Selective elimination of mitochondrial mutations in the germline by genome editing

Pradeep Reddy; Alejandro Ocampo; Keiichiro Suzuki; Jinping Luo; Sandra R Bacman; Sion L 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'Callaghan; Jaime Campistol; Huimin Zhao; Josep M Campistol; Carlos T Moraes; Juan Carlos Izpisua Belmonte

doi:10.1016/j.cell.2015.03.051

Selective elimination of mitochondrial mutations in the germline by genome editing

Pradeep Reddy, Alejandro Ocampo, Keiichiro Suzuki, Jinping Luo, Sandra R Bacman, Sion L 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

Centre for Stem Cells & Regenerative Medicine

Research output: Contribution to journal › Article › peer-review

244 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 language	English
Pages (from-to)	459-69
Number of pages	11
Journal	Cell
Volume	161
Issue number	3
DOIs	https://doi.org/10.1016/j.cell.2015.03.051
Publication status	Published - 23 Apr 2015

Keywords

Animals
Cell Fusion
DNA, Mitochondrial
Embryo, Mammalian
Endonucleases
Female
Gene Targeting
Humans
Male
Mice
Mice, Inbred BALB C
Mice, Inbred NZB
Mitochondrial Diseases
Mutation
Oocytes

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.cell.2015.03.051

Cite this

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), 459-69. https://doi.org/10.1016/j.cell.2015.03.051

@article{53a91fb05e1d423ca2a44372edbf366f,

title = "Selective elimination of mitochondrial mutations in the germline by genome editing",

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.",

keywords = "Animals, Cell Fusion, DNA, Mitochondrial, Embryo, Mammalian, Endonucleases, Female, Gene Targeting, Humans, Male, Mice, Mice, Inbred BALB C, Mice, Inbred NZB, Mitochondrial Diseases, Mutation, Oocytes",

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

year = "2015",

month = apr,

day = "23",

doi = "10.1016/j.cell.2015.03.051",

language = "English",

volume = "161",

pages = "459--69",

journal = "Cell",

issn = "0092-8674",

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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, G-H, 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. 459-69. https://doi.org/10.1016/j.cell.2015.03.051

TY - JOUR

T1 - Selective elimination of mitochondrial mutations in the germline by genome editing

AU - Reddy, Pradeep

AU - Ocampo, Alejandro

AU - Suzuki, Keiichiro

AU - Luo, Jinping

AU - Bacman, Sandra R

AU - Williams, Sion L

AU - Sugawara, Atsushi

AU - Okamura, Daiji

AU - Tsunekawa, Yuji

AU - Wu, Jun

AU - Lam, David

AU - Xiong, Xiong

AU - Montserrat, Nuria

AU - Esteban, Concepcion Rodriguez

AU - Liu, Guang-Hui

AU - Sancho-Martinez, Ignacio

AU - Manau, Dolors

AU - Civico, Salva

AU - Cardellach, Francesc

AU - Del Mar O'Callaghan, Maria

AU - Campistol, Jaime

AU - Zhao, Huimin

AU - Campistol, Josep M

AU - Moraes, Carlos T

AU - Izpisua Belmonte, Juan Carlos

PY - 2015/4/23

Y1 - 2015/4/23

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.

AB - 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.

KW - Animals

KW - Cell Fusion

KW - DNA, Mitochondrial

KW - Embryo, Mammalian

KW - Endonucleases

KW - Female

KW - Gene Targeting

KW - Humans

KW - Male

KW - Mice

KW - Mice, Inbred BALB C

KW - Mice, Inbred NZB

KW - Mitochondrial Diseases

KW - Mutation

KW - Oocytes

U2 - 10.1016/j.cell.2015.03.051

DO - 10.1016/j.cell.2015.03.051

M3 - Article

C2 - 25910206

SN - 0092-8674

VL - 161

SP - 459

EP - 469

JO - Cell

JF - Cell

IS - 3

ER -

Selective elimination of mitochondrial mutations in the germline by genome editing

Abstract

Keywords

UN SDGs

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