Selective elimination of mitochondrial mutations in the germline by genome editing

Pradeep Reddy, Alejandro Ocampo, Keiichiro Suzuki, Jinping Luo, Sandra R. Bacman, Sion Llewelyn Williams, Atsushi Sugawara, Daiji Okamura, Yuji Tsunekawa, Jun Wu, David Lam, Xiong Xiong, Nuria Montserrat, Concepcion Rodriguez Esteban, Guang Hui Liu, Ignacio Sancho-Martinez, Dolors Manau, Salva Civico, Francesc Cardellach, Maria Del Mar O'CallaghanJaime Campistol, Huimin Zhao, Josep M. Campistol, Carlos T Moraes, Juan Carlos Izpisua Belmonte

Research output: Contribution to journalArticle

136 Scopus citations

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 transgenerational transmission of human mitochondrial diseases caused by mutations in mtDNA. PaperClip

Original languageEnglish (US)
Pages (from-to)459-469
Number of pages11
JournalCell
Volume161
Issue number3
DOIs
StatePublished - Apr 23 2015

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Reddy, P., Ocampo, A., Suzuki, K., Luo, J., Bacman, S. R., Williams, S. L., Sugawara, A., Okamura, D., Tsunekawa, Y., Wu, J., Lam, D., Xiong, X., Montserrat, N., Esteban, C. R., Liu, G. H., Sancho-Martinez, I., Manau, D., Civico, S., Cardellach, F., ... Izpisua Belmonte, J. C. (2015). Selective elimination of mitochondrial mutations in the germline by genome editing. Cell, 161(3), 459-469. https://doi.org/10.1016/j.cell.2015.03.051