Mitochondrial DNA Replacement Techniques to Prevent Human Mitochondrial Diseases

Abstract

Background: Mitochondrial DNA (mtDNA) diseases are a group of maternally inherited genetic disorders caused by a lack of energy production. Currently, mtDNA diseases have a poor prognosis and no known cure. The chance to have unaffected offspring with a genetic link is important for the affected families, and mitochondrial replacement techniques (MRTs) allow them to do so. MRTs consist of transferring the nuclear DNA from an oocyte with pathogenic mtDNA to an enucleated donor oocyte without pathogenic mtDNA. This paper aims to determine the efficacy, associated risks, and main ethical and legal issues related to MRTs. Methods: A bibliographic review was performed on the MEDLINE and Web of Science databases, along with searches for related clinical trials and news. Results: A total of 48 publications were included for review. Five MRT procedures were identified and their efficacy was compared. Three main risks associated with MRTs were discussed, and the ethical views and legal position of MRTs were reviewed. Conclusions: MRTs are an effective approach to minimizing the risk of transmitting mtDNA diseases, but they do not remove it entirely. Global legal regulation of MRTs is required.

The Mitochondrial Genome in Aging and Disease and the Future of Mitochondrial Therapeutics

“…The emerging role of mitochondrial health in fertility has led to more active research into both preventative and curative treatment options, including mitochondrial replacement technologies [ 78 ] and gene editing approaches [ 79 , 80 ], such as with directed nucleases [ 81 ] or nucleic acid therapies [ 82 , 83 ]. Strategies to directly manipulate mtDNA sequences and thereby shift heteroplasmy levels have also been attempted using sequence-specific DNA editing enzymes, such as zinc-finger nucleases and TALENs.…”

Ultrastructural Evaluation of the Human Oocyte at the Germinal Vesicle Stage during the Application of Assisted Reproductive Technologies

“…To date, several techniques are eligible for MRT, which consists preferably of the removal of the nuclear genome from the oocyte or zygote carrying the mtDNA mutation and transferring to a healthy enucleated oocyte [108,109]. Among the MRT techniques, ooplasm transfer (OT), spindle transfer (ST), pronuclear transfer (PNT) and polar body transfer (PBT) are the most widely known and used in ART procedures [107,110]. The OT technique consists of the transfer of 5-15% of the ooplasm of a healthy donated oocyte to the oocyte-carrying mutated mtDNA and is one of the most controversial among MRTs [111].…”

The benefits, risks and alternatives of mitochondrial replacement therapy – bringing proportionality into public policy debate

“…The media commonly refer to an MRT child as a ‘three parent baby’, 30 a designation that has been criticised as a misrepresentation that is ‘unfair and senseless’. 20 The primary objection has been that the mitochondrial donor contributes just 37 genes, whereas the intended parent contributes at least 20,000 nuclear genes.… it is 0.1 percent of the total amount of genetic material in terms of what makes us us … the mitochondrial DNA really is only involved in making energy; it’s not about other physical, cognitive or behavioural characteristics. 31 …”

“…Second, the reagents used to enable nuclear transfer could damage the subsequent altered embryo, a risk that has not been the subject of sufficient investigation to provide any clarity. 20,21 These risks may explain why the development of early human MRT embryos has been found to be poorer than that of control embryos. 9,22…”

“…The media commonly refer to an MRT child as a 'three parent baby', 30 a designation that has been criticised as a misrepresentation that is 'unfair and senseless'. 20 The primary objection has been that the mitochondrial donor contributes just 37 genes, whereas the intended parent contributes at least 20,000 nuclear genes.…”