Clinical Genetics: Mitochondrial Replacement Techniques Under the Spotlight

RESEARCH HIGHLIGHTS Nature Reviews Genetics | AOP, published online 1 July 2014; doi:10.1038/nrg3784 BRAND X PICTURES CLINICAL GENETICS Mitochondrial replacement techniques under the spotlight Mutations in the mitochondrial genome have and quantitative PCR showed that PBs contain been associated with diverse forms of human dis- fewer mitochondria than pronuclei in zygotes and ease, such as Leber’s hereditary optic neuropathy than spindle–chromosome complexes in oocytes. and Leigh’s syndrome, a neurometabolic disorder. The researchers then evaluated the feasibility A preclinical mouse model now demonstrates the of PB1 or PB2 transfer in mice and compared feasibility of using polar body (PB) genomes as their efficacies with that of MST or PNT. Genetic donor genomes in a new type of mitochondrial analysis showed that oocytes generated by PB1 replacement technique aimed at preventing the genome transfer were fertilized at rates that are inheritance of mitochondrial diseases. comparable to those obtained for oocytes ferti- 2014 has seen a surge in interest from both lized after MST (89.5% and 87.5%, respectively). the UK Human Fertilisation and Embryology Moreover, 87.5% of PB1–oocytes and 85.7% Authority (HFEA) and the US Food and Drug of MST–oocytes developed into blastocysts. Administration (FDA) in evaluating methods By contrast, PNT–embryos developed into designed to prevent the transmission of mito- blastocysts more frequently than PB2–oocytes chondrial diseases. One approach that is currently (81.3% and 55.5%, respectively), despite similar under investigation is mitochondrial replacement cleavage rates. by pronuclear transfer (PNT), in which the paren- Normal live progeny were obtained with all of tal pronuclei of a fertilized egg containing the these techniques at birth rates similar to those mother’s mutated mitochondrial DNA (mtDNA) of an intact control group. High-throughput pyro are transferred into an enucleated zygote with sequencing to examine the level of heteroplasmy healthy mitochondria. A second approach, called (that is, the proportions of donor and recipient maternal spindle transfer (MST), involves replac- mitochondria) revealed that the F1 generation ing the mutated mtDNA of a patient’s unfertilized generated by PB genome transfer had signifi- oocyte with a healthy mitochondrial genome by cantly less donor mtDNA carryover than the F1 isolating and transplanting the patient’s chromo- generation obtained by PNT or MST. Finally, the somes into the cytoplasm of an enucleated oocyte investigators showed that the mtDNA genotype donated by a healthy volunteer. was stable in F2 offspring created through PB During oogenesis, PBs are created to reduce genome transfer. one half of the diploid chromosome set that arises Importantly, in addition to demonstrating the from meiosis. The primary oocyte divides asym- feasibility and efficacy of the PB genome transfer metrically to form the haploid secondary oocyte approach, this study indicates a means of mark- and PB1. In a second meiotic division, PB2 is gen- edly improving the efficiency of mitochondrial erated together with the ootid, which eventually replacement therapy — as a single oocyte can matures into the ovum. Given that PBs have little yield two donor genomes — thus halving the or no cytoplasm but contain the same genomic number of oocytes that must be obtained from material as their sister oocytes, Wang et al. a patient for a given procedure. Linda Koch hypothesized that the use of these cells as genome donors would reduce the carryover of unhealthy ORIGINAL RESEARCH PAPER Wang, T. et al. Polar body genome mitochondria that has been reported for other transfer for preventing the transmission of inherited mitochondrial diseases. Cell 157, 1591–1604 (2014) techniques. Indeed, immunofluorescence staining NATURE REVIEWS | GENETICS VOLUME 15 | AUGUST 2014 © 2014 Macmillan Publishers Limited. All rights reserved.

Load more