BEST1 Gene Therapy Corrects a Diffuse Retina-Wide Microdetachment Modulated by Light Exposure

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dc.contributor.authorGuziewicz, Karina E
dc.contributor.authorCideciyan, Artur V
dc.contributor.authorBeltran, William A
dc.contributor.authorKomáromy, András M
dc.contributor.authorGuziewicz, Karina E
dc.contributor.authorCideciyan, Artur V
dc.contributor.authorAguirre, Gustavo D
dc.contributor.authorRuthel, Gordon
dc.contributor.authorKomáromy, András M
dc.contributor.authorDufour, Valerie L
dc.contributor.authorSwider, Malgorzata
dc.contributor.authorJacobson, Samuel G
dc.contributor.authorSumaroka, Alexander
dc.contributor.authorKendrick, Brian T
dc.contributor.authorRuthel, Gordon
dc.contributor.authorChiodo, Vince A
dc.contributor.authorHeon, Elise
dc.contributor.authorHauswirth, William W
dc.contributor.authorJacobson, Samuel G
dc.date2023-05-17T19:56:11.000
dc.date.accessioned2023-05-23T04:44:56Z
dc.date.available2023-05-23T04:44:56Z
dc.date.issued2018-03-20
dc.date.submitted2018-04-19T12:03:29-07:00
dc.description.abstractMutations 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.
dc.identifier.urihttps://repository.upenn.edu/handle/20.500.14332/48921
dc.legacy.articleid1166
dc.legacy.fields10.1073/pnas.1720662115
dc.legacy.fulltexturlhttps://repository.upenn.edu/cgi/viewcontent.cgi?article=1166&context=vet_papers&unstamped=1
dc.rights<p>This open access article is distributed under Creative Commons Attribution-NonCommercialNoDerivatives License 4.0 (CC BY-NC-ND).</p>
dc.source.beginpageE2839
dc.source.endpageE2848
dc.source.issue158
dc.source.issue12
dc.source.journalDepartmental Papers (Vet)
dc.source.journaltitleProceedings of the National Academy of Sciences
dc.source.peerreviewedtrue
dc.source.statuspublished
dc.source.volume115
dc.subject.otherAAV BEST1 gene therapy
dc.subject.otherRPE bestrophinopathy
dc.subject.othermicrovilli
dc.subject.otherphotoreceptors
dc.subject.otherMedicine and Health Sciences
dc.subject.otherVeterinary Medicine
dc.titleBEST1 Gene Therapy Corrects a Diffuse Retina-Wide Microdetachment Modulated by Light Exposure
dc.typeArticle
digcom.contributor.authorisAuthorOfPublication|email:karinag@vet.upenn.edu|institution:University of Pennsylvania|Guziewicz, Karina E
digcom.contributor.authorisAuthorOfPublication|email:cideciya@mail.med.upenn.edu|institution:University of Pennsylvania|Cideciyan, Artur V
digcom.contributor.authorisAuthorOfPublication|email:wbeltran@vet.upenn.edu|institution:University of Pennsylvania|Beltran, William A
digcom.contributor.authorisAuthorOfPublication|email:komaromy@vet.upenn.edu|institution:University of Pennsylvania|Komáromy, András M
digcom.contributor.authorDufour, Valerie L
digcom.contributor.authorSwider, Malgorzata
digcom.contributor.authorIwabe, Simone
digcom.contributor.authorSumaroka, Alexander
digcom.contributor.authorKendrick, Brian T
digcom.contributor.authorisAuthorOfPublication|email:goruthel@vet.upenn.edu|institution:University of Pennsylvania|Ruthel, Gordon
digcom.contributor.authorChiodo, Vince A
digcom.contributor.authorHeon, Elise
digcom.contributor.authorHauswirth, William W
digcom.contributor.authorisAuthorOfPublication|email:jacobsos@mail.med.upenn.edu|institution:University of Pennsylvania|Jacobson, Samuel G
digcom.contributor.authorisAuthorOfPublication|email:gda@vet.upenn.edu|institution:University of Pennsylvania|Aguirre, Gustavo D
digcom.identifiervet_papers/158
digcom.identifier.contextkey11992562
digcom.identifier.submissionpathvet_papers/158
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upenn.schoolDepartmentCenterDepartmental Papers (Vet)
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