Journal article
Human gene therapy for RPE65 isomerase deficiency activates the retinoid cycle of vision but with slow rod kinetics
Proceedings of the National Academy of Sciences - PNAS, Vol.105(39), pp.15112-15117
09/30/2008
DOI: 10.1073/pnas.0807027105
PMCID: PMC2567501
PMID: 18809924
Abstract
The RPE65 gene encodes the isomerase of the retinoid cycle, the enzymatic pathway that underlies mammalian vision. Mutations in RPE65 disrupt the retinoid cycle and cause a congenital human blindness known as Leber congenital amaurosis (LCA). We used adeno