Selective Elimination of Mitochondrial Mutations in the Germline by Genome Editing
Mitochondrial diseases include a group of maternally inherited genetic disorders caused by mutations in mtDNA. In most of these patients, mutated mtDNA coexists with wild-type mtDNA, a situation known as mtDNA heteroplasmy. Here, we report on a strategy toward preventing germline transmission of mitochondrial diseases by inducing mtDNA heteroplasmy shift through the selective elimination of mutated mtDNA. As a proof of concept, we took advantage of NZB/BALB heteroplasmic mice, which contain two mtDNA haplotypes, BALB and NZB, and selectively prevented their germline transmission using either mitochondria-targeted restriction endonucleases or TALENs. In addition, we successfully reduced human mutated mtDNA levels responsible for Leber's hereditary optic neuropathy (LHOND), and neurogenic muscle weakness, ataxia, and retinitis pigmentosa (NARP), in mammalian oocytes using mitochondria-targeted TALEN (mito-TALENs). Our approaches represent a potential therapeutic avenue for preventing the trans-generational transmission of human mitochondrial diseases caused by mutations in mtDNA.
Mitochondrial diseases include a group of maternally inherited genetic disorders caused by mutations in mtDNA. In most of these patients, mutated mtDNA coexists with wild-type mtDNA, a situation known as mtDNA heteroplasmy. Here, we report on a strategy toward preventing germline transmission of mitochondrial diseases by inducing mtDNA heteroplasmy shift through the selective elimination of mutated mtDNA. As a proof of concept, we took advantage of NZB/BALB heteroplasmic mice, which contain two mtDNA haplotypes, BALB and NZB, and selectively prevented their germline transmission using either mitochondria-targeted restriction endonucleases or TALENs. In addition, we successfully reduced human mutated mtDNA levels responsible for Leber's hereditary optic neuropathy (LHOND), and neurogenic muscle weakness, ataxia, and retinitis pigmentosa (NARP), in mammalian oocytes using mitochondria-targeted TALEN (mito-TALENs). Our approaches represent a potential therapeutic avenue for preventing the trans-generational transmission of human mitochondrial diseases caused by mutations in mtDNA.
Campistol, Josep M.、Zhao, Huimin、Campistol, Jaime、Okamura, Daiji、O'Callaghan, Maria del Mar、Manau, Dolors、Sancho-Martinez, Ignacio、Liu, Guang-Hui、Liu, Guang-Hui、Williams, Sion L.、Luo, Jinping、Lam, David、Belmonte, Juan Carlos Izpisua、Civico, Salva、Wu, Jun、Reddy, Pradeep、Tsunekawa, Yuji、Esteban, Concepcion Rodriguez、Liu, Guang-Hui、Cardellach, Francesc、Moraes, Carlos T.、Suzuki, Keiichiro、Ocampo, Alejandro、Xiong, Xiong、Moraes, Carlos T.、Sugawara, Atsushi、Cardellach, Francesc、Montserrat, Nuria、Bacman, Sandra R.
基础医学遗传学分子生物学
NA MUTATIONSISEASERANSMISSIONHETEROPLASMYEGRADATIONSEQUENCEEMBRYOSRIFT
Campistol, Josep M.,Zhao, Huimin,Campistol, Jaime,Okamura, Daiji,O'Callaghan, Maria del Mar,Manau, Dolors,Sancho-Martinez, Ignacio,Liu, Guang-Hui,Liu, Guang-Hui,Williams, Sion L.,Luo, Jinping,Lam, David,Belmonte, Juan Carlos Izpisua,Civico, Salva,Wu, Jun,Reddy, Pradeep,Tsunekawa, Yuji,Esteban, Concepcion Rodriguez,Liu, Guang-Hui,Cardellach, Francesc,Moraes, Carlos T.,Suzuki, Keiichiro,Ocampo, Alejandro,Xiong, Xiong,Moraes, Carlos T.,Sugawara, Atsushi,Cardellach, Francesc,Montserrat, Nuria,Bacman, Sandra R..Selective Elimination of Mitochondrial Mutations in the Germline by Genome Editing[EB/OL].(2016-05-12)[2025-08-02].https://chinaxiv.org/abs/201605.01363.点此复制
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