Intravitreal delivery of AAV-NDI1 provides functional benefit in a murine model of Leber hereditary optic neuropathy

Publikationstyp:
Zeitschriftenaufsatz
Metadaten:
Autoren
  • Naomi Chadderton
  • Arpad Palfi
  • Sophia Millington-Ward
  • Oliverio Gobbo
  • Nora Overlack
  • Matthew Carrigan
  • Mary O'Reilly
  • Matthew Campbell
  • Carsten Ehrhardt
  • Uwe Wolfrum
  • Peter Humphries
  • Paul F Kenna
  • G Jane Farrar
Autoren-URL
https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000312492500014&DestLinkType=FullRecord&DestApp=WOS_CPL
DOI
10.1038/ejhg.2012.112
eISSN
1476-5438
Externe Identifier
  • Clarivate Analytics Document Solution ID: 056LX
  • PubMed Identifier: 22669418
ISSN
1018-4813
Ausgabe der Veröffentlichung
1
Zeitschrift
EUROPEAN JOURNAL OF HUMAN GENETICS
Schlüsselwörter
  • AAV
  • LHON
  • NDI1
  • gene therapy
  • mitochondria
  • retina
Paginierung
62 - 68
Datum der Veröffentlichung
2013
Status
Published
Titel
Intravitreal delivery of AAV-<i>NDI1</i> provides functional benefit in a murine model of Leber hereditary optic neuropathy
Sub types
  • Article
Ausgabe der Zeitschrift
21

Datenquelle: Web of Science (Lite)

Andere Metadatenquellen:
Autoren
  • Naomi Chadderton
  • Arpad Palfi
  • Sophia Millington-Ward
  • Oliverio Gobbo
  • Nora Overlack
  • Matthew Carrigan
  • Mary O'Reilly
  • Matthew Campbell
  • Carsten Ehrhardt
  • Uwe Wolfrum
  • Peter Humphries
  • Paul F Kenna
  • G Jane Farrar
DOI
10.1038/ejhg.2012.112
eISSN
1476-5438
ISSN
1018-4813
Ausgabe der Veröffentlichung
1
Zeitschrift
European Journal of Human Genetics
Sprache
en
Online publication date
2012
Paginierung
62 - 68
Datum der Veröffentlichung
2013
Status
Published
Herausgeber
Springer Science and Business Media LLC
Herausgeber URL
http://dx.doi.org/10.1038/ejhg.2012.112
Datum der Datenerfassung
2023
Titel
Intravitreal delivery of AAV-NDI1 provides functional benefit in a murine model of Leber hereditary optic neuropathy
Ausgabe der Zeitschrift
21

Datenquelle: Crossref

Abstract
Leber hereditary optic neuropathy (LHON) is a mitochondrially inherited form of visual dysfunction caused by mutations in several genes encoding subunits of the mitochondrial respiratory NADH-ubiquinone oxidoreductase complex (complex I). Development of gene therapies for LHON has been impeded by genetic heterogeneity and the need to deliver therapies to the mitochondria of retinal ganglion cells (RGCs), the cells primarily affected in LHON. The therapy under development entails intraocular injection of a nuclear yeast gene NADH-quinone oxidoreductase (NDI1) that encodes a single subunit complex I equivalent and as such is mutation independent. NDI1 is imported into mitochondria due to an endogenous mitochondrial localisation signal. Intravitreal injection represents a clinically relevant route of delivery to RGCs not previously used for NDI1. In this study, recombinant adenoassociated virus (AAV) serotype 2 expressing NDI1 (AAV-NDI1) was shown to protect RGCs in a rotenone-induced murine model of LHON. AAV-NDI1 significantly reduced RGC death by 1.5-fold and optic nerve atrophy by 1.4-fold. This led to a significant preservation of retinal function as assessed by manganese enhanced magnetic resonance imaging and optokinetic responses. Intraocular injection of AAV-NDI1 overcomes many barriers previously associated with developing therapies for LHON and holds great therapeutic promise for a mitochondrial disorder for which there are no effective therapies.
Addresses
  • School of Genetics and Microbiology, Smurfit Institute of Genetics, Trinity College Dublin, Dublin, Ireland. chaddern@tcd.ie
Autoren
  • Naomi Chadderton
  • Arpad Palfi
  • Sophia Millington-Ward
  • Oliverio Gobbo
  • Nora Overlack
  • Matthew Carrigan
  • Mary O'Reilly
  • Matthew Campbell
  • Carsten Ehrhardt
  • Uwe Wolfrum
  • Peter Humphries
  • Paul F Kenna
  • G Jane Farrar
DOI
10.1038/ejhg.2012.112
eISSN
1476-5438
Externe Identifier
  • PubMed Identifier: 22669418
  • PubMed Central ID: PMC3522193
Open access
true
ISSN
1018-4813
Ausgabe der Veröffentlichung
1
Zeitschrift
European journal of human genetics : EJHG
Schlüsselwörter
  • Retinal Ganglion Cells
  • Animals
  • Humans
  • Mice
  • Dependovirus
  • Optic Atrophy
  • Optic Atrophy, Hereditary, Leber
  • Disease Models, Animal
  • Electron Transport Complex I
  • Microtubule-Associated Proteins
  • Saccharomyces cerevisiae Proteins
  • Genetic Vectors
  • Intravitreal Injections
Sprache
eng
Medium
Print-Electronic
Online publication date
2012
Open access status
Open Access
Paginierung
62 - 68
Datum der Veröffentlichung
2013
Status
Published
Publisher licence
CC BY-NC-ND
Datum der Datenerfassung
2012
Titel
Intravitreal delivery of AAV-NDI1 provides functional benefit in a murine model of Leber hereditary optic neuropathy.
Sub types
  • Research Support, Non-U.S. Gov't
  • research-article
  • Journal Article
Ausgabe der Zeitschrift
21

