Towards germline gene therapy of inherited mitochondrial diseases
| Autor: | Masahito Tachibana, Shoukhrat Mitalipov, Nuria Marti Gutierrez, Jeffrey T. Jensen, Keith Masterson, David M. Lee, Richard L. Stouffer, Diana Wu, Phillip E. Patton, Paula Amato, Michelle Sparman, Hyo Sang Lee, Rebecca Tippner-Hedges, David Battaglia, Dario Melguizo Sanchis, Hong Ma, Joy Woodward, Eunju Kang, Sumita Gokhale, Cathy Ramsey |
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| Rok vydání: | 2012 |
| Předmět: |
0303 health sciences
Homoplasmy Mitochondrial DNA 030219 obstetrics & reproductive medicine Multidisciplinary Zygote Embryo Biology Embryonic stem cell Molecular biology Heteroplasmy 3. Good health 03 medical and health sciences 0302 clinical medicine medicine.anatomical_structure Spindle transfer medicine Blastocyst 030304 developmental biology |
| Zdroj: | Nature. 493:627-631 |
| ISSN: | 1476-4687 0028-0836 |
| DOI: | 10.1038/nature11647 |
| Popis: | 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 . |
| Databáze: | OpenAIRE |
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