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Towards germline gene therapy of inherited mitochondrial diseases

Author

Listed:
  • 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
    Center for Women’s Health, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, 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
    Roger Williams Medical Center)

  • Richard Stouffer

    (Oregon National Primate Research Center, Oregon Health & Science University, 505 NW 185th Avenue, Beaverton, Oregon 97006, USA
    Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, USA)

  • Shoukhrat Mitalipov

    (Oregon National Primate Research Center, Oregon Health & Science University, 505 NW 185th Avenue, Beaverton, Oregon 97006, USA
    Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, USA)

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.

Suggested Citation

  • 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 & Keit, 2013. "Towards germline gene therapy of inherited mitochondrial diseases," Nature, Nature, vol. 493(7434), pages 627-631, January.
    • Handle: RePEc:nat:nature:v:493:y:2013:i:7434:d:10.1038_nature11647
    DOI: 10.1038/nature11647
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