Towards clinical application of pronuclear transfer to prevent mitochondrial DNA diseaseMore about Open Access at the Crick
Authors listLouise A Hyslop Paul Blakeley Lyndsey Craven Jessica Richardson Norah Fogarty Elpida Fragouli Mahdi Lamb Sissy E Wamaitha Nilendran Prathalingam Qi Zhang Hannah O'Keefe Yuko Takeda Lucia Arizzi Samer Alfarawati Helen A Tuppen Laura Irving Dimitrios Kalleas Meenakshi Choudhary Dagan Wells Alison P Murdoch Douglass M Turnbull Kathy Niakan Mary Herbert
Mitochondrial DNA (mtDNA) mutations are maternally inherited and are associated with a broad range of debilitating and fatal diseases. Reproductive technologies designed to uncouple the inheritance of mtDNA from nuclear DNA may enable affected women to have a genetically related child with a greatly reduced risk of mtDNA disease. Here we report the first preclinical studies on pronuclear transplantation (PNT). Surprisingly, techniques used in proof-of-concept studies involving abnormally fertilized human zygotes were not well tolerated by normally fertilized zygotes. We have therefore developed an alternative approach based on transplanting pronuclei shortly after completion of meiosis rather than shortly before the first mitotic division. This promotes efficient development to the blastocyst stage with no detectable effect on aneuploidy or gene expression. After optimization, mtDNA carryover was reduced to <2% in the majority (79%) of PNT blastocysts. The importance of reducing carryover to the lowest possible levels is highlighted by a progressive increase in heteroplasmy in a stem cell line derived from a PNT blastocyst with 4% mtDNA carryover. We conclude that PNT has the potential to reduce the risk of mtDNA disease, but it may not guarantee prevention.
Issue number 7607