Towards clinical application of pronuclear transfer to prevent mitochondrial DNA disease (Hyslop et al, translational, 2016).
Mitochondrial DNA (mtDNA) mutations are maternally inherited and are associated with a broad range of debilitating and fatal diseases1. Reproductive technologies designed to uncouple the inheritance of mtDNA from nuclear DNA may enable affected women to have a genetically related child with a greatly reduced risk of mtDNA disease. Here we report the first preclinical studies on pronuclear transplantation (PNT). Surprisingly, techniques used in proof-of-concept studies involving abnormally fertilized human zygotes2 were not well tolerated by normally fertilized zygotes. We have therefore developed an alternative approach based on transplanting pronuclei shortly after completion of meiosis rather than shortly before the first mitotic division. This promotes efficient development to the blastocyst stage with no detectable effect on aneuploidy or gene expression. After optimization, mtDNA carryover was reduced to <2% in the majority (79%) of PNT blastocysts. The importance of reducing carryover to the lowest possible levels is highlighted by a progressive increase in heteroplasmy in a stem cell line derived from a PNT blastocyst with 4% mtDNA carryover. We conclude that PNT has the potential to reduce the risk of mtDNA disease, but it may not guarantee prevention.
Promise and Pitfalls of Mitochondrial Replacement for Prevention and Cure of Heritable Neurodegenerative Diseases Caused by Deleterious Mutations in Mitochondrial DNA (Paine and Jaiswal, opinion, 2016)
No abstract available. PMC free text here.
Ethical aspects of nuclear and mitochondrial DNA transfer (Blesa et al, ethical analysis, 2016)
Somatic cell nuclear transfer (SCNT) (cloning), as a reproductive or therapeutic method, and mitochondrial DNA transfer, as a method to prevent the transmission of mitochondrial diseases, are analyzed in this paper from a bioethics perspective. The licit purpose of being able to treat certain diseases, as in the case of SCNT, cannot justify, in any case, resorting to illicit means such as the manipulation, selection, and elimination of human embryos in the blastocyst phase, by using cell lines obtained from them. Crossing this line paves the way (as utilitarian ethics advocates) to assuming any cost in scientific experimentation so long as satisfactory results are obtained. With mitochondrial replacement, either human embryos are directly manipulated (pronuclear transfer) or germline cells are manipulated (maternal spindle transfer); changes in these could be transmitted to the offspring.
Lay Summary: This article analyzes somatic cell nuclear transfer (cloning) and mitochondrial DNA transfer techniques, in both reproductive and therapeutic applications, and preventive methods in the transmission of mitochondrial diseases, from a bioethical perspective. The manipulation, selection, and elimination of human embryos delimits the ethical acceptability of these promising techniques.
Mitochondrial Donation: Serious Concerns for Science, Safety, and Ethics (Condic, memorandum to House of Lords, 2015)
No abstract available. Full text here.
Are You My Mommies? (Nichols, ethical analysis, 2012)
Researchers seek government support for “three-parent IVF” in the United Kingdom, for the purpose of bringing to clinical practice new techniques for avoiding inherited mitochondrial diseases. The author describes the development and processes of pronuclear transfer and maternal spindle transfer and offers an ethical evaluation of this cutting-edge science in light of the Church’s teaching in Dignitas personae. Promoting a eugenic mentality, both pronuclear transfer and maternal spindle transfer involve a radical manipulation of the human genome, inherited from three parents and passed on to future generations. Pronuclear transfer and maternal spindle transfer are immoral, because they represent an offense to marriage and the marital act and involve the destruction of innocent human life.