Canine and Human Visual Cortex Intact and Responsive Despite Early Retinal Blindness from RPE65 Mutation

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dc.contributor.authorAguirre, Geoffrey K
dc.contributor.authorKomáromy, András M
dc.contributor.authorCideciyan, Artur V
dc.contributor.authorBrainard, David H
dc.contributor.authorAleman, Tomas S
dc.contributor.authorAvants, Brian B
dc.contributor.authorGee, James C
dc.contributor.authorAguirre, Geoffrey K
dc.contributor.authorKomáromy, András M
dc.contributor.authorAguirre, Gustavo D
dc.contributor.authorCideciyan, Artur V
dc.contributor.authorJacobson, Samuel G
dc.contributor.authorBrainard, David H
dc.contributor.authorAleman, Tomas S
dc.contributor.authorRoman, Alejandro J
dc.contributor.authorAvants, Brian B
dc.contributor.authorGee, James C
dc.contributor.authorKorczykowski, Marc
dc.contributor.authorHauswirth, William W
dc.contributor.authorAcland, Gregory M
dc.contributor.authorJacobson, Samuel G
dc.date2023-05-17T07:56:35.000
dc.date.accessioned2023-05-23T04:45:08Z
dc.date.available2023-05-23T04:45:08Z
dc.date.issued2007-06-26
dc.date.submitted2013-08-20T14:44:00-07:00
dc.description.abstractBackground RPE65 is an essential molecule in the retinoid-visual cycle, and RPE65 gene mutations cause the congenital human blindness known as Leber congenital amaurosis (LCA). Somatic gene therapy delivered to the retina of blind dogs with an RPE65 mutation dramatically restores retinal physiology and has sparked international interest in human treatment trials for this incurable disease. An unanswered question is how the visual cortex responds after prolonged sensory deprivation from retinal dysfunction. We therefore studied the cortex of RPE65-mutant dogs before and after retinal gene therapy. Then, we inquired whether there is visual pathway integrity and responsivity in adult humans with LCA due to RPE65 mutations (RPE65-LCA). Methods and Findings RPE65-mutant dogs were studied with fMRI. Prior to therapy, retinal and subcortical responses to light were markedly diminished, and there were minimal cortical responses within the primary visual areas of the lateral gyrus (activation amplitude mean ± standard deviation [SD] = 0.07% ± 0.06% and volume = 1.3 ± 0.6 cm3). Following therapy, retinal and subcortical response restoration was accompanied by increased amplitude (0.18% ± 0.06%) and volume (8.2 ± 0.8 cm3) of activation within the lateral gyrus (p < 0.005 for both). Cortical recovery occurred rapidly (within a month of treatment) and was persistent (as long as 2.5 y after treatment). Recovery was present even when treatment was provided as late as 1–4 y of age. Human RPE65-LCA patients (ages 18–23 y) were studied with structural magnetic resonance imaging. Optic nerve diameter (3.2 ± 0.5 mm) was within the normal range (3.2 ± 0.3 mm), and occipital cortical white matter density as judged by voxel-based morphometry was slightly but significantly altered (1.3 SD below control average, p = 0.005). Functional magnetic resonance imaging in human RPE65-LCA patients revealed cortical responses with a markedly diminished activation volume (8.8 ± 1.2 cm3) compared to controls (29.7 ± 8.3 cm3, p < 0.001) when stimulated with lower intensity light. Unexpectedly, cortical response volume (41.2 ± 11.1 cm3) was comparable to normal (48.8 ± 3.1 cm3, p = 0.2) with higher intensity light stimulation. Conclusions Visual cortical responses dramatically improve after retinal gene therapy in the canine model of RPE65-LCA. Human RPE65-LCA patients have preserved visual pathway anatomy and detectable cortical activation despite limited visual experience. Taken together, the results support the potential for human visual benefit from retinal therapies currently being aimed at restoring vision to the congenitally blind with genetic retinal disease.
dc.identifier.urihttps://repository.upenn.edu/handle/20.500.14332/48942
dc.legacy.articleid1026
dc.legacy.fieldstrue
dc.legacy.fields10.1371/journal.pmed.0040230
dc.legacy.fulltexturlhttps://repository.upenn.edu/cgi/viewcontent.cgi?article=1026&amp;context=vet_papers&amp;unstamped=1
dc.rights<p>© 2007 Aguirre et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.</p>
dc.source.beginpagee230
dc.source.issue27
dc.source.issue6
dc.source.journalDepartmental Papers (Vet)
dc.source.journaltitlePLoS Medicine
dc.source.peerreviewedtrue
dc.source.statuspublished
dc.source.volume4
dc.subject.otherComparative and Laboratory Animal Medicine
dc.subject.otherCongenital, Hereditary, and Neonatal Diseases and Abnormalities
dc.subject.otherEye Diseases
dc.subject.otherMedicine and Health Sciences
dc.subject.otherOphthalmology
dc.subject.otherVeterinary Medicine
dc.titleCanine and Human Visual Cortex Intact and Responsive Despite Early Retinal Blindness from RPE65 Mutation
dc.typeArticle
digcom.contributor.authorisAuthorOfPublication|email:aguirreg@mail.med.upenn.edu|institution:University of Pennsylvania|Aguirre, Geoffrey K
digcom.contributor.authorisAuthorOfPublication|email:komaromy@vet.upenn.edu|institution:University of Pennsylvania|Komáromy, András M
digcom.contributor.authorisAuthorOfPublication|email:cideciya@mail.med.upenn.edu|institution:University of Pennsylvania|Cideciyan, Artur V
digcom.contributor.authorisAuthorOfPublication|email:brainard@psych.upenn.edu|institution:University of Pennsylvania|Brainard, David H
digcom.contributor.authorisAuthorOfPublication|email:aleman@mail.med.upenn.edu|institution:University of Pennsylvania|Aleman, Tomas S
digcom.contributor.authorRoman, Alejandro J
digcom.contributor.authorisAuthorOfPublication|email:avants@grasp.cis.upenn.edu|institution:University of Pennsylvania|Avants, Brian B
digcom.contributor.authorisAuthorOfPublication|email:gee@mail.med.upenn.edu|institution:University of Pennsylvania|Gee, James C
digcom.contributor.authorKorczykowski, Marc
digcom.contributor.authorHauswirth, William W
digcom.contributor.authorAcland, Gregory M
digcom.contributor.authorisAuthorOfPublication|email:gda@vet.upenn.edu|institution:University of Pennsylvania|Aguirre, Gustavo D
digcom.contributor.authorisAuthorOfPublication|email:jacobsos@mail.med.upenn.edu|institution:University of Pennsylvania|Jacobson, Samuel G
digcom.identifiervet_papers/27
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upenn.schoolDepartmentCenterDepartmental Papers (Vet)
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