schliessen

Filtern

 

Bibliotheken

Genome editing in mitochondria corrects a pathogenic mtDNA mutation in vivo

Mutations of the mitochondrial genome (mtDNA) underlie a substantial portion of mitochondrial disease burden. These disorders are currently incurable and effectively untreatable, with heterogeneous penetrance, presentation and prognosis. To address the lack of effective treatment for these disorders... Full description

Journal Title: Nature medicine 2018, Vol.24 (11), p.1691-1695
Main Author: Gammage, Payam A
Other Authors: Viscomi, Carlo , Simard, Marie-Lune , Costa, Ana S H , Gaude, Edoardo , Powell, Christopher A , Van Haute, Lindsey , McCann, Beverly J , Rebelo-Guiomar, Pedro , Cerutti, Raffaele , Zhang, Lei , Rebar, Edward J , Zeviani, Massimo , Frezza, Christian , Stewart, James B , Minczuk, Michal
Format: Electronic Article Electronic Article
Language: English
Subjects:
Publisher: United States: Nature Publishing Group
ID: ISSN: 1078-8956
Link: https://www.ncbi.nlm.nih.gov/pubmed/30250142
Zum Text:
SendSend as email Add to Book BagAdd to Book Bag
Staff View
recordid: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6225988
title: Genome editing in mitochondria corrects a pathogenic mtDNA mutation in vivo
format: Article
creator:
  • Gammage, Payam A
  • Viscomi, Carlo
  • Simard, Marie-Lune
  • Costa, Ana S H
  • Gaude, Edoardo
  • Powell, Christopher A
  • Van Haute, Lindsey
  • McCann, Beverly J
  • Rebelo-Guiomar, Pedro
  • Cerutti, Raffaele
  • Zhang, Lei
  • Rebar, Edward J
  • Zeviani, Massimo
  • Frezza, Christian
  • Stewart, James B
  • Minczuk, Michal
subjects:
  • Analysis
  • Animals
  • Care and treatment
  • Coronary artery disease
  • Dependovirus - genetics
  • Disease Models, Animal
  • Disorders
  • DNA binding proteins
  • DNA, Mitochondrial - genetics
  • Extrachromosomal DNA
  • Gene Editing
  • Gene mutations
  • Genetic aspects
  • Genetic diversity
  • Genomes
  • Genomics
  • Health aspects
  • Heart
  • Heart diseases
  • Heteroplasmy
  • Humans
  • Mice
  • Mitochondria
  • Mitochondria, Heart - genetics
  • Mitochondria, Heart - pathology
  • Mitochondrial diseases
  • Mitochondrial Diseases - genetics
  • Mitochondrial Diseases - pathology
  • Mitochondrial Diseases - therapy
  • Mitochondrial DNA
  • Models
  • Mutation
  • Mutation - genetics
  • Nuclease
  • Nucleases
  • Phenotypes
  • Prognosis
  • Reversion
  • RNA, Transfer - genetics
  • Viruses
  • Zinc
  • Zinc Finger Nucleases - genetics
  • Zinc Finger Nucleases - therapeutic use
ispartof: Nature medicine, 2018, Vol.24 (11), p.1691-1695
description: Mutations of the mitochondrial genome (mtDNA) underlie a substantial portion of mitochondrial disease burden. These disorders are currently incurable and effectively untreatable, with heterogeneous penetrance, presentation and prognosis. To address the lack of effective treatment for these disorders, we exploited a recently developed mouse model that recapitulates common molecular features of heteroplasmic mtDNA disease in cardiac tissue: the m.5024C>T tRNA mouse. Through application of a programmable nuclease therapy approach, using systemically administered, mitochondrially targeted zinc-finger nucleases (mtZFN) delivered by adeno-associated virus, we induced specific elimination of mutant mtDNA across the heart, coupled to a reversion of molecular and biochemical phenotypes. These findings constitute proof of principle that mtDNA heteroplasmy correction using programmable nucleases could provide a therapeutic route for heteroplasmic mitochondrial diseases of diverse genetic origin.
