Selective Elimination of Mitochondrial Mutations in the Germline by Genome Editing

Subjects: Biology >> Biophysics >> Biochemistry & Molecular Biology submitted time 2016-05-12

Reddy, Pradeep Ocampo, Alejandro Suzuki, Keiichiro Luo, Jinping Sugawara, Atsushi Okamura, Daiji Wu, Jun Lam, David Esteban, Concepcion Rodriguez Sancho-Martinez, Ignacio Belmonte, Juan Carlos Izpisua Bacman, Sandra R. Williams, Sion L. Moraes, Carlos T. Tsunekawa, Yuji Xiong, Xiong Zhao, Huimin Montserrat, Nuria Liu, Guang-Hui Liu, Guang-Hui

Abstract： 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.

Peer Review Status:Awaiting Review

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