线粒体捐赠—极体基因组移植治疗遗传性线粒体疾病

Mitochondrial Donation—Polar Body Genome Transfer for Preventing the Transmission of Inherited Mitochondrial Diseases

遗传性线粒体DNA(mitochondrial DNA,mt DNA)疾病通过母亲遗传给下一代,引起破坏性的临床结果。因无有效的治疗方法,故预防该疾病向子代传递成为首选。在患者卵子与健康者的卵子之间进行核置换,可阻止突变mt DNA向子代传递,这一技术称为线粒体捐赠。该研究成果发表前,线粒体捐赠技术包括原核移植和纺锤体移植,但这两种手段都不能彻底阻止疾病线粒体向子代传递。结果发现:极体中线粒体含量极少并与卵子拥有相同的基因组物质,故有望成为线粒体捐赠的首选核供体。基于此,利用小鼠模型比较了四种不同的生殖细胞基因组(纺锤体–染色体复合物、原核、第一极体、第二极体)移植的特点和有效性。研究结果显示,重构卵/胚胎支持正常受精、发育及诞生后代。遗传分析证实:相对于纺锤体–染色体和原核移植,极体移植产生的F1代体内携带的核供体来源的mt DNA量极少,其中第一极体移植(first polar body transfer,PB1T)子代中未检测到核供体来源的线粒体。更重要的是,mt DNA基因型在极体移植后的子二代中仍保持稳定,提示极体基因组移植有望阻止遗传性线粒体疾病向子代的遗传。

Inherited mitochondria disease inherit through the maternal line and develop severe systemic diseases. Nuclear genome transfer between patients’ and healthy eggs to replace mutant mt DNAs holds promises to prevent the transmission of mitochondria diseases. This technique is named mitochondria donation, including pronuclei transfer（PNT） and spindle-chromosome complex transfer（ST） before publishing our paper. However, PNT and ST couldn’t thoroughly prevent the transmission of mitochondria diseases. We found polar body（PB） was able to be the prior candidate, since PB contains few mitochondria, and PB nucleus is identical to female nucleus in ooplasm. We compared the effects of different types of germline genome transfer, including ST, PT, PB1 T and PB2 T in mice. Our results showed reconstructed embryos support normal fertilization and produce live offspring. Genetic analysis conf irms that the F1 generation from polar body transfer possesses minimal donor mtD NA compared to the F1 generation of the other procedures. Moreover, the mtD NA genotype remains stable in F2 progeny after polar body transfer, suggesting first polar body transfer（PB1T） has great potential to prevent inherited mtD NA diseases.