Cargando…
BEST1 gene therapy corrects a diffuse retina-wide microdetachment modulated by light exposure
Mutations in the BEST1 gene cause detachment of the retina and degeneration of photoreceptor (PR) cells due to a primary channelopathy in the neighboring retinal pigment epithelium (RPE) cells. The pathophysiology of the interaction between RPE and PR cells preceding the formation of retinal detachm...
Autores principales: | , , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
National Academy of Sciences
2018
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5866594/ https://www.ncbi.nlm.nih.gov/pubmed/29507198 http://dx.doi.org/10.1073/pnas.1720662115 |
_version_ | 1783308852337311744 |
---|---|
author | Guziewicz, Karina E. Cideciyan, Artur V. Beltran, William A. Komáromy, András M. Dufour, Valerie L. Swider, Malgorzata Iwabe, Simone Sumaroka, Alexander Kendrick, Brian T. Ruthel, Gordon Chiodo, Vince A. Héon, Elise Hauswirth, William W. Jacobson, Samuel G. Aguirre, Gustavo D. |
author_facet | Guziewicz, Karina E. Cideciyan, Artur V. Beltran, William A. Komáromy, András M. Dufour, Valerie L. Swider, Malgorzata Iwabe, Simone Sumaroka, Alexander Kendrick, Brian T. Ruthel, Gordon Chiodo, Vince A. Héon, Elise Hauswirth, William W. Jacobson, Samuel G. Aguirre, Gustavo D. |
author_sort | Guziewicz, Karina E. |
collection | PubMed |
description | Mutations in the BEST1 gene cause detachment of the retina and degeneration of photoreceptor (PR) cells due to a primary channelopathy in the neighboring retinal pigment epithelium (RPE) cells. The pathophysiology of the interaction between RPE and PR cells preceding the formation of retinal detachment remains not well-understood. Our studies of molecular pathology in the canine BEST1 disease model revealed retina-wide abnormalities at the RPE-PR interface associated with defects in the RPE microvillar ensheathment and a cone PR-associated insoluble interphotoreceptor matrix. In vivo imaging demonstrated a retina-wide RPE–PR microdetachment, which contracted with dark adaptation and expanded upon exposure to a moderate intensity of light. Subretinal BEST1 gene augmentation therapy using adeno-associated virus 2 reversed not only clinically detectable subretinal lesions but also the diffuse microdetachments. Immunohistochemical analyses showed correction of the structural alterations at the RPE–PR interface in areas with BEST1 transgene expression. Successful treatment effects were demonstrated in three different canine BEST1 genotypes with vector titers in the 0.1-to-5E11 vector genomes per mL range. Patients with biallelic BEST1 mutations exhibited large regions of retinal lamination defects, severe PR sensitivity loss, and slowing of the retinoid cycle. Human translation of canine BEST1 gene therapy success in reversal of macro- and microdetachments through restoration of cytoarchitecture at the RPE–PR interface has promise to result in improved visual function and prevent disease progression in patients affected with bestrophinopathies. |
format | Online Article Text |
id | pubmed-5866594 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | National Academy of Sciences |
record_format | MEDLINE/PubMed |
spelling | pubmed-58665942018-03-29 BEST1 gene therapy corrects a diffuse retina-wide microdetachment modulated by light exposure Guziewicz, Karina E. Cideciyan, Artur V. Beltran, William A. Komáromy, András M. Dufour, Valerie L. Swider, Malgorzata Iwabe, Simone Sumaroka, Alexander Kendrick, Brian T. Ruthel, Gordon Chiodo, Vince A. Héon, Elise Hauswirth, William W. Jacobson, Samuel G. Aguirre, Gustavo D. Proc Natl Acad Sci U S A PNAS Plus Mutations in the BEST1 gene cause detachment of the retina and degeneration of photoreceptor (PR) cells due to a primary channelopathy in the neighboring retinal pigment epithelium (RPE) cells. The pathophysiology of the interaction between RPE and PR cells preceding the formation of retinal detachment remains not well-understood. Our studies of molecular pathology in the canine BEST1 disease model revealed retina-wide abnormalities at the RPE-PR interface associated with defects in the RPE microvillar ensheathment and