In vivo mitochondrial base editing via adeno-associated viral delivery to mouse post-mitotic tissue.
In vivo mitochondrial base editing via adeno-associated viral delivery to mouse post-mitotic tissue.
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DOI：
10.1038/s41467-022-28358-w
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发表时间：
2022-02-08
影响因子：
16.6
通讯作者：
Minczuk M
中科院分区：
文献类型：
--
作者：
Silva-Pinheiro P;Nash PA;Van Haute L;Mutti CD;Turner K;Minczuk M
线粒体宿主对细胞能量供应至关重要的关键代谢过程，并且对细胞命运决定至关重要。它们受到核DNA和它们自己的多拷贝基因组-线粒体DNA（mtDNA）的独特遗传控制。线粒体DNA突变通常导致临床异质性的母系遗传疾病，这些疾病在生命的任何阶段都表现出不同的器官特异性表现。长期以来，哺乳动物mtDNA的遗传操作一直是一个重大挑战，阻碍了我们理解线粒体疾病的基础线粒体生物学和机制的能力。然而，最近出现了一种重要的mtDNA诱变新工具，即双链DNA脱氨酶（DddA）衍生的胞嘧啶碱基编辑器（DdCBE）。在这里，我们通过使用腺相关病毒（腺相关病毒）载体将DdCBE递送到小鼠心脏来测试这种新兴工具的体内使用，并表明它可以在成年和新生小鼠中安装所需的线粒体DNA编辑。这项工作为使用DdCBE在有丝分裂后组织中体内诱变mtDNA提供了概念验证，并为潜在的人类体细胞基因校正疗法提供了重要的见解，以治疗原发性线粒体疾病表型。线粒体DNA突变可导致临床异质性疾病。在这里，作者证明了通过AAV递送DddA衍生的胞嘧啶碱基编辑器（DdCBE）在有丝分裂后组织中对小鼠线粒体DNA的体内碱基编辑。
Mitochondria host key metabolic processes vital for cellular energy provision and are central to cell fate decisions. They are subjected to unique genetic control by both nuclear DNA and their own multi-copy genome - mitochondrial DNA (mtDNA). Mutations in mtDNA often lead to clinically heterogeneous, maternally inherited diseases that display different organ-specific presentation at any stage of life. For a long time, genetic manipulation of mammalian mtDNA has posed a major challenge, impeding our ability to understand the basic mitochondrial biology and mechanisms underpinning mitochondrial disease. However, an important new tool for mtDNA mutagenesis has emerged recently, namely double-stranded DNA deaminase (DddA)-derived cytosine base editor (DdCBE). Here, we test this emerging tool for in vivo use, by delivering DdCBEs into mouse heart using adeno-associated virus (AAV) vectors and show that it can install desired mtDNA edits in adult and neonatal mice. This work provides proof-of-concept for use of DdCBEs to mutagenize mtDNA in vivo in post-mitotic tissues and provides crucial insights into potential translation to human somatic gene correction therapies to treat primary mitochondrial disease phenotypes. Mutations in mitochondrial DNA can lead to clinically heterogeneous disease. Here the authors demonstrate in vivo base editing of mouse mitochondrial DNA in a post-mitotic tissue by AAV delivery of DddA-derived cytosine base editor (DdCBE).
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影响因子：
82.9
作者：
Gammage PA;Viscomi C;Simard ML;Costa ASH;Gaude E;Powell CA;Van Haute L;McCann BJ;Rebelo-Guiomar P;Cerutti R;Zhang L;Rebar EJ;Zeviani M;Frezza C;Stewart JB;Minczuk M
通讯作者：
Minczuk M
影响因子：
48
作者：
Langmead, Ben;Salzberg, Steven L.
通讯作者：
Salzberg, Steven L.
影响因子：
12.4
作者：
Hashimoto, Masami;Bacman, Sandra R.;Moraes, Carlos T.
通讯作者：
Moraes, Carlos T.
与成年线粒体疾病有关的核和线粒体DNA突变的患病率。
影响因子：
11.2
作者：
Gorman GS;Schaefer AM;Ng Y;Gomez N;Blakely EL;Alston CL;Feeney C;Horvath R;Yu-Wai-Man P;Chinnery PF;Taylor RW;Turnbull DM;McFarland R
通讯作者：
McFarland R
影响因子：
14.9
作者：
Gammage PA;Gaude E;Van Haute L;Rebelo-Guiomar P;Jackson CB;Rorbach J;Pekalski ML;Robinson AJ;Charpentier M;Concordet JP;Frezza C;Minczuk M
通讯作者：
Minczuk M