AAV-Mediated Clarin-1 Expression in the Mouse Retina: Implications for USH3A Gene Therapy

Publication type:
Journal article
Metadata:
Autoren
  • Astra Dinculescu
  • Rachel M Stupay
  • Wen-Tao Deng
  • Frank M Dyka
  • Seok-Hong Min
  • Sanford L Boye
  • Vince A Chiodo
  • Carolina E Abrahan
  • Ping Zhu
  • Qiuhong Li
  • Enrica Strettoi
  • Elena Novelli
  • Kerstin Nagel-Wolfrum
  • Uwe Wolfrum
  • W Clay Smith
  • William W Hauswirth
Autoren-URL
https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000371219000028&DestLinkType=FullRecord&DestApp=WOS_CPL
DOI
10.1371/journal.pone.0148874
Externe Identifier
  • Clarivate Analytics Document Solution ID: DF3BP
  • PubMed Identifier: 26881841
ISSN
1932-6203
Ausgabe der Veröffentlichung
2
Zeitschrift
PLOS ONE
Artikelnummer
ARTN e0148874
Datum der Veröffentlichung
2016
Status
Published
Titel
AAV-Mediated Clarin-1 Expression in the Mouse Retina: Implications for USH3A Gene Therapy
Sub types
  • Article
Ausgabe der Zeitschrift
11

Data source: Web of Science (Lite)

Other metadata sources:
Autoren
  • Astra Dinculescu
  • Rachel M Stupay
  • Wen-Tao Deng
  • Frank M Dyka
  • Seok-Hong Min
  • Sanford L Boye
  • Vince A Chiodo
  • Carolina E Abrahan
  • Ping Zhu
  • Qiuhong Li
  • Enrica Strettoi
  • Elena Novelli
  • Kerstin Nagel-Wolfrum
  • Uwe Wolfrum
  • W Clay Smith
  • William W Hauswirth
DOI
10.1371/journal.pone.0148874
Editoren
  • Steven Barnes
eISSN
1932-6203
Ausgabe der Veröffentlichung
2
Zeitschrift
PLOS ONE
Sprache
en
Online publication date
2016
Paginierung
e0148874 - e0148874
Status
Published online
Herausgeber
Public Library of Science (PLoS)
Herausgeber URL
http://dx.doi.org/10.1371/journal.pone.0148874
Datum der Datenerfassung
2018
Titel
AAV-Mediated Clarin-1 Expression in the Mouse Retina: Implications for USH3A Gene Therapy
Ausgabe der Zeitschrift
11

Data source: Crossref

Abstract
Usher syndrome type III (USH3A) is an autosomal recessive disorder caused by mutations in clarin-1 (CLRN1) gene, leading to progressive retinal degeneration and sensorineural deafness. Efforts to develop therapies for preventing photoreceptor cell loss are hampered by the lack of a retinal phenotype in the existing USH3 mouse models and by conflicting reports regarding the endogenous retinal localization of clarin-1, a transmembrane protein of unknown function. In this study, we used an AAV-based approach to express CLRN1 in the mouse retina in order to determine the pattern of its subcellular localization in different cell types. We found that all major classes of retinal cells express AAV-delivered CLRN1 driven by the ubiquitous, constitutive small chicken β-actin promoter, which has important implications for the design of future USH3 gene therapy studies. Within photoreceptor cells, AAV-expressed CLRN1 is mainly localized at the inner segment region and outer plexiform layer, similar to the endogenous expression of other usher proteins. Subretinal delivery using a full strength viral titer led to significant loss of retinal function as evidenced by ERG analysis, suggesting that there is a critical limit for CLRN1 expression in photoreceptor cells. Taken together, these results suggest that CLRN1 expression is potentially supported by a variety of retinal cells, and the right combination of AAV vector dose, promoter, and delivery method needs to be selected to develop safe therapies for USH3 disorder.
Addresses
  • Ophthalmology, University of Florida, Gainesville, FL, United States of America.
Autoren
  • Astra Dinculescu
  • Rachel M Stupay
  • Wen-Tao Deng
  • Frank M Dyka
  • Seok-Hong Min
  • Sanford L Boye
  • Vince A Chiodo
  • Carolina E Abrahan
  • Ping Zhu
  • Qiuhong Li
  • Enrica Strettoi
  • Elena Novelli
  • Kerstin Nagel-Wolfrum
  • Uwe Wolfrum
  • W Clay Smith
  • William W Hauswirth
DOI
10.1371/journal.pone.0148874
eISSN
1932-6203
Externe Identifier
  • PubMed Identifier: 26881841
  • PubMed Central ID: PMC4755610
Funding acknowledgements
  • NEI NIH HHS: P30EY021721
  • NCATS NIH HHS: UL1 TR001427
  • NEI NIH HHS: T32 EY007132
  • NEI NIH HHS: P30 EY021721
Open access
true
ISSN
1932-6203
Ausgabe der Veröffentlichung
2
Zeitschrift
PloS one
Schlüsselwörter
  • Retina
  • Animals
  • Humans
  • Mice
  • Dependovirus
  • Retinal Degeneration
  • Disease Models, Animal
  • Membrane Proteins
  • Gene Expression Regulation
  • Usher Syndromes
  • Genetic Therapy
Sprache
eng
Medium
Electronic-eCollection
Online publication date
2016
Open access status
Open Access
Paginierung
e0148874
Datum der Veröffentlichung
2016
Status
Published
Publisher licence
CC BY
Datum der Datenerfassung
2016
Titel
AAV-Mediated Clarin-1 Expression in the Mouse Retina: Implications for USH3A Gene Therapy.
Sub types
  • Research Support, Non-U.S. Gov't
  • research-article
  • Journal Article
  • Research Support, N.I.H., Extramural
Ausgabe der Zeitschrift
11

