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Cell. 2015 Apr 23;161(3):459-469. doi: 10.1016/j.cell.2015.03.051.

Selective elimination of mitochondrial mutations in the germline by genome editing.

Author information

1
Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
2
Department of Neurology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
3
Laboratory for Cell Asymmetry, RIKEN Center for Developmental Biology, Kobe, Hyogo 650-0047, Japan.
4
Department of Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
5
Pluripotent Stem Cells and Organ Regeneration, Institute for Bioengineering of Catalonia (IBEC), Barcelona 08028, Spain.
6
National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; Center for Molecular and Translational Medicine (CMTM), Beijing 100101, China; Beijing Institute for Brain Disorders, Beijing100069, China.
7
Institut Clínic of Gynecology, Obstetrics and Neonatology (ICGON), Hospital Clinic, University of Barcelona, Barcelona 08036, Spain.
8
Mitochondrial Research Laboratory, IDIBAPS/CIBER on Rare Diseases, University of Barcelona and Internal Medicine Department, Hospital Clínic, University of Barcelona, Barcelona 08036, Spain.
9
Neuropediatric Department/CIBERER, Hospital Universitari Sant Joan de Déu, Esplugues de Llobregat 08950, Spain.
10
Renal Division, Hospital Clinic, University of Barcelona, IDIBAPS, Barcelona 08036, Spain.
11
Department of Neurology, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Department of Cell Biology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
12
Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA. Electronic address: belmonte@salk.edu.

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.

PMID:
25910206
PMCID:
PMC4505837
DOI:
10.1016/j.cell.2015.03.051
[Indexed for MEDLINE]
Free PMC Article

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