期刊
EMBO MOLECULAR MEDICINE
卷 6, 期 4, 页码 458-466出版社
WILEY-BLACKWELL
DOI: 10.1002/emmm.201303672
关键词
heteroplasmy; zinc finger nuclease; mitochondrial disease; gene therapy
资金
- Medical Research Council
- Medical Research Council [MC_U105697135] Funding Source: researchfish
- MRC [MC_U105697135] Funding Source: UKRI
We designed and engineered mitochondrially targeted obligate heterodimeric zinc finger nucleases (mtZFNs) for site-specific elimination of pathogenic human mitochondrial DNA (mtDNA). We used mtZFNs to target and cleave mtDNA harbouring the m.8993T>G point mutation associated with neuropathy, ataxia, retinitis pigmentosa (NARP) and the common deletion (CD), a 4977-bp repeat-flanked deletion associated with adult-onset chronic progressive external ophthalmoplegia and, less frequently, Kearns-Sayre and Pearson's marrow pancreas syndromes. Expression of mtZFNs led to a reduction in mutant mtDNA haplotype load, and subsequent repopulation of wild-type mtDNA restored mitochondrial respiratory function in a CD cybrid cell model. This study constitutes proof-of-principle that, through heteroplasmy manipulation, delivery of site-specific nuclease activity to mitochondria can alleviate a severe biochemical phenotype in primary mitochondrial disease arising from deleted mtDNA species.
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