Files

https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0148874&type=printable https://europepmc.org/articles/PMC4755610?pdf=render

Data source: Europe PubMed Central

Abstract
Usher syndrome type III (USH3A) is an autosomal recessive disorder caused by mutations in clarin-1 (CLRN1) gene, leading to progressive retinal degeneration and sensorineural deafness. Efforts to develop therapies for preventing photoreceptor cell loss are hampered by the lack of a retinal phenotype in the existing USH3 mouse models and by conflicting reports regarding the endogenous retinal localization of clarin-1, a transmembrane protein of unknown function. In this study, we used an AAV-based approach to express CLRN1 in the mouse retina in order to determine the pattern of its subcellular localization in different cell types. We found that all major classes of retinal cells express AAV-delivered CLRN1 driven by the ubiquitous, constitutive small chicken β-actin promoter, which has important implications for the design of future USH3 gene therapy studies. Within photoreceptor cells, AAV-expressed CLRN1 is mainly localized at the inner segment region and outer plexiform layer, similar to the endogenous expression of other usher proteins. Subretinal delivery using a full strength viral titer led to significant loss of retinal function as evidenced by ERG analysis, suggesting that there is a critical limit for CLRN1 expression in photoreceptor cells. Taken together, these results suggest that CLRN1 expression is potentially supported by a variety of retinal cells, and the right combination of AAV vector dose, promoter, and delivery method needs to be selected to develop safe therapies for USH3 disorder.
Date of acceptance
2016
Autoren
  • Astra Dinculescu
  • Rachel M Stupay
  • Wen-Tao Deng
  • Frank M Dyka
  • Seok-Hong Min
  • Sanford L Boye
  • Vince A Chiodo
  • Carolina E Abrahan
  • Ping Zhu
  • Qiuhong Li
  • Enrica Strettoi
  • Elena Novelli
  • Kerstin Nagel-Wolfrum
  • Uwe Wolfrum
  • W Clay Smith
  • William W Hauswirth
Autoren-URL
https://www.ncbi.nlm.nih.gov/pubmed/26881841
DOI
10.1371/journal.pone.0148874
eISSN
1932-6203
Externe Identifier
  • PubMed Central ID: PMC4755610
Funding acknowledgements
  • NEI NIH HHS: P30 EY021721
  • NEI NIH HHS: T32 EY007132
  • NCATS NIH HHS: UL1 TR001427
  • NEI NIH HHS: P30EY021721
Ausgabe der Veröffentlichung
2
Zeitschrift
PLoS One
Schlüsselwörter
  • Animals
  • Dependovirus
  • Disease Models, Animal
  • Gene Expression Regulation
  • Genetic Therapy
  • Humans
  • Membrane Proteins
  • Mice
  • Retina
  • Retinal Degeneration
  • Usher Syndromes
Sprache
eng
Country
United States
Paginierung
e0148874
PII
PONE-D-15-19003
Datum der Veröffentlichung
2016
Status
Published online
Datum, an dem der Datensatz öffentlich gemacht wurde
2016
Titel
AAV-Mediated Clarin-1 Expression in the Mouse Retina: Implications for USH3A Gene Therapy.
Sub types
  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
Ausgabe der Zeitschrift
11

Data source: PubMed

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