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, Shoukhrat Mitalipov

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224 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)627-631
Number of pages5
JournalNature
Volume493
Issue number7434
DOIs
Publication statusPublished - Jan 31 2013

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Tachibana, M., Amato, P., Sparman, M., Woodward, J., Sanchis, D. M., Ma, H., ... Mitalipov, S. (2013). Towards germline gene therapy of inherited mitochondrial diseases. Nature, 493(7434), 627-631. https://doi.org/10.1038/nature11647