Institute of Medical Science, The University of Toronto, Toronto, ON, Canada.
Adv Exp Med Biol. 2019;1158:257-267. doi: 10.1007/978-981-13-8367-0_14.
Mitochondrial disease can arise due to pathogenic sequence variants in the mitochondrial DNA (mtDNA) that prevent cells from meeting their energy demands. Mitochondrial diseases are often fatal and currently there are no treatments directed towards the underlying cause of disease. Pathogenic variants in mtDNA often exist in a state of heteroplasmy, with coexistence of pathogenic and wild type mtDNA. The load of heteroplasmy, defined as the relative amount of pathogenic mtDNA to wild type mtDNA, corresponds to timing and symptom severity. Thus, changing the heteroplasmy load may lead to a shift in disease onset and symptom severity. Here we review techniques aimed at preventing inheritance of pathogenic mtDNA via mitochondrial replacement therapy (MRT) and strategies geared toward shifting of heteroplasmy in individuals with active mitochondrial disease. MRT strategies seek to create embryos with the nuclear genetic makeup of the intended parents and wild type mtDNA from a donor in order to avoid known maternal pathogenic variants. Heteroplasmy shift approaches in patients are of two categories: nuclease dependent and nuclease independent strategies. Despite initial success in mouse models and patient cells, these techniques have not reached clinical use. Translational attempts in this area are urgently needed to improve therapies for a currently untreatable set of disorders.
线粒体疾病可能是由于线粒体 DNA（mtDNA）中的致病性序列变异引起的，这些变异使细胞无法满足其能量需求。线粒体疾病通常是致命的，目前尚无针对疾病根本原因的治疗方法。mtDNA 中的致病性变体通常处于异质性状态，即致病性和野生型 mtDNA 共存。异质性负荷定义为致病性 mtDNA 与野生型 mtDNA 的相对量，与发病时间和症状严重程度相对应。因此，改变异质性负荷可能会导致疾病发作和症状严重程度的改变。在这里，我们回顾了旨在通过线粒体替代疗法（MRT）预防致病性 mtDNA 遗传的技术，以及针对有活性的线粒体疾病患者异质性转移的策略。MRT 策略旨在创建具有预期父母核遗传背景和供体野生型 mtDNA 的胚胎，以避免已知的母体致病性变体。患者中的异质性转移方法有两种类型：依赖核酸酶和不依赖核酸酶的策略。尽管在小鼠模型和患者细胞中最初取得了成功，但这些技术尚未达到临床应用。在这一领域的转化尝试迫切需要改善目前无法治疗的一系列疾病的治疗方法。
