Clinical and ethical implications of mitochondrial gene transfer

doi:10.1016/j.tem.2013.09.001

Trends in Endocrinology & Metabolism

Volume 25, Issue 1, January 2014, Pages 5-7

https://doi.org/10.1016/j.tem.2013.09.001 Get rights and content

Inherited diseases caused by mitochondrial gene (mtDNA) mutations affect at least 1 in 5000–10 000 children and are associated with severe clinical symptoms. Novel reproductive techniques designed to replace mutated mtDNA in oocytes or early embryos have been proposed to prevent transmission of disease from parents to their children. Here we review the efficacy and safety of these approaches and their associated ethical and regulatory issues.

Section snippets

Mitochondrial gene disorders

These are distinct genetic diseases attributable to mutations in the cytoplasmic DNA residing in the cellular mitochondria, organelles involved in cellular respiration and energy production. Each cell contains thousands of circular mtDNA molecules comprising 37 genes (13 proteins, 22 tRNAs and 2 rRNAs) crucial for energy production by oxidative phosphorylation (OXPHOS). The mitochondrial genome is inherited maternally because only mtDNA from the unfertilized egg is found in offspring. Mutations

Techniques for mtDNA replacement

A promising recent advancement in assisted reproductive technologies (ARTs) involves the efficient replacement of mutant mtDNA in unfertilized oocytes or zygotes with normal donor mitochondria, thereby allowing women carrying mtDNA mutations to circumvent passage of the condition to their children 3, 4. Two microsurgical nuclear transfer procedures, termed spindle transfer (ST) and pronuclear transfer (PNT), have been developed. The first approach is conducted at the mature oocyte stage when

Safety and efficacy of mtDNA replacement

The safety and efficacy of the ARTs has been established over many years of clinical application without much attention or dependence on animal based research, let alone controlled clinical trials. Clearly, establishing safety and efficacy for any new technology, especially when involving germline gene therapy, represents a major challenge. Several relevant observations are cited below.

In the case of mitochondrial gene replacement, the possibility that the procedure might fail secondary to the

Regulatory, legal, and ethical questions

The techniques of ST and PNT described herein induce permanent changes to mtDNA that would be transmitted through generations, thus qualifying as germline gene therapy. As such, in the USA, reproductive applications of mtDNA transfer fall under the jurisdiction of the Food and Drug Administration (FDA) requiring that first applications for patient treatment must be done as part of clinical trials. In the UK, current regulations set by the Human Fertilisation and Embryology Act (HFEA) 1990 ‘only

Acknowledgments

Research supported by National Institutes of Health grants HD063276, HD057121, HD059946, 8P51OD011092 and the Leducq Foundation. The authors wish to thank Eric Baker for help with illustrative material.

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There are more references available in the full text version of this article.

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Trends in Endocrinology & Metabolism

Science & SocietyClinical and ethical implications of mitochondrial gene transfer

Section snippets

Mitochondrial gene disorders

Techniques for mtDNA replacement

Safety and efficacy of mtDNA replacement

Regulatory, legal, and ethical questions

Acknowledgments

Am. J. Hum. Genet.

Mitochondrial DNA mutation associated with Lebers hereditary optic neuropathy

Science

Mitochondrial gene replacement in primate offspring and embryonic stem cells

Nature

Pronuclear transfer in human embryos to prevent transmission of mitochondrial DNA disease

Nature

Science & Society
Clinical and ethical implications of mitochondrial gene transfer