Files

https://www.nature.com/articles/ejhg2012112.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22669418/pdf/?tool=EBI https://europepmc.org/articles/PMC3522193?pdf=render

Datenquelle: Europe PubMed Central

Abstract
Leber hereditary optic neuropathy (LHON) is a mitochondrially inherited form of visual dysfunction caused by mutations in several genes encoding subunits of the mitochondrial respiratory NADH-ubiquinone oxidoreductase complex (complex I). Development of gene therapies for LHON has been impeded by genetic heterogeneity and the need to deliver therapies to the mitochondria of retinal ganglion cells (RGCs), the cells primarily affected in LHON. The therapy under development entails intraocular injection of a nuclear yeast gene NADH-quinone oxidoreductase (NDI1) that encodes a single subunit complex I equivalent and as such is mutation independent. NDI1 is imported into mitochondria due to an endogenous mitochondrial localisation signal. Intravitreal injection represents a clinically relevant route of delivery to RGCs not previously used for NDI1. In this study, recombinant adenoassociated virus (AAV) serotype 2 expressing NDI1 (AAV-NDI1) was shown to protect RGCs in a rotenone-induced murine model of LHON. AAV-NDI1 significantly reduced RGC death by 1.5-fold and optic nerve atrophy by 1.4-fold. This led to a significant preservation of retinal function as assessed by manganese enhanced magnetic resonance imaging and optokinetic responses. Intraocular injection of AAV-NDI1 overcomes many barriers previously associated with developing therapies for LHON and holds great therapeutic promise for a mitochondrial disorder for which there are no effective therapies.
Autoren
  • Naomi Chadderton
  • Arpad Palfi
  • Sophia Millington-Ward
  • Oliverio Gobbo
  • Nora Overlack
  • Matthew Carrigan
  • Mary O'Reilly
  • Matthew Campbell
  • Carsten Ehrhardt
  • Uwe Wolfrum
  • Peter Humphries
  • Paul F Kenna
  • G Jane Farrar
Autoren-URL
https://www.ncbi.nlm.nih.gov/pubmed/22669418
DOI
10.1038/ejhg.2012.112
eISSN
1476-5438
Externe Identifier
  • PubMed Central ID: PMC3522193
Ausgabe der Veröffentlichung
1
Zeitschrift
Eur J Hum Genet
Schlüsselwörter
  • Animals
  • Dependovirus
  • Disease Models, Animal
  • Electron Transport Complex I
  • Genetic Vectors
  • Humans
  • Intravitreal Injections
  • Mice
  • Microtubule-Associated Proteins
  • Optic Atrophy
  • Optic Atrophy, Hereditary, Leber
  • Retinal Ganglion Cells
  • Saccharomyces cerevisiae Proteins
Sprache
eng
Country
England
Paginierung
62 - 68
PII
ejhg2012112
Datum der Veröffentlichung
2013
Status
Published
Datum, an dem der Datensatz öffentlich gemacht wurde
2013
Titel
Intravitreal delivery of AAV-NDI1 provides functional benefit in a murine model of Leber hereditary optic neuropathy.
Sub types
  • Journal Article
  • Research Support, Non-U.S. Gov't
Ausgabe der Zeitschrift
21

Datenquelle: PubMed

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