after fertilization, and in vitro fertilization . It has all the risks of those procedures. [3] : 60

In addition, both procedures used in MRT entail their own risks. On one level, the procedures of two oocytes, removing nuclear genetic material from the recipient of the egg or fertilized egg, and inserting the nuclear genetic material into the donor unfertilized or fertilized egg; the manipulations for both procedures may cause various forms of damage that have not been understood as of 2016. [8] : 23

Maternal mitochondria will be carried over to the donor egg; as of 2016 it was estimated that using techniques in the UK, maternal mitochondria will be included only around 2% or less of mitochondria in the resulting egg, which is considered safe by the HFEA and within the limits of mitochondrial variation that most people have. [8] : 23-24

Because MRT procedures involve actions at specific times during egg development and fertilization, and involves manipulating eggs, there is a risk that eggs may mature abnormally or that fertilization may occur abnormally; as of 2016 the HFEA judged that the techniques in the UK have been made to manage these risks to proceed cautiously with making MRT available. [8] : 33-34

Because mitochondria in the final egg is a third party, different from the two parts of DNA is in the nucleus, and because of nuclear DNA codes for genes that make some of the proteins and mRNAs used by mitochondria, there is a theoretical risk of adverse “mito-nuclear” interactions. While this theoretical risk Could Possibly be managed by Attempting to match the haplotype of the donor and the recipient, as of 2016 There Was No evidence That Was an actual risk. [8] : 34-37

Finally, there is a risk of epigenetic modification to DNA in the nucleus and mitochondria, caused by the procedure itself, or by mito-nuclear interactions. As of 2016 these risks have been minimized by the long-term study of children from the procedure. [8] : 38

History

In the United States in 1996 embryologist Jacques Cohen and others at the Institute for Reproductive Medicine and Science , St. Barnabas Medical Center in Livingston, New Jersey first used cytoplasmic transfer in a human assisted reproduction procedure. [9] In 1997 the first baby was born using this procedure (Emma Ott). In 2001, Cohen and others reported that 10 single babies, twins, and quadruplets at his New Jersey clinic and a further six children in Israel had been born using his technique. Using Eastern Virginia Medical School , a baby had been born at Eastern Virginia Medical School, five children at the Women’s Hospital Infertility Clinic in Taichung, Taiwan . [10]twins in Naples, Italy [11] and a twins in India. [12] In total as of 2016, 30-50 children worldwide using cytoplasmic transfer. [13]

In 2002, the US Food and Drug Administration (FDA) asked a review of the Biological Response Modifiers Advisory Committee to advise on the technique of cytoplasmic transfer to treat infertility. This committee felt that the risk of inadvertent transfer of chromosomes and enhanced survival of abnormal embryos. [13] The FDA reported that they considered the cytoplasmic transfer technique as a new treatment, and, as such, it would require an Investigational New Drug (IND) application. Cohen’s clinic started the pre-IND application but the clinic then went private, funding for the application dried up, the application was abandoned, the research team disbanded, [14]and the cytoplasmic transfer procedure fell out of favor. [15] In 2016, 12 (out of the 13) parents of children using cytoplasmic transfer at the Saint Barnabas Center participated in a limited follow-up survey via online questionnaire. Children reported 13-18 reported no major problems. [16]

In 2009, a team in Japan published studies of mitochondrial donation. [17] In the same year, a team led by scientists at Oregon Health & Science University published results of mitochondrial donation in monkeys; that team published an update on the health of the monkeys born with the technique, on the other hand it had done on human embryos. [18]

Human trials in oocytes in 2010 by Craven, et al. were successful in reducing transmission of mutated mtDNA. The results of the study found the mean tDNA carryover to stay under 2% in all of the experimental embryos. This was true for both the MI-SCC and the PN transfer methods of MTR. This research is not intended for the purpose of clinical practice, but it is intended that the results of this study should be considered as viable representations of whole embryos. Because of these speculations and to further the viability of MTR as a safe and effective technique, further research and clinical trials in MTR in the long term in human patients. [19]

