Review
Special Issue: Nurturing the Next Generation
Mitochondrial replacement therapy in reproductive medicine

https://doi.org/10.1016/j.molmed.2014.12.001Get rights and content

Highlights

  • Mitochondrial dysfunction is implicated in disease and infertility.

  • Mitochondrial replacement therapy averts transmission of mtDNA defects to children.

  • Efficacy, safety, regulation, and ethical issues are considered.

Mitochondrial dysfunction is implicated in disease and age-related infertility. Mitochondrial replacement therapies (MRT) in oocytes or zygotes, such as pronuclear (PNT), spindle (ST), or polar body (PBT) transfer, could prevent second-generation transmission of mitochondrial DNA (mtDNA) defects. PNT, associated with high levels of mtDNA carryover in mice but low levels in human embryos, carries ethical issues secondary to donor embryo destruction. ST, developed in primates, supports normal development to adults and low mtDNA carryover. PBT in mice, coupled with PN or ST, may increase the yield of reconstructed embryos with low mtDNA carryover. MRT also offers replacement of the deficient cytoplasm in oocytes from older patients, with the expectation of high pregnancy rates following in vitro fertilization.

Section snippets

MtDNA and its role in pathologies

Mitochondria are cytoplasmic organelles with their own genome that have a major role in energy generation by oxidative phosphorylation (OXPHOS; see Glossary). The enzymatic machinery involved in OXPHOS requires both nuclear and mtDNA participation and, while the latter encodes only 37 genes, there are large numbers of mitochondria per cell, particularly in the oocyte. MtDNA in eukaryotes derives evolutionarily from bacteria and may have roles far beyond those described here [1]. Mutations in

Techniques for MRT

Alternatives to germline gene therapy have been described for couples at risk of transmitting mtDNA-based disorders, including prenatal and preimplantation genetic diagnosis (PGD). Although potentially useful for low heteroplasmic conditions, these alternatives are inappropriate for homoplasmic conditions where the patient mutant load is 100% [7]. Novel approaches for circumventing mtDNA-based disease transmission that involve germline gene therapy are described here, including PNT, ST, and PBT.

MRT for infertility patients

Advanced female age (over 35) is a major factor responsible for infertility, embryonic and fetal loss (i.e., miscarriages), and birth defects, such as Down syndrome. While direct patient treatment options are limited to low-temperature storage of oocytes recovered at earlier ages, normal pregnancies and live birth rates can also be realized when oocytes or embryos donated by younger women are substituted. Parenthetically, oocyte cryopreservation supports acceptable IVF outcomes as determined by

Ethics and regulation

Somatic gene therapy has generally met with ethical acceptance because it results in genetic changes that are not passed on to the next generation. However, germline gene therapy involves permanent correction of mutated genes in the germ cells, resulting in passage of the alteration to subsequent generations. Concerns over human germline gene therapy are largely related to safety and efficacy limitations associated with current nuclear gene transfer approaches involving recombinant DNA.

Concluding remarks

The need for MRT is apparent for families carrying mtDNA-based disease and for older infertility patients without cryostored young oocytes and refractile to conventional IVF. So, if the need exists, and the risk to benefit ratio is favorable, then the question becomes how we move towards implementation. Regulatory agencies in the USA and UK are evaluating safety and efficacy issues based on animal models and human studies, such as those described here. One of the most important unresolved

Acknowledgments

This work was supported by grants from National Institutes of Health R01-HD063276, R01-HD057121, R01-HD059946, R01-EY021214, P51-OD011092, a grant from the Leducq Foundation, and OHSU institutional funds.

Glossary

ATP
an important biological molecule that contains high-energy chemical bonds. Energy, for metabolic purposes, is released when one or more of the bonds in ATP are broken, yielding AMP or ADP.
Blastocyst
a young, spherically shaped embryo typically formed 5–6 days after fertilization, and before implantation. The blastocyst contains an outer layer of cells called the trophectoderm and an inner cluster called the inner cell mass (ICM).
Cumulus cells
an extensive, adherent cluster of cells surrounding

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