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Towards germline gene therapy of inherited mitochondrial diseases

Published on Jan 1, 2013in Nature43.07
· DOI :10.1038/nature11647
Masahito Tachibana14
Estimated H-index: 14
(OHSU: Oregon Health & Science University),
Paula Amato21
Estimated H-index: 21
(OHSU: Oregon Health & Science University)
+ 17 AuthorsShoukhrat Mitalipov36
Estimated H-index: 36
(OHSU: Oregon Health & Science University)
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. Mitochondrial DNA is localized in the cell’s cytoplasm, whereas chromosomal genes are confined to the nucleus. Each cell may have thousands of mtDNA copies, which may all be mutated (homoplasmy) or exist as a mixture (heteroplasmy). The clinical manifestations of mtDNA diseases vary, but often affect organs and tissues with the highest energy requirements, including the brain, heart, muscle, pancreas and kidney 1 . The expression and severity of disease symptoms depends on the specific mutation and heteroplasmy levels 1 .
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  • References (24)
  • Citations (218)
References24
Newest
#1Hyo Sang Lee (Oregon National Primate Research Center)H-Index: 6
#2Hong Ma (Oregon National Primate Research Center)H-Index: 27
Last.Paula Amato (OHSU: Oregon Health & Science University)H-Index: 21
view all 13 authors...
#1Jacques Donnez (Cliniques Universitaires Saint-Luc)H-Index: 79
#2Sherman J. Silber (Mount Sinai St. Luke's and Mount Sinai Roosevelt)H-Index: 61
Last.Marie-Madeleine Dolmans (Cliniques Universitaires Saint-Luc)H-Index: 45
view all 8 authors...
#1Masahito Tachibana (OHSU: Oregon Health & Science University)H-Index: 14
#2Michelle Sparman (Oregon National Primate Research Center)H-Index: 14
Last.Shoukhrat Mitalipov (Oregon National Primate Research Center)H-Index: 36
view all 3 authors...
#1Masahito Tachibana (OHSU: Oregon Health & Science University)H-Index: 14
#2Michelle Sparman (OHSU: Oregon Health & Science University)H-Index: 14
Last.Shoukhrat Mitalipov (OHSU: Oregon Health & Science University)H-Index: 36
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#1Hannah R Elliott (Newcastle University)H-Index: 13
#2David C. Samuels (VT: Virginia Tech)H-Index: 42
Last.Patrick F. Chinnery (Newcastle University)H-Index: 84
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#1Andrew M. Schaefer (Newcastle University)H-Index: 23
#2Robert McFarland (Newcastle University)H-Index: 40
Last.Douglass M. Turnbull (Newcastle University)H-Index: 93
view all 8 authors...
#1Richard H. Haas (UCSD: University of California, San Diego)H-Index: 37
#2Sumit Parikh (Cleveland Clinic)H-Index: 15
Last.Bruce H. Cohen (Cleveland Clinic)H-Index: 33
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#1Jörg Patrick Burgstaller (University of Veterinary Medicine Vienna)H-Index: 4
#2Pamela Schinogl (University of Veterinary Medicine Vienna)H-Index: 4
Last.Ralf Steinborn (University of Veterinary Medicine Vienna)H-Index: 22
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Cited By218
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#1Justin C. St. John (Monash University, Clayton campus)H-Index: 32
#2Yogeshwar Makanji (Monash University, Clayton campus)H-Index: 17
Last.Mulyoto Pangestu (Monash University, Clayton campus)H-Index: 5
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#1Tania Bubela (SFU: Simon Fraser University)H-Index: 2
#2Erika Kleiderman (McGill University)H-Index: 5
Last.Bartha Maria Knoppers (McGill University)H-Index: 49
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#1Geoffrey E. Hill (AU: Auburn University)H-Index: 66
#2Justin C. Havird (University of Texas at Austin)H-Index: 14
Last.Damian K. Dowling (Monash University, Clayton campus)H-Index: 25
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#1Don P. Wolf (OHSU: Oregon Health & Science University)H-Index: 42
#2Paul A. Mitalipov (OHSU: Oregon Health & Science University)
Last.Shoukhrat Mitalipov (OHSU: Oregon Health & Science University)H-Index: 36
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#1M. Aravintha Siva (SASTRA: Shanmugha Arts, Science, Technology & Research Academy)
#2R. Mahalakshmi (SASTRA: Shanmugha Arts, Science, Technology & Research Academy)
Last.Gunjan Guha (SASTRA: Shanmugha Arts, Science, Technology & Research Academy)H-Index: 18
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#1Anna Klucnika (University of Cambridge)
#2Hansong Ma (University of Cambridge)H-Index: 12
Last.Hansong Ma (University of Cambridge)
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