Adeno-Associated Virus-Mediated Rhodopsin Replacement Provides Therapeutic Benefit in Mice with a Targeted Disruption of the Rhodopsin Gene

Publication type:
Journal article
Metadata:
Autoren
  • Arpad Palfi
  • Sophia Millington-Ward
  • Naomi Chadderton
  • Mary O'Reilly
  • Tobias Goldmann
  • Marian M Humphries
  • Tiansen Li
  • 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:000275680700006&DestLinkType=FullRecord&DestApp=WOS_CPL
DOI
10.1089/hum.2009.119
Externe Identifier
  • Clarivate Analytics Document Solution ID: 570LV
  • PubMed Identifier: 19824806
ISSN
1043-0342
Ausgabe der Veröffentlichung
3
Zeitschrift
HUMAN GENE THERAPY
Paginierung
311 - 323
Datum der Veröffentlichung
2010
Status
Published
Titel
Adeno-Associated Virus-Mediated Rhodopsin Replacement Provides Therapeutic Benefit in Mice with a Targeted Disruption of the Rhodopsin Gene
Sub types
  • Article
Ausgabe der Zeitschrift
21

Data source: Web of Science (Lite)

Other metadata sources:
Autoren
  • Arpad Palfi
  • Sophia Millington-Ward
  • Naomi Chadderton
  • Mary O'Reilly
  • Tobias Goldmann
  • Marian M Humphries
  • Tiansen Li
  • Uwe Wolfrum
  • Peter Humphries
  • Paul F Kenna
  • G Jane Farrar
DOI
10.1089/hum.2009.119
eISSN
1557-7422
ISSN
1043-0342
Ausgabe der Veröffentlichung
3
Zeitschrift
Human Gene Therapy
Sprache
en
Paginierung
311 - 323
Datum der Veröffentlichung
2010
Status
Published
Herausgeber
Mary Ann Liebert Inc
Herausgeber URL
http://dx.doi.org/10.1089/hum.2009.119
Datum der Datenerfassung
2018
Titel
Adeno-Associated Virus-Mediated Rhodopsin Replacement Provides Therapeutic Benefit in Mice with a Targeted Disruption of the Rhodopsin Gene
Ausgabe der Zeitschrift
21

Data source: Crossref

Abstract
The rhodopsin gene (RHO) encodes a highly expressed G protein-coupled receptor that is central to visual transduction in rod photoreceptors. A suite of recombinant 2/5 adeno-associated viral (AAV) RHO replacement vectors has been generated in an attempt to recapitulate endogenous rhodopsin levels from exogenously delivered AAV vectors in the retina of mice with a targeted disruption in the rhodopsin gene (Rho(-/-) mice). Approximately 40% of wild-type mouse rhodopsin mRNA levels (RNA taken from whole retinas) was achieved in vivo in AAV-RHO-injected eyes, representing approximately 50-fold increases in expression compared with the initial vector. The main focus of this study was to test whether expression of AAV-RHO replacement in Rho(-/-) mice provided therapeutic benefit, which to date had not been achieved. Rho(-/-) mice neither elaborate rod outer segments nor have rod-derived electroretinograms (ERGs). Our results indicate for the first time in this model that subretinal AAV-RHO delivery leads not only to RHO immunolabeling but the generation of rod outer segments as evaluated by light and transmission electron microscopy. Improved histology was accompanied by rod photoreceptor activity as assessed by ERG for at least 12 weeks postinjection. The most efficient AAV-RHO constructs presented in this study provide sufficient levels of RHO to be of therapeutic benefit in Rho(-/-) mice and therefore represent important steps toward generating potent AAV-RHO replacement genes for gene therapy in RHO-linked human retinopathies.
Addresses
  • Department of Genetics, Trinity College Dublin, Dublin 2, Ireland. palfia@tcd.ie
Autoren
  • Arpad Palfi
  • Sophia Millington-Ward
  • Naomi Chadderton
  • Mary O'Reilly
  • Tobias Goldmann
  • Marian M Humphries
  • Tiansen Li
  • Uwe Wolfrum
  • Peter Humphries
  • Paul F Kenna
  • G Jane Farrar
DOI
10.1089/hum.2009.119
eISSN
1557-7422
Externe Identifier
  • PubMed Identifier: 19824806
Open access
false
ISSN
1043-0342
Ausgabe der Veröffentlichung
3
Zeitschrift
Human gene therapy
Schlüsselwörter
  • Retina
  • Animals
  • Mice, Knockout
  • Humans
  • Mice
  • Dependovirus
  • Rhodopsin
  • RNA, Messenger
  • Electroretinography
  • Blotting, Western
  • Gene Transfer Techniques
  • Reverse Transcriptase Polymerase Chain Reaction
  • Genetic Vectors
  • Retinal Rod Photoreceptor Cells
  • Genetic Therapy
Sprache
eng
Medium
Print
Paginierung
311 - 323
Datum der Veröffentlichung
2010
Status
Published
Datum der Datenerfassung
2009
Titel
Adeno-associated virus-mediated rhodopsin replacement provides therapeutic benefit in mice with a targeted disruption of the rhodopsin gene.
Sub types
  • Research Support, Non-U.S. Gov't
  • Journal Article
Ausgabe der Zeitschrift
21