language: eng
source:
identifier: ISSN: 1078-8956
fulltext: no_fulltext
issn:
  • 1078-8956
  • 1546-170X
url: Link


@attributes
NO1
SEARCH_ENGINEprimo_central_multiple_fe
SEARCH_ENGINE_TYPEPrimo Central Search Engine
RANK2.8041468
LOCALfalse
PrimoNMBib
record
control
sourceidgale_pubme
recordidTN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6225988
sourceformatXML
sourcesystemPC
galeidA573111889
sourcerecordidA573111889
originalsourceidFETCH-LOGICAL-1621t-eaf27c1bc18a84a967d57f4e5ea4a6af82aefe1ffdc9910e21827ce0495243e30
addsrcrecordideNp9km9r1TAUh4sobk4_gG-kIIi-6MxJmzZ5M7hMncPhwH_4LmTpaW9Gm1yb9KLf3pRe5-0YI5SE9jlPOD2_JHkO5BhIzt_6ApiAjACPT8ky8SA5BFaUGVTk58N4JhXPuGDlQfLE-2tCSE6YeJwc5IQyAgU9TD6doXU9plibYGybGpv2Jji9drYejEq1GwbUwacq3aiwdi1ao9M-vPu8SvsxqGCcnYq2ZuueJo8a1Xl8ttuPku8f3n87_ZhdXJ6dn64uMigphAxVQysNVxq44oUSZVWzqimQoSpUqRpOFTYITVNrIYAgBR55JIVgtMgxJ0fJyezdjFc91hptGFQnN4Pp1fBHOmXk8os1a9m6rSwpZYLzKHi9Ewzu14g-yN54jV2nLLrRSwpAQQDnIqIvb6HXbhxsbC9S8TeKqqDFf6pVHUpjGxfv1ZNUrliVA-xcx3dQcdXYG-0sNia-XxS8uKNA7gNvFkCUBPwdWjV6L8-_flnK7mMvfyzZV3vsGlUX1t514zRtvwRhBvXgvB-wuZkCEDllVM4ZlTGjcsqo3OtqHtJNxb9QRqC6JdVmTlps33T3qP8CF_7ujQ
sourcetypeOpen Access Repository
isCDItrue
recordtypearticle
pqid2130297424
display
typearticle
titleGenome editing in mitochondria corrects a pathogenic mtDNA mutation in vivo
creatorGammage, Payam A ; Viscomi, Carlo ; Simard, Marie-Lune ; Costa, Ana S H ; Gaude, Edoardo ; Powell, Christopher A ; Van Haute, Lindsey ; McCann, Beverly J ; Rebelo-Guiomar, Pedro ; Cerutti, Raffaele ; Zhang, Lei ; Rebar, Edward J ; Zeviani, Massimo ; Frezza, Christian ; Stewart, James B ; Minczuk, Michal
creatorcontribGammage, Payam A ; Viscomi, Carlo ; Simard, Marie-Lune ; Costa, Ana S H ; Gaude, Edoardo ; Powell, Christopher A ; Van Haute, Lindsey ; McCann, Beverly J ; Rebelo-Guiomar, Pedro ; Cerutti, Raffaele ; Zhang, Lei ; Rebar, Edward J ; Zeviani, Massimo ; Frezza, Christian ; Stewart, James B ; Minczuk, Michal
descriptionMutations of the mitochondrial genome (mtDNA) underlie a substantial portion of mitochondrial disease burden. These disorders are currently incurable and effectively untreatable, with heterogeneous penetrance, presentation and prognosis. To address the lack of effective treatment for these disorders, we exploited a recently developed mouse model that recapitulates common molecular features of heteroplasmic mtDNA disease in cardiac tissue: the m.5024C>T tRNA mouse. Through application of a programmable nuclease therapy approach, using systemically administered, mitochondrially targeted zinc-finger nucleases (mtZFN) delivered by adeno-associated virus, we induced specific elimination of mutant mtDNA across the heart, coupled to a reversion of molecular and biochemical phenotypes. These findings constitute proof of principle that mtDNA heteroplasmy correction using programmable nucleases could provide a therapeutic route for heteroplasmic mitochondrial diseases of diverse genetic origin.
