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

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Abstract
Mitochondrial DNA (mtDNA) mutations passed down from a mother to offspring are a common cause of genetic disease, including neurological, muscle and heart problems, deafness and type 2 diabetes. It was shown recently in non-human primates that nuclear transfer techniques can prevent their transmission. Now, that proof-of-principle work has been extended to human embryos (see News, http://go.nature.com/xqgWXf ). A multi-department team based at Newcastle University transferred pronuclei between human zygotes, and obtained onward development to the blastocyst stage in vitro. Carry-over of donor zygote mtDNA is minimal, so the technique could potentially prevent the transmission of mtDNA disease in humans. Mutations in mitochondrial DNA (mtDNA) are a common cause of human genetic disease. It has been shown in non-human primates that nuclear transfer techniques might be an approach to prevent the transmission of mtDNA mutations. The proof of principle has now been extended to human embryos. Pronuclei were transferred between human zygotes, which developed onwards to the blastocyst stage in vitro. Carry-over of mtDNA from the donor zygotes to the recipients was minimal. Mutations in mitochondrial DNA (mtDNA) are a common cause of genetic disease. Pathogenic mutations in mtDNA are detected in approximately 1 in 250 live births1,2,3 and at least 1 in 10,000 adults in the UK are affected by mtDNA disease4. Treatment options for patients with mtDNA disease are extremely limited and are predominantly supportive in nature. Mitochondrial DNA is transmitted maternally and it has been proposed that nuclear transfer techniques may be an approach for the prevention of transmission of human mtDNA disease5,6. Here we show that transfer of pronuclei between abnormally fertilized human zygotes results in minimal carry-over of donor zygote mtDNA and is compatible with onward development to the blastocyst stage in vitro. By optimizing the procedure we found the average level of carry-over after transfer of two pronuclei is less than 2.0%, with many of the embryos containing no detectable donor mtDNA. We believe that pronuclear transfer between zygotes, as well as the recently described metaphase II spindle transfer, has the potential to prevent the transmission of mtDNA disease in humans.