rAAV2/5 Gene-Targeting to Rods: Dose-Dependent Efficiency and Complications Associated With Different Promoters

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dc.contributor.authorBeltran, William
dc.contributor.authorAguirre, Gustavo D
dc.contributor.authorBeltran, William
dc.contributor.authorAguirre, Gustavo D
dc.contributor.authorBoye, Sanford L
dc.contributor.authorBoye, Shannon E
dc.contributor.authorChiodo, Vince A
dc.contributor.authorLewin, Alfred S
dc.contributor.authorHauswirth, William W
dc.date2023-05-17T11:20:14.000
dc.date.accessioned2023-05-23T04:45:58Z
dc.date.available2023-05-23T04:45:58Z
dc.date.issued2010-09-01
dc.date.submitted2015-04-09T13:57:09-07:00
dc.description.abstractA prerequisite for using corrective gene therapy to treat humans with inherited retinal degenerative diseases that primarily affect rods is to develop viral vectors that target specifically this population of photoreceptors. The delivery of a viral vector with photoreceptor tropism coupled with a rod-specific promoter is likely to be the safest and most efficient approach to target expression of the therapeutic gene to rods. Three promoters that included a fragment of the proximal mouse opsin promoter (mOP), the human G-protein-coupled receptor protein kinase 1 promoter (hGRK1), or the cytomegalovirus immediate early enhancer combined with the chicken β actin proximal promoter CBA were evaluated for their specificity and robustness in driving GFP reporter gene expression in rods, when packaged in a recombinant adeno-associated viral vector of serotype 2/5 (AAV2/5), and delivered via subretinal injection to the normal canine retina. Photoreceptor-specific promoters (mOP, hGRK1) targeted robust GFP expression to rods, whereas the ubiquitously expressed CBA promoter led to transgene expression in the retinal pigment epithelium, rods, cones and rare Müller, horizontal and ganglion cells. Late onset inflammation was frequently observed both clinically and histologically with all three constructs when the highest viral titers were injected. Cone loss in the injected regions of the retinas that received the highest titers occurred with both the hGRK1 and CBA promoters. Efficient and specific rod transduction, together with preservation of retinal structure was achieved with both mOP and hGRK1 promoters when viral titers in the order of 1011 vg ml–1 were used.
dc.identifier.urihttps://repository.upenn.edu/handle/20.500.14332/49016
dc.legacy.articleid1116
dc.legacy.fields10.1038/gt.2010.56
dc.legacy.fulltexturlhttps://repository.upenn.edu/cgi/viewcontent.cgi?article=1116&context=vet_papers&unstamped=1
dc.source.beginpage1162
dc.source.endpage1174
dc.source.issue94
dc.source.issue9
dc.source.journalDepartmental Papers (Vet)
dc.source.journaltitleGene Therapy
dc.source.peerreviewedtrue
dc.source.statuspublished
dc.source.volume17
dc.subject.otherrAAV vectors
dc.subject.otherpromoters
dc.subject.otherrod
dc.subject.otherretina
dc.subject.othergene transfer
dc.subject.otherdog
dc.subject.otherEye Diseases
dc.subject.otherMedical Genetics
dc.subject.otherOphthalmology
dc.subject.otherVeterinary Medicine
dc.titlerAAV2/5 Gene-Targeting to Rods: Dose-Dependent Efficiency and Complications Associated With Different Promoters
dc.typeArticle
digcom.contributor.authorisAuthorOfPublication|email:wbeltran@vet.upenn.edu|institution:University of Pennsylvania|Beltran, William
digcom.contributor.authorBoye, Sanford L
digcom.contributor.authorBoye, Shannon E
digcom.contributor.authorChiodo, Vince A
digcom.contributor.authorLewin, Alfred S
digcom.contributor.authorHauswirth, William W
digcom.contributor.authorisAuthorOfPublication|email:gda@vet.upenn.edu|institution:University of Pennsylvania|Aguirre, Gustavo D
digcom.identifiervet_papers/94
digcom.identifier.contextkey6966822
digcom.identifier.submissionpathvet_papers/94
digcom.typearticle
dspace.entity.typePublication
person.identifier.orcid0000-0002-5228-256X
person.identifier.orcid0000-0002-5228-256X
relation.isAuthorOfPublicationce628e7c-dff0-4210-9d35-d3494f5eee01
relation.isAuthorOfPublication1a18ef39-6294-4816-a00d-fe4b64c3295a
relation.isAuthorOfPublication.latestForDiscoveryce628e7c-dff0-4210-9d35-d3494f5eee01
upenn.schoolDepartmentCenterDepartmental Papers (Vet)
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