Human Retinal Gene Therapy for Leber Congential Amaurosis Shows Advancing Retinal Degeneration Despite Enduring Visual Improvement

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dc.contributor.authorCideciyan, Artur V
dc.contributor.authorJacobson, Samuel G
dc.contributor.authorBeltran, William A
dc.contributor.authorCideciyan, Artur V
dc.contributor.authorJacobson, Samuel G
dc.contributor.authorAguirre, Gustavo D
dc.contributor.authorBeltran, William A
dc.contributor.authorSumaroka, Alexander
dc.contributor.authorKomáromy, András M
dc.contributor.authorIwabe, Simone
dc.contributor.authorRoman, Alejandro J
dc.contributor.authorOlivares, Melani B
dc.contributor.authorSchwartz, Sharon B
dc.contributor.authorKomáromy, András M
dc.contributor.authorHauswirth, William W
dc.date2023-05-17T19:56:18.000
dc.date.accessioned2023-05-23T04:44:58Z
dc.date.available2023-05-23T04:44:58Z
dc.date.issued2013-02-05
dc.date.submitted2018-04-19T12:28:53-07:00
dc.description.abstractLeber congenital amaurosis (LCA) associated with retinal pigment epithelium-specific protein 65 kDa (RPE65) mutations is a severe hereditary blindness resulting from both dysfunction and degeneration of photoreceptors. Clinical trials with gene augmentation therapy have shown partial reversal of the dysfunction, but the effects on the degeneration are not known. We evaluated the consequences of gene therapy on retinal degeneration in patients with RPE65-LCA and its canine model. In untreated RPE65-LCA patients, there was dysfunction and degeneration of photoreceptors, even at the earliest ages. Examined serially over years, the outer photoreceptor nuclear layer showed progressive thinning. Treated RPE65-LCA showed substantial visual improvement in the short term and no detectable decline from this new level over the long term. However, retinal degeneration continued to progress unabated. In RPE65-mutant dogs, the first one-quarter of their lifespan showed only dysfunction, and there was normal outer photoreceptor nuclear layer thickness retina-wide. Dogs treated during the earlier dysfunction-only stage showed improved visual function and dramatic protection of treated photoreceptors from degeneration when measured 5–11 y later. Dogs treated later during the combined dysfunction and degeneration stage also showed visual function improvement, but photoreceptor loss continued unabated, the same as in human RPE65-LCA. The results suggest that, in RPE65 disease treatment, protection from visual function deterioration cannot be assumed to imply protection from degeneration. The effects of gene augmentation therapy are complex and suggest a need for a combinatorial strategy in RPE65-LCA to not only improve function in the short term but also slow retinal degeneration in the long term.
dc.identifier.urihttps://repository.upenn.edu/handle/20.500.14332/48924
dc.legacy.articleid1168
dc.legacy.fields10.1073/pnas.1218933110
dc.legacy.fulltexturlhttps://repository.upenn.edu/cgi/viewcontent.cgi?article=1168&context=vet_papers&unstamped=1
dc.rights<p>© 2013 National Academy of Sciences.</p>
dc.source.beginpageE517
dc.source.endpageE525
dc.source.issue160
dc.source.issue6
dc.source.journalDepartmental Papers (Vet)
dc.source.journaltitleProceedings of the National Academy of Sciences
dc.source.peerreviewedtrue
dc.source.statuspublished
dc.source.volume110
dc.subject.otherMedicine and Health Sciences
dc.subject.otherVeterinary Medicine
dc.titleHuman Retinal Gene Therapy for Leber Congential Amaurosis Shows Advancing Retinal Degeneration Despite Enduring Visual Improvement
dc.typeArticle
digcom.contributor.authorisAuthorOfPublication|email:cideciya@mail.med.upenn.edu|institution:University of Pennsylvania|Cideciyan, Artur V
digcom.contributor.authorisAuthorOfPublication|email:jacobsos@mail.med.upenn.edu|institution:University of Pennsylvania|Jacobson, Samuel G
digcom.contributor.authorisAuthorOfPublication|email:wbeltran@vet.upenn.edu|institution:University of Pennsylvania|Beltran, William A
digcom.contributor.authorSumaroka, Alexander
digcom.contributor.authorSwider, Malgorzata
digcom.contributor.authorIwabe, Simone
digcom.contributor.authorRoman, Alejandro J
digcom.contributor.authorOlivares, Melani B
digcom.contributor.authorSchwartz, Sharon B
digcom.contributor.authorisAuthorOfPublication|email:komaromy@vet.upenn.edu|institution:University of Pennsylvania|Komáromy, András M
digcom.contributor.authorHauswirth, William W
digcom.contributor.authorisAuthorOfPublication|email:gda@vet.upenn.edu|institution:University of Pennsylvania|Aguirre, Gustavo D
digcom.identifiervet_papers/160
digcom.identifier.contextkey11992872
digcom.identifier.submissionpathvet_papers/160
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upenn.schoolDepartmentCenterDepartmental Papers (Vet)
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