异质性
线粒体DNA
核酸酶
生物
突变体
粒线体疾病
遗传学
人类线粒体遗传学
突变
分子生物学
症候群
线粒体
DNA
基因
线粒体肌病
作者
Wendy Shoop,Janel Lape,Megan Trum,Anne M. Powell,Emma Sevigny,Adam Mischler,Sandra R. Bacman,Flavia Fontanesi,Jeff Smith,Derek Jantz,Cassandra L. Gorsuch,Carlos T. Moraes
标识
DOI:10.1038/s42255-023-00932-6
摘要
Nuclease-mediated editing of heteroplasmic mitochondrial DNA (mtDNA) seeks to preferentially cleave and eliminate mutant mtDNA, leaving wild-type genomes to repopulate the cell and shift mtDNA heteroplasmy. Various technologies are available, but many suffer from limitations based on size and/or specificity. The use of ARCUS nucleases, derived from naturally occurring I-CreI, avoids these pitfalls due to their small size, single-component protein structure and high specificity resulting from a robust protein-engineering process. Here we describe the development of a mitochondrial-targeted ARCUS (mitoARCUS) nuclease designed to target one of the most common pathogenic mtDNA mutations, m.3243A>G. mitoARCUS robustly eliminated mutant mtDNA without cutting wild-type mtDNA, allowing for shifts in heteroplasmy and concomitant improvements in mitochondrial protein steady-state levels and respiration. In vivo efficacy was demonstrated using a m.3243A>G xenograft mouse model with mitoARCUS delivered systemically by adeno-associated virus. Together, these data support the development of mitoARCUS as an in vivo gene-editing therapeutic for m.3243A>G-associated diseases.
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