scholarly journals Mitochondrial replacement therapy and the “three parent baby”

SURG Journal ◽  
2017 ◽  
Vol 9 (1) ◽  
pp. 48-56 ◽  
Author(s):  
Suzanna Tai
Keyword(s):  
Mitochondrial Dna ◽  
Replacement Therapy ◽  
Polar Body ◽  
Genetic Material ◽  
Eukaryotic Cells ◽  
Mtdna Mutation ◽  
Donor Oocyte ◽  
Polar Bodies ◽  
Mitochondrial Replacement Therapy ◽  
Pronuclear Transfer

The mitochondria contained in eukaryotic cells have their own DNA, and heritable mutations in mitochondrial DNA (mtDNA) can cause a variety of disorders in humans. A new therapy, mitochondrial replacement therapy (MRT), is currently being developed to address these mitochondrial disorders by eliminating the mutated mtDNA from the germline. The two main MRT techniques are pronuclear transfer, conducted in the zygote after fertilization, and spindle-chromosomal complex transfer, conducted in the oocyte before fertilization. In pronuclear transfer, the pronuclei from a zygote affected by a mtDNA mutation are transferred to an enucleated normal zygote. In spindle-chromosomal complex transfer, the genetic material from an oocyte affected by a mtDNA mutation is inserted into the cytoplasm of a donor oocyte that contains healthy mitochondria. A third method, polar body genome transfer, attempts to increase the efficiency of the above techniques by using polar bodies to supply the genetic material. While MRT is legally and ethically controversial, it has recently been implemented successfully in a clinical setting.

scholarly journals The need for donor consent in mitochondrial replacement

2018 ◽  
Vol 44 (12) ◽  
pp. 825-829 ◽  
Author(s):  
G Owen Schaefer
Keyword(s):  
Mitochondrial Dna ◽  
Genetic Material ◽  
Oocyte Donation ◽  
Consent Process ◽  
In Vitro Fertilisation ◽  
Oocyte Donor ◽  
Mitochondrial Replacement Therapy ◽  
Donor Consent ◽  
Future Practice

Mitochondrial replacement therapy (MRT) requires oocytes of women whose mitochondrial DNA will be transmitted to resultant children. These techniques are scientifically, ethically and socially controversial; it is likely that some women who donate their oocytes for general in vitro fertilisation usage would nevertheless oppose their genetic material being used in MRT. The possibility of oocytes being used in MRT is therefore relevant to oocyte donation and should be included in the consent process when applicable. In present circumstances (especially because MRT is still an emerging technique), specific consent should be obtained. However, once MRT becomes more routine, such consent could be incorporated into the general consent process for oocyte donation. The reported lack of proper consent for MRT from the oocyte donor in the first baby born via the technique is an ethical failing and should be corrected in any future practice of MRT.

scholarly journals Polar bodies are efficient donors for reconstruction of human embryos for potential mitochondrial replacement therapy

Cell Research ◽  
2017 ◽  
Vol 27 (8) ◽  
pp. 1069-1072 ◽  
Author(s):  
Keliang Wu ◽  
Cuiqing Zhong ◽  
Tailai Chen ◽  
Xiaoyu Zhang ◽  
Wenrong Tao ◽  
...  
Keyword(s):  
Replacement Therapy ◽  
Human Embryos ◽  
Polar Bodies ◽  
Mitochondrial Replacement Therapy

scholarly journals Mito-nuclear Incompatibilities and Mitochondrial Replacement Therapy

2016 ◽  
Author(s):  
Adam Eyre-Walker
Keyword(s):  
Mitochondrial Dna ◽  
Mitochondrial Genome ◽  
Replacement Therapy ◽  
Nuclear Genome ◽  
Reproductive Technology ◽  
Mitochondrial Mutations ◽  
Mitochondrial Replacement Therapy ◽  
Human Reproductive ◽  
Nuclear Genomes ◽  
Native Strains

AbstractMitochondrial replacement therapy (MRT) is a human reproductive technology by which the mitochondria of a recipient’s eggs are effectively replaced by those of a donor, potentially eliminating harmful mitochondrial mutations carried by the recipient. However, concerns have been raised that MRT may lead to problems due to incompatibilities between the nuclear genome of the recipient and mitochondrial genome of the donor. Whether this is likely to be a problem is investigated using 226 estimates, taken from the literature, of the effect of replacing the “native” by a “foreign” mitochondrial DNA (mtDNA) from the same species in a variety of animals. In approximately half of the cases (45%), strains with the foreign mtDNA have higher fitness than those with the native mtDNA, and on average the native strains are only 3% fitter. Based on these results it is argued that incompatibilities between the mitochondrial and nuclear genomes are not likely to be a problem for MRT.