In the United Kingdom, following animal experiments and the recommendations of a government commissioned expert committee, [20] the Human Fertilization and Embryology (Research Purposes) Regulations were passed in 2001 regulating and allowing research into human embryos. In 2004, the Newcastle University Applied for the Promotion of Pronuclear Transfer to Mitochondrial Disease Mitigation, [21] and was granted the license in 2005. Following further research by Newcastle and the Wellcome Foundation , [22] [23] scientific review, [24] public consultations, and debate, the UK government recommended that mitochondrial donation be legalized in 2013.[25] In 2015 parliament passed the Human Fertilization and Embryology (Mitochondrial Donation) Regulations, which came into force on October 29, 2015, making human mitochondrial donation legal in the UK. The Human Fertilization and Embryology Authority (HFEA) has been licensed to regulate medical centers, which is intended to use human mitochondrial donation. [26] The HFEA Safety Committee issued its fourth report in November 2016 HFEA should authorize MRT, [8]the HFEA issued their regulations in December 2016 [2] [4] and granted their first license (to Newcastle University) in March 2017. [27]

Professor Douglass Turnbull , the driving force behind mitochondrial research at Newcastle University, was awarded a knighthood in 2016. [28] [29]

In 2016, John Zhang and his team at New Hope Fertility Center in New York, USA used the technique to help Jordanian woman to give birth to a baby boy in Mexico where there was no law against using such technique. The mother had the disease and died of miscarriages. [30] Ukrainian doctors at the Nadiya clinic in Kiev also reported that they had used the pronuclear transfer method of mitichondrial donation to help two previously infertile women aged 34 and 29 become pregnant. The doctors first got approval from an ethical review board of the Ukrainian Association of Reproductive Medicine but there was no law in Ukraine against mitochondrial donation.[31] A baby boy was born to the 34-year-old woman in January 2017 and the genetic test results were reported as normal. [32]

In August 2017, in a letter to Darwin Life, Inc. and New Hope Fertility Center, the FDA warned that the technique should not be marketed in the US [33]

Society and culture

Regulation

As of February 2016, the United States had no regulations governing mitochondrial donation, and Congress barred the FDA from invoking any applications that involved implanting modified embryos into a woman. [34]

The United Kingdom becomes the first country to legalize the procedure; the UK’s chief medical officer recommended it be legalized in 2013; [25] parliament passed The Human Fertilization and Embryology (Mitochondrial Donation) Regulations in 2015, [1] [35] and the regulatory authority published regulations in 2016. [2]

Ethics

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Despite the promising outcomes of the two techniques, pronuclear transfer and spindle transfer, mitochondrial gene replacement raises ethical and social concerns. [36]

Mitochondrial donation involves modifications of the germline , and these changes would be passed on to subsequent generations. [37] Using human embryos for in vitro research is also controversial, as embryos are created specifically for research and financial compensation of egg donors. [38]

Implications for identity is another ethical concern with psychological and emotional impacts on a child’s life. It debates whether the genetic make-up of children is a result of mitochondrial replacement affect their emotional well-being when they are aware that they are different from other healthy children. [39]

Opponents argue that scientists are ” playing God ” and that children with three genetic parents may suffer both psychological and physical damage. [40]

On the other hand, New York University researcher James Grifo , a critic of the American ban, has argued that society “would never have made advances in the treatment of infertility. [41]

On February 3, 2016, a report was issued by the Institute of Medicine of the National Academies of Sciences, Engineering, and Medicine (commissioned by the US Food and Drug Administration ) MRT) to continue. The report, titled Mitochondrial Replacement Techniques: Ethical, Social, and Policy Considerationsmultiple facets of the arguments surrounding MRT and concludes that it is ethically permissible to continue clinical investigations of MRT, so long as certain conditions are met. They recommended that it should only be used for embryos to ensure that mitochondrial DNA will not be passed on. [3]

References

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