identifier
0ISSN: 1078-8956
1EISSN: 1546-170X
2DOI: 10.1038/s41591-018-0165-9
3PMID: 30250142
languageeng
publisherUnited States: Nature Publishing Group
subjectAnalysis ; Animals ; Care and treatment ; Coronary artery disease ; Dependovirus - genetics ; Disease Models, Animal ; Disorders ; DNA binding proteins ; DNA, Mitochondrial - genetics ; Extrachromosomal DNA ; Gene Editing ; Gene mutations ; Genetic aspects ; Genetic diversity ; Genomes ; Genomics ; Health aspects ; Heart ; Heart diseases ; Heteroplasmy ; Humans ; Mice ; Mitochondria ; Mitochondria, Heart - genetics ; Mitochondria, Heart - pathology ; Mitochondrial diseases ; Mitochondrial Diseases - genetics ; Mitochondrial Diseases - pathology ; Mitochondrial Diseases - therapy ; Mitochondrial DNA ; Models ; Mutation ; Mutation - genetics ; Nuclease ; Nucleases ; Phenotypes ; Prognosis ; Reversion ; RNA, Transfer - genetics ; Viruses ; Zinc ; Zinc Finger Nucleases - genetics ; Zinc Finger Nucleases - therapeutic use
ispartofNature medicine, 2018, Vol.24 (11), p.1691-1695
rights
0COPYRIGHT 2018 Nature Publishing Group
1Copyright Nature Publishing Group Nov 2018
lds50peer_reviewed
oafree_for_read
citedbyFETCH-LOGICAL-1621t-eaf27c1bc18a84a967d57f4e5ea4a6af82aefe1ffdc9910e21827ce0495243e30
citesFETCH-LOGICAL-1621t-eaf27c1bc18a84a967d57f4e5ea4a6af82aefe1ffdc9910e21827ce0495243e30
orcidid0000-0002-3293-7397 ; 0000-0001-6050-0566 ; 0000-0003-1968-1726 ; 0000-0002-2902-4968 ; 0000-0001-8242-1420
links
openurl$$Topenurl_article
thumbnail$$Usyndetics_thumb_exl
backlink$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30250142$$D View this record in MEDLINE/PubMed
search
creatorcontrib
0Gammage, Payam A
1Viscomi, Carlo
2Simard, Marie-Lune
3Costa, Ana S H
4Gaude, Edoardo
5Powell, Christopher A
6Van Haute, Lindsey
7McCann, Beverly J
8Rebelo-Guiomar, Pedro
9Cerutti, Raffaele
10Zhang, Lei
11Rebar, Edward J
12Zeviani, Massimo
13Frezza, Christian
14Stewart, James B
15Minczuk, Michal
title
0Genome editing in mitochondria corrects a pathogenic mtDNA mutation in vivo
1Nature medicine
addtitleNat Med
descriptionMutations of the mitochondrial genome (mtDNA) underlie a substantial portion of mitochondrial disease burden. These disorders are currently incurable and effectively untreatable, with heterogeneous penetrance, presentation and prognosis. To address the lack of effective treatment for these disorders, we exploited a recently developed mouse model that recapitulates common molecular features of heteroplasmic mtDNA disease in cardiac tissue: the m.5024C>T tRNA mouse. Through application of a programmable nuclease therapy approach, using systemically administered, mitochondrially targeted zinc-finger nucleases (mtZFN) delivered by adeno-associated virus, we induced specific elimination of mutant mtDNA across the heart, coupled to a reversion of molecular and biochemical phenotypes. These findings constitute proof of principle that mtDNA heteroplasmy correction using programmable nucleases could provide a therapeutic route for heteroplasmic mitochondrial diseases of diverse genetic origin.
subject
0Analysis
1Animals
2Care and treatment
3Coronary artery disease
4Dependovirus - genetics
5Disease Models, Animal
6Disorders
7DNA binding proteins
8DNA, Mitochondrial - genetics
9Extrachromosomal DNA
10Gene Editing
11Gene mutations
12Genetic aspects
13Genetic diversity
14Genomes
15Genomics
16Health aspects
17Heart
18Heart diseases
19Heteroplasmy
20Humans
21Mice
22Mitochondria
23Mitochondria, Heart - genetics
24Mitochondria, Heart - pathology
25Mitochondrial diseases
26Mitochondrial Diseases - genetics
27Mitochondrial Diseases - pathology
28Mitochondrial Diseases - therapy
29Mitochondrial DNA
30Models
31Mutation
32Mutation - genetics
33Nuclease
34Nucleases
35Phenotypes
36Prognosis
37Reversion
38RNA, Transfer - genetics
39Viruses
40Zinc
41Zinc Finger Nucleases - genetics
42Zinc Finger Nucleases - therapeutic use
issn
01078-8956
11546-170X
fulltextfalse
rsrctypearticle
creationdate2018
recordtypearticle
recordideNp9km9r1TAUh4sobk4_gG-kIIi-6MxJmzZ5M7hMncPhwH_4LmTpaW9Gm1yb9KLf3pRe5-0YI5SE9jlPOD2_JHkO5BhIzt_6ApiAjACPT8ky8SA5BFaUGVTk58N4JhXPuGDlQfLE-2tCSE6YeJwc5IQyAgU9TD6doXU9plibYGybGpv2Jji9drYejEq1GwbUwacq3aiwdi1ao9M-vPu8SvsxqGCcnYq2ZuueJo8a1Xl8ttuPku8f3n87_ZhdXJ6dn64uMigphAxVQysNVxq44oUSZVWzqimQoSpUqRpOFTYITVNrIYAgBR55JIVgtMgxJ0fJyezdjFc91hptGFQnN4Pp1fBHOmXk8os1a9m6rSwpZYLzKHi9Ewzu14g-yN54jV2nLLrRSwpAQQDnIqIvb6HXbhxsbC9S8TeKqqDFf6pVHUpjGxfv1ZNUrliVA-xcx3dQcdXYG-0sNia-XxS8uKNA7gNvFkCUBPwdWjV6L8-_flnK7mMvfyzZV3vsGlUX1t514zRtvwRhBvXgvB-wuZkCEDllVM4ZlTGjcsqo3OtqHtJNxb9QRqC6JdVmTlps33T3qP8CF_7ujQ
startdate201811
enddate201811
creator
0Gammage, Payam A
1Viscomi, Carlo
2Simard, Marie-Lune
3Costa, Ana S H
4Gaude, Edoardo
5Powell, Christopher A
6Van Haute, Lindsey
7McCann, Beverly J
8Rebelo-Guiomar, Pedro
9Cerutti, Raffaele
10Zhang, Lei
11Rebar, Edward J
12Zeviani, Massimo
13Frezza, Christian
14Stewart, James B
15Minczuk, Michal
generalNature Publishing Group
scope
0CGR
1CUY
2CVF
3ECM
4EIF
5NPM
6AAYXX
7CITATION
8BKMMT
9BSHEE
103V.