scholarly journals Development of mitochondrial replacement therapy: A review

Heliyon ◽  
2020 ◽  
Vol 6 (9) ◽  
pp. e04643
Author(s):  
Hitika Sharma ◽  
Drishtant Singh ◽  
Ankush Mahant ◽  
Satwinder Kaur Sohal ◽  
Anup Kumar Kesavan ◽  
...  
Keyword(s):  
Replacement Therapy ◽  
Mitochondrial Replacement Therapy

scholarly journals Mitochondrial DNA Replacement Techniques to Prevent Human Mitochondrial Diseases

2021 ◽  
Vol 22 (2) ◽  
pp. 551
Author(s):  
Luis Sendra ◽  
Alfredo García-Mares ◽  
María José Herrero ◽  
Salvador F. Aliño
Keyword(s):  
Mitochondrial Dna ◽  
Nuclear Dna ◽  
Genetic Disorders ◽  
Mitochondrial Diseases ◽  
Legal Regulation ◽  
Donor Oocyte ◽  
Legal Position ◽  
Ethical And Legal Issues ◽  
Mitochondrial Replacement Techniques ◽  
Do So

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.

Abstract 17097: Non-Synonymous Mitochondrial DNA Variants Are Common in Myocardial Tissue of Heart Failure Patients

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Pappu Ananya ◽  
Michael Binder ◽  
Yang Wanjun ◽  
Rebecca McClellan ◽  
Brittney Murray ◽  
...  
Keyword(s):  
Heart Failure ◽  
Mitochondrial Dna ◽  
Nuclear Dna ◽  
Left Ventricular ◽  
Individual Risk ◽  
Myocardial Tissue ◽  
Mtdna Mutation ◽  
Mtdna Mutations ◽  
Ventricular Tissue ◽  
Mtdna Variants

Introduction: Mitochondrial heart disease due to pathogenic mitochondrial DNA (mtDNA) mutations can present as hypertrophic or dilated cardiomyopathy, ventricular arrhythmias and conduction disease. It is estimated that the mutation rate of mtDNA is 10 to 20-fold higher than that of nuclear DNA genes due to damage from reactive oxygen species released as byproducts during oxidative phosphorylation. When a new mtDNA mutation arises, it creates an intracellular heteroplasmic mixture of mutant and normal mtDNAs, called heteroplasmy. Heteroplasmy levels can vary in various tissues and examining mtDNA variants in blood may not be representative for the heart. The frequency of pathogenic mtDNA variants in myocardial tissues in unknown. Hypothesis: Human ventricular tissue may contain mtDNA mutations which can lead to alterations in mitochondrial function and increase individual risk for heart failure. Methods: Mitochondrial DNA was isolated from 61 left ventricular myocardial samples obtained from failing human hearts at the time of transplantation. mtDNA was sequenced with 23 primer pairs. In silico prediction of non-conservative missense variants was performed via PolyPhen-2. Heteroplasmy levels of variants predicted to be pathogenic were quantified using allele-specific ARMS-PCR. Results: We identified 21 mtDNA non-synonymous variants predicted to be pathogenic in 17 hearts. Notably, one heart contained four pathogenic mtDNA variants (ATP6: p.M104; ND5: p.P265S; ND4: p.N390S and p.L445F). Heteroplasmy levels exceeded 90% for all four variants in myocardial tissue and were significantly lower in blood. No pathogenic mtDNA variants were identified in 44 hearts. Hearts with mtDNA mutations had higher levels of myocardial GDF-15 (growth differentiation factor-15; 6.2±2.3 vs. 1.3±0.18, p=0.045), an established serum biomarker in various mitochondrial diseases. Conclusions: Non-synonymous mtDNA variants predicted to be pathogenic are common in human left ventricular tissue and may be an important modifier of the heart failure phenotype. Future studies are necessary to correlate myocardial mtDNA mutations with cardiovascular outcomes and to assess whether serum GDF-15 allows identifying patients with myocardial mtDNA mutations.

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