Zhang J, Liu H, Luo S, Lu Z, Chávez-Badiola A, Liu Z, Yang M, Merhi Z, Silber SJ, Munné S, Konstantinidis M, Wells D, Tang JJ, Huang T. Live birth derived from oocyte spindle transfer to prevent mitochondrial disease. Reprod Biomed Online. 2017 Apr;34(4):361-368. doi: 10.1016/j.rbmo.2017.01.013. Erratum in: Reprod Biomed Online. 2017 Jul;35(1):49.
Mutations in mitochondrial DNA (mtDNA) are maternally inherited and can cause fatal or debilitating mitochondrial disorders. The severity of clinical symptoms is often associated with the level of mtDNA mutation load or degree of heteroplasmy. Current clinical options to prevent transmission of mtDNA mutations to offspring are limited. Experimental spindle transfer in metaphase II oocytes, also called mitochondrial replacement therapy, is a novel technology for preventing mtDNA transmission from oocytes to pre-implantation embryos. Here, we report a female carrier of Leigh syndrome (mtDNA mutation 8993T > G), with a long history of multiple undiagnosed pregnancy losses and deaths of offspring as a result of this disease, who underwent IVF after reconstitution of her oocytes by spindle transfer into the cytoplasm of enucleated donor oocytes. A male euploid blastocyst wasobtained from the reconstituted oocytes, which had only a 5.7% mtDNA mutation load. Transfer of the embryo resulted in a pregnancy with delivery of a boy with neonatal mtDNA mutation load of 2.36-9.23% in his tested tissues. The boy is currently healthy at 7 months of age, although long-term follow-up of the child's longitudinal development remains crucial.
Slone J, Zhang J, Huang T. Experience from the First Live-Birth Derived From Oocyte Nuclear Transfer as a Treatment Strategy for Mitochondrial Diseases. J Mol Genet Med. 2017 Jun;11(2).
Our latest breakthrough involves the successful application of mitochondrial replacement therapy (MRT) and has attracted worldwide attention. This has also raised a considerable debate regarding the safety of mitochondrial replacement therapy. In particular, there is a concern about carryover of small amounts of the mother’s mutant mtDNA into the baby, and whether the levels of this mutant mtDNA can drift over time to replace the donated, healthy mtDNA (thus defeating the entire purpose of the procedure). Such heteroplasmy drift could occur in a variety of ways; however, the most commonly debated mechanism involves nuclear-mitochondrial incompatibility. That is, in cases where nuclear transfer occurs between oocytes of women from widely divergent haplogroups, there is a possibility that the newly created combination of nuclear and mitochondrial genomes may experience deleterious interactions. Whether this originates from the mother’s nuclear genome or the donor’s mitochondrial genome, the ultimate effect would be the same; a selective pressure that favors the proliferation of the original, mutant mtDNA. It has been reported in several recent in vitro studies that, even though the low levels of heteroplasmy introduced into human oocytes often vanish, they can sometimes result in mtDNA genotypic drift and reversion to the original genotype in some of the reconstituted human embryonic-derived stem cell (hESC) lines. There is, however, a serious question of the rigor of these studies and whether these in vitro experiments reflect the in vivo applications.
Is the Food and Drug Administration moving to assert more control over the genetic manipulation of embryos being used by the reproductive health industry?
On Friday, regulators issued a sternly worded letter to fertility doctor John Zhang, who helped a mother with a genetic disorder give birth to a healthy baby boy by using a procedure that combines DNA from her, her husband and an egg donor. The embryo was created in New York, where Zhang's company is based, and was taken to Mexico, where it was implanted in the mother.
The FDA says that's not allowed. Since 2015, Congress has forbidden the FDA from accepting submissions for clinical investigations that involve intentionally creating a human embryo with a heritable genetic modification. But Zhang's research does just this.
The letter notes that Zhang — who is chief executive of a clinic called New Hope Fertility Center and a research company called Darwin Life — had already agreed not to create any more “three-parent” embryos in the United States, but the letter takes issue with the company's continued marketing of the service. On websites, the companies say the technology will “prevent maternally transmitted diseases” and help prolong “natural fertility.”…
The controversial birth of the first “three-parent” baby was revealed in September 2016, and the science was described in more detail in an article in Reproductive Biomedicine Online in January 2017.
It's unclear why the FDA is weighing in now, almost a year after the experiment became public, although the Trump administration has taken a more conservative approach to reproductive health issues than previous administrations.
The FDA and other government agencies have become more aggressive over the past few years in asserting their powers over emerging industries, but the extent to which their mandates, which were written decades before these technologies were imagined, give them control has been hotly debated. The FDA has been recently working with liquid biopsy companies that aim to detect early signs of cancer in blood and with personal genomic testing companies to ensure they are able to deliver on the marketing promises they are making to consumers.
The United States remains among the most loosely regulated countries when it comes to sperm and egg donation and in vitro fertilization, and there aren't a lot of signs that will change anytime soon. The FDA letter deals with only one company and technology — mitochondrial replacement technology, or MRT — that can be used to form a genetically modified embryo, but things are moving so quickly in the reproductive sciences that experts say it's difficult to predict where we are headed.