Towards germline gene therapy of inherited mitochondrial diseases.
Towards germline gene therapy of inherited mitochondrial diseases.
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线粒体 DNA (mtDNA) 突变与严重的人类疾病有关，并且是从母亲的卵子遗传的。在这里，我们研究了通过纺锤体移植（ST）替代人类卵母细胞线粒体DNA的可行性。在捐赠用于研究的 106 个人类卵母细胞中，65 个接受了相互 ST，33 个作为对照。 ST 卵母细胞的受精率 (73%) 与对照 (75%) 相似。然而，很大一部分 ST 受精卵（52%）表现出受精异常，这由原核数量不规则决定。在正常受精的 ST 受精卵中，囊胚发育 (62%) 和胚胎干细胞 (ESC) 分离 (38%) 率与对照组相当。所有来自 ST 受精卵的 ESC 系都显示出正常的整倍体核型，并且只含有供体 mtDNA。线粒体DNA可以在人类卵母细胞中被有效替换。尽管一些 ST 卵母细胞表现出受精异常，但剩余的胚胎能够发育成囊胚并产生类似于对照的 ESC。
Mutations in mitochondrial DNA (mtDNA) are associated with serious human diseases and inherited from mother's eggs. Here we investigated the feasibility of mtDNA replacement in human oocytes by spindle transfer (ST). 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%) displayed abnormal fertilization as determined by irregular number of pronuclei. Among normally fertilized ST zygotes, blastocyst development (62%) and embryonic stem cell (ESC) isolation (38%) rates were comparable to controls. All ESC lines derived from ST zygotes displayed 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 ESCs similar to controls.
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