a cone PR-associated insoluble interphotoreceptor matrix. In vivo imaging demonstrated a retina-wide RPE–PR microdetachment, which contracted with dark adaptation and expanded upon exposure to a moderate intensity of light. Subretinal BEST1 gene augmentation therapy using adeno-associated virus 2 reversed not only clinically detectable subretinal lesions but also the diffuse microdetachments. Immunohistochemical analyses showed correction of the structural alterations at the RPE–PR interface in areas with BEST1 transgene expression. Successful treatment effects were demonstrated in three different canine BEST1 genotypes with vector titers in the 0.1-to-5E11 vector genomes per mL range. Patients with biallelic BEST1 mutations exhibited large regions of retinal lamination defects, severe PR sensitivity loss, and slowing of the retinoid cycle. Human translation of canine BEST1 gene therapy success in reversal of macro- and microdetachments through restoration of cytoarchitecture at the RPE–PR interface has promise to result in improved visual function and prevent disease progression in patients affected with bestrophinopathies. National Academy of Sciences 2018-03-20 2018-03-05 /pmc/articles/PMC5866594/ /pubmed/29507198 http://dx.doi.org/10.1073/pnas.1720662115 Text en Copyright © 2018 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/ This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) . |
spellingShingle | PNAS Plus Guziewicz, Karina E. Cideciyan, Artur V. Beltran, William A. Komáromy, András M. Dufour, Valerie L. Swider, Malgorzata Iwabe, Simone Sumaroka, Alexander Kendrick, Brian T. Ruthel, Gordon Chiodo, Vince A. Héon, Elise Hauswirth, William W. Jacobson, Samuel G. Aguirre, Gustavo D. BEST1 gene therapy corrects a diffuse retina-wide microdetachment modulated by light exposure |
title | BEST1 gene therapy corrects a diffuse retina-wide microdetachment modulated by light exposure |
title_full | BEST1 gene therapy corrects a diffuse retina-wide microdetachment modulated by light exposure |
title_fullStr | BEST1 gene therapy corrects a diffuse retina-wide microdetachment modulated by light exposure |
title_full_unstemmed | BEST1 gene therapy corrects a diffuse retina-wide microdetachment modulated by light exposure |
title_short | BEST1 gene therapy corrects a diffuse retina-wide microdetachment modulated by light exposure |
title_sort | best1 gene therapy corrects a diffuse retina-wide microdetachment modulated by light exposure |
topic | PNAS Plus |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5866594/ https://www.ncbi.nlm.nih.gov/pubmed/29507198 http://dx.doi.org/10.1073/pnas.1720662115 |
work_keys_str_mv | AT guziewiczkarinae best1genetherapycorrectsadiffuseretinawidemicrodetachmentmodulatedbylightexposure AT cideciyanarturv best1genetherapycorrectsadiffuseretinawidemicrodetachmentmodulatedbylightexposure AT beltranwilliama best1genetherapycorrectsadiffuseretinawidemicrodetachmentmodulatedbylightexposure AT komaromyandrasm best1genetherapycorrectsadiffuseretinawidemicrodetachmentmodulatedbylightexposure AT dufourvaleriel best1genetherapycorrectsadiffuseretinawidemicrodetachmentmodulatedbylightexposure AT swidermalgorzata best1genetherapycorrectsadiffuseretinawidemicrodetachmentmodulatedbylightexposure AT iwabesimone best1genetherapycorrectsadiffuseretinawidemicrodetachmentmodulatedbylightexposure AT sumarokaalexander best1genetherapycorrectsadiffuseretinawidemicrodetachmentmodulatedbylightexposure AT kendrickbriant best1genetherapycorrectsadiffuseretinawidemicrodetachmentmodulatedbylightexposure AT ruthelgordon best1genetherapycorrectsadiffuseretinawidemicrodetachmentmodulatedbylightexposure AT chiodovincea best1genetherapycorrectsadiffuseretinawidemicrodetachmentmodulatedbylightexposure AT heonelise best1genetherapycorrectsadiffuseretinawidemicrodetachmentmodulatedbylightexposure AT hauswirthwilliamw best1genetherapycorrectsadiffuseretinawidemicrodetachmentmodulatedbylightexposure AT jacobsonsamuelg best1genetherapycorrectsadiffuseretinawidemicrodetachmentmodulatedbylightexposure AT aguirregustavod best1genetherapycorrectsadiffuseretinawidemicrodetachmentmodulatedbylightexposure |