117QG
127QL
137QP
147QR
157T5
167TK
177TM
187TO
197U7
207U9
217X7
227XB
2388A
2488E
2588I
268AO
278FD
288FE
298FH
308FI
318FJ
328FK
338G5
34ABUWG
35AZQEC
36BBNVY
37BENPR
38BHPHI
39C1K
40DWQXO
41FR3
42FYUFA
43GHDGH
44GNUQQ
45GUQSH
46H94
47HCIFZ
48K9.
49LK8
50M0S
51M1P
52M2O
53M2P
54M7N
55M7P
56MBDVC
57P64
58PADUT
59PQEST
60PQQKQ
61PQUKI
62PRINS
63Q9U
64RC3
657X8
665PM
orcidid
0https://orcid.org/0000-0002-3293-7397
1https://orcid.org/0000-0001-6050-0566
2https://orcid.org/0000-0003-1968-1726
3https://orcid.org/0000-0002-2902-4968
4https://orcid.org/0000-0001-8242-1420
sort
creationdate201811
titleGenome editing in mitochondria corrects a pathogenic mtDNA mutation in vivo
authorGammage, Payam A ; Viscomi, Carlo ; Simard, Marie-Lune ; Costa, Ana S H ; Gaude, Edoardo ; Powell, Christopher A ; Van Haute, Lindsey ; McCann, Beverly J ; Rebelo-Guiomar, Pedro ; Cerutti, Raffaele ; Zhang, Lei ; Rebar, Edward J ; Zeviani, Massimo ; Frezza, Christian ; Stewart, James B ; Minczuk, Michal
facets
frbrtype5
frbrgroupidcdi_FETCH-LOGICAL-1621t-eaf27c1bc18a84a967d57f4e5ea4a6af82aefe1ffdc9910e21827ce0495243e30
rsrctypearticles
prefilterarticles
languageeng
creationdate2018
topic
0Analysis
1Animals
2Care and treatment
3Coronary artery disease
4Dependovirus - genetics
5Disease Models, Animal
6Disorders
7DNA binding proteins
8DNA, Mitochondrial - genetics
9Extrachromosomal DNA
10Gene Editing
11Gene mutations
12Genetic aspects
13Genetic diversity
14Genomes
15Genomics
16Health aspects
17Heart
18Heart diseases
19Heteroplasmy
20Humans
21Mice
22Mitochondria
23Mitochondria, Heart - genetics
24Mitochondria, Heart - pathology
25Mitochondrial diseases
26Mitochondrial Diseases - genetics
27Mitochondrial Diseases - pathology
28Mitochondrial Diseases - therapy
29Mitochondrial DNA
30Models
31Mutation
32Mutation - genetics
33Nuclease
34Nucleases
35Phenotypes
36Prognosis
37Reversion
38RNA, Transfer - genetics
39Viruses
40Zinc
41Zinc Finger Nucleases - genetics
42Zinc Finger Nucleases - therapeutic use
toplevelpeer_reviewed
creatorcontrib
0Gammage, Payam A
1Viscomi, Carlo
2Simard, Marie-Lune
3Costa, Ana S H
4Gaude, Edoardo
5Powell, Christopher A
6Van Haute, Lindsey
7McCann, Beverly J
8Rebelo-Guiomar, Pedro
9Cerutti, Raffaele
10Zhang, Lei
11Rebar, Edward J
12Zeviani, Massimo
13Frezza, Christian
14Stewart, James B
15Minczuk, Michal
collection
0Medline
1MEDLINE
2MEDLINE (Ovid)
3MEDLINE
4MEDLINE
5PubMed
6CrossRef
7Gale General OneFile (A&I only)
8Academic OneFile (A&I only)
9ProQuest Central (Corporate)
10Animal Behavior Abstracts
11Bacteriology Abstracts (Microbiology B)
12Calcium & Calcified Tissue Abstracts
13Chemoreception Abstracts
14Immunology Abstracts
15Neurosciences Abstracts
16Nucleic Acids Abstracts
17Oncogenes and Growth Factors Abstracts
18Toxicology Abstracts
19Virology and AIDS Abstracts
20Health & Medical Collection
21ProQuest Central (purchase pre-March 2016)
22Biology Database (Alumni Edition)
23Medical Database (Alumni Edition)
24Science Database (Alumni Edition)
25ProQuest Pharma Collection
26Technology Research Database
27ProQuest SciTech Collection
28ProQuest Natural Science Collection
29Hospital Premium Collection
