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

116 Citations (Scopus)

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

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Germ-Line Mutation
Mitochondrial DNA
Genes
Mitochondrial Diseases
Mitochondria
Leber's Hereditary Optic Atrophy
Gene Editing
Mutation
Inborn Genetic Diseases
DNA Restriction Enzymes
Haplotypes
Oocytes
Muscle
Optics

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Reddy, P., Ocampo, A., Suzuki, K., Luo, J., Bacman, S. R., Williams, S. L., ... 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

Selective elimination of mitochondrial mutations in the germline by genome editing. / Reddy, Pradeep; Ocampo, Alejandro; Suzuki, Keiichiro; Luo, Jinping; Bacman, Sandra R.; Williams, Sion Llewelyn; Sugawara, Atsushi; Okamura, Daiji; Tsunekawa, Yuji; Wu, Jun; Lam, David; Xiong, Xiong; Montserrat, Nuria; Esteban, Concepcion Rodriguez; Liu, Guang Hui; Sancho-Martinez, Ignacio; Manau, Dolors; Civico, Salva; Cardellach, Francesc; Del Mar O'Callaghan, Maria; Campistol, Jaime; Zhao, Huimin; Campistol, Josep M.; Moraes, Carlos T; Izpisua Belmonte, Juan Carlos.

In: Cell, Vol. 161, No. 3, 23.04.2015, p. 459-469.

Research output: Contribution to journalArticle

Reddy, P, Ocampo, A, Suzuki, K, Luo, J, Bacman, SR, Williams, SL, Sugawara, A, Okamura, D, Tsunekawa, Y, Wu, J, Lam, D, Xiong, X, Montserrat, N, Esteban, CR, Liu, GH, Sancho-Martinez, I, Manau, D, Civico, S, Cardellach, F, Del Mar O'Callaghan, M, Campistol, J, Zhao, H, Campistol, JM, Moraes, CT & Izpisua Belmonte, JC 2015, 'Selective elimination of mitochondrial mutations in the germline by genome editing', Cell, vol. 161, no. 3, pp. 459-469. https://doi.org/10.1016/j.cell.2015.03.051
Reddy, Pradeep ; Ocampo, Alejandro ; Suzuki, Keiichiro ; Luo, Jinping ; Bacman, Sandra R. ; Williams, Sion Llewelyn ; Sugawara, Atsushi ; Okamura, Daiji ; Tsunekawa, Yuji ; Wu, Jun ; Lam, David ; Xiong, Xiong ; Montserrat, Nuria ; Esteban, Concepcion Rodriguez ; Liu, Guang Hui ; Sancho-Martinez, Ignacio ; Manau, Dolors ; Civico, Salva ; Cardellach, Francesc ; Del Mar O'Callaghan, Maria ; Campistol, Jaime ; Zhao, Huimin ; Campistol, Josep M. ; Moraes, Carlos T ; Izpisua Belmonte, Juan Carlos. / Selective elimination of mitochondrial mutations in the germline by genome editing. In: Cell. 2015 ; Vol. 161, No. 3. pp. 459-469.
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AU - Del Mar O'Callaghan, Maria

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N2 - 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

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