Data source: Europe PubMed Central

Abstract
The rhodopsin gene (RHO) encodes a highly expressed G protein-coupled receptor that is central to visual transduction in rod photoreceptors. A suite of recombinant 2/5 adeno-associated viral (AAV) RHO replacement vectors has been generated in an attempt to recapitulate endogenous rhodopsin levels from exogenously delivered AAV vectors in the retina of mice with a targeted disruption in the rhodopsin gene (Rho(-/-) mice). Approximately 40% of wild-type mouse rhodopsin mRNA levels (RNA taken from whole retinas) was achieved in vivo in AAV-RHO-injected eyes, representing approximately 50-fold increases in expression compared with the initial vector. The main focus of this study was to test whether expression of AAV-RHO replacement in Rho(-/-) mice provided therapeutic benefit, which to date had not been achieved. Rho(-/-) mice neither elaborate rod outer segments nor have rod-derived electroretinograms (ERGs). Our results indicate for the first time in this model that subretinal AAV-RHO delivery leads not only to RHO immunolabeling but the generation of rod outer segments as evaluated by light and transmission electron microscopy. Improved histology was accompanied by rod photoreceptor activity as assessed by ERG for at least 12 weeks postinjection. The most efficient AAV-RHO constructs presented in this study provide sufficient levels of RHO to be of therapeutic benefit in Rho(-/-) mice and therefore represent important steps toward generating potent AAV-RHO replacement genes for gene therapy in RHO-linked human retinopathies.
Autoren
  • Arpad Palfi
  • Sophia Millington-Ward
  • Naomi Chadderton
  • Mary O'Reilly
  • Tobias Goldmann
  • Marian M Humphries
  • Tiansen Li
  • Uwe Wolfrum
  • Peter Humphries
  • Paul F Kenna
  • G Jane Farrar
Autoren-URL
https://www.ncbi.nlm.nih.gov/pubmed/19824806
DOI
10.1089/hum.2009.119
eISSN
1557-7422
Ausgabe der Veröffentlichung
3
Zeitschrift
Hum Gene Ther
Schlüsselwörter
  • Animals
  • Blotting, Western
  • Dependovirus
  • Electroretinography
  • Gene Transfer Techniques
  • Genetic Therapy
  • Genetic Vectors
  • Humans
  • Mice
  • Mice, Knockout
  • RNA, Messenger
  • Retina
  • Retinal Rod Photoreceptor Cells
  • Reverse Transcriptase Polymerase Chain Reaction
  • Rhodopsin
Sprache
eng
Country
United States
Paginierung
311 - 323
Datum der Veröffentlichung
2010
Status
Published
Datum, an dem der Datensatz öffentlich gemacht wurde
2010
Titel
Adeno-associated virus-mediated rhodopsin replacement provides therapeutic benefit in mice with a targeted disruption of the rhodopsin gene.
Sub types
  • Journal Article
  • Research Support, Non-U.S. Gov't
Ausgabe der Zeitschrift
21

Data source: PubMed

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