30Hospital Premium Collection (Alumni Edition)
31ProQuest Central (Alumni) (purchase pre-March 2016)
32Research Library (Alumni Edition)
33ProQuest Central (Alumni Edition)
34ProQuest Central Essentials
35Biological Science Collection
36ProQuest Central
37Natural Science Collection
38Environmental Sciences and Pollution Management
39ProQuest Central Korea
40Engineering Research Database
41Health Research Premium Collection
42Health Research Premium Collection (Alumni)
43ProQuest Central Student
44Research Library Prep
45AIDS and Cancer Research Abstracts
46SciTech Premium Collection
47ProQuest Health & Medical Complete (Alumni)
48ProQuest Biological Science Collection
49Health & Medical Collection (Alumni Edition)
50Medical Database
51Research Library
52Science Database
53Algology Mycology and Protozoology Abstracts (Microbiology C)
54Biological Science Database
55Research Library (Corporate)
56Biotechnology and BioEngineering Abstracts
57Research Library China
58ProQuest One Academic Eastern Edition
59ProQuest One Academic
60ProQuest One Academic UKI Edition
61ProQuest Central China
62ProQuest Central Basic
63Genetics Abstracts
64MEDLINE - Academic
65PubMed Central (Full Participant titles)
jtitleNature medicine
delivery
delcategoryRemote Search Resource
fulltextno_fulltext
addata
au
0Gammage, Payam A
1Viscomi, Carlo
2Simard, Marie-Lune
3Costa, Ana S H
4Gaude, Edoardo
5Powell, Christopher A
6Van Haute, Lindsey
7McCann, Beverly J
8Rebelo-Guiomar, Pedro
9Cerutti, Raffaele
10Zhang, Lei
11Rebar, Edward J
12Zeviani, Massimo
13Frezza, Christian
14Stewart, James B
15Minczuk, Michal
formatjournal
genrearticle
ristypeJOUR
atitleGenome editing in mitochondria corrects a pathogenic mtDNA mutation in vivo
jtitleNature medicine
addtitleNat Med
date2018-11
risdate2018
volume24
issue11
spage1691
epage1695
pages1691-1695
issn1078-8956
eissn1546-170X
abstractMutations of the mitochondrial genome (mtDNA) underlie a substantial portion of mitochondrial disease burden. These disorders are currently incurable and effectively untreatable, with heterogeneous penetrance, presentation and prognosis. To address the lack of effective treatment for these disorders, we exploited a recently developed mouse model that recapitulates common molecular features of heteroplasmic mtDNA disease in cardiac tissue: the m.5024C>T tRNA mouse. Through application of a programmable nuclease therapy approach, using systemically administered, mitochondrially targeted zinc-finger nucleases (mtZFN) delivered by adeno-associated virus, we induced specific elimination of mutant mtDNA across the heart, coupled to a reversion of molecular and biochemical phenotypes. These findings constitute proof of principle that mtDNA heteroplasmy correction using programmable nucleases could provide a therapeutic route for heteroplasmic mitochondrial diseases of diverse genetic origin.
copUnited States
pubNature Publishing Group
pmid30250142
doi10.1038/s41591-018-0165-9
tpages5
orcidid
0https://orcid.org/0000-0002-3293-7397
1https://orcid.org/0000-0001-6050-0566
2https://orcid.org/0000-0003-1968-1726
3https://orcid.org/0000-0002-2902-4968
4https://orcid.org/0000-0001-8242-1420
oafree_for_read