Towards germline gene therapy of inherited mitochondrial diseases

Masahito Tachibana, Paula Amato, Michelle Sparman, Joy Woodward, Dario Melguizo Sanchis, Hong Ma, Nuria Marti Gutierrez, Rebecca Tippner-Hedges, Eunju Kang, Hyo-Sang Lee, Cathy Ramsey, Keith Masterson, David Battaglia, David Lee, Diana Wu, Jeffrey Jensen, Phillip Patton, Sumita Gokhale, Richard Stouffer and Shoukhrat Mitalipov ()
Additional contact information
Masahito Tachibana: Oregon National Primate Research Center, Oregon Health & Science University, 505 NW 185th Avenue, Beaverton, Oregon 97006, USA
Paula Amato: Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, USA
Michelle Sparman: Oregon National Primate Research Center, Oregon Health & Science University, 505 NW 185th Avenue, Beaverton, Oregon 97006, USA
Joy Woodward: Oregon National Primate Research Center, Oregon Health & Science University, 505 NW 185th Avenue, Beaverton, Oregon 97006, USA
Dario Melguizo Sanchis: Oregon National Primate Research Center, Oregon Health & Science University, 505 NW 185th Avenue, Beaverton, Oregon 97006, USA
Hong Ma: Oregon National Primate Research Center, Oregon Health & Science University, 505 NW 185th Avenue, Beaverton, Oregon 97006, USA
Nuria Marti Gutierrez: Oregon National Primate Research Center, Oregon Health & Science University, 505 NW 185th Avenue, Beaverton, Oregon 97006, USA
Rebecca Tippner-Hedges: Oregon National Primate Research Center, Oregon Health & Science University, 505 NW 185th Avenue, Beaverton, Oregon 97006, USA
Eunju Kang: Oregon National Primate Research Center, Oregon Health & Science University, 505 NW 185th Avenue, Beaverton, Oregon 97006, USA
Hyo-Sang Lee: Oregon National Primate Research Center, Oregon Health & Science University, 505 NW 185th Avenue, Beaverton, Oregon 97006, USA
Cathy Ramsey: Oregon National Primate Research Center, Oregon Health & Science University, 505 NW 185th Avenue, Beaverton, Oregon 97006, USA
Keith Masterson: Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, USA
David Battaglia: Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, USA
David Lee: Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, USA
Diana Wu: Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, USA
Jeffrey Jensen: Oregon National Primate Research Center, Oregon Health & Science University, 505 NW 185th Avenue, Beaverton, Oregon 97006, USA
Phillip Patton: Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, USA
Sumita Gokhale: University Pathologists, LLC, Boston University School of Medicine
Richard Stouffer: Oregon National Primate Research Center, Oregon Health & Science University, 505 NW 185th Avenue, Beaverton, Oregon 97006, USA
Shoukhrat Mitalipov: Oregon National Primate Research Center, Oregon Health & Science University, 505 NW 185th Avenue, Beaverton, Oregon 97006, USA

Nature, 2013, vol. 493, issue 7434, 627-631

Abstract: Abstract Mutations in mitochondrial DNA (mtDNA) are associated with severe human diseases and are maternally inherited through the egg’s cytoplasm. Here we investigated the feasibility of mtDNA replacement in human oocytes by spindle transfer (ST; also called spindle–chromosomal complex transfer). Of 106 human oocytes donated for research, 65 were subjected to reciprocal ST and 33 served as controls. Fertilization rate in ST oocytes (73%) was similar to controls (75%); however, a significant portion of ST zygotes (52%) showed abnormal fertilization as determined by an irregular number of pronuclei. Among normally fertilized ST zygotes, blastocyst development (62%) and embryonic stem cell isolation (38%) rates were comparable to controls. All embryonic stem cell lines derived from ST zygotes had normal euploid karyotypes and contained exclusively donor mtDNA. The mtDNA can be efficiently replaced in human oocytes. Although some ST oocytes displayed abnormal fertilization, remaining embryos were capable of developing to blastocysts and producing embryonic stem cells similar to controls.

Date: 2013
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DOI: 10.1038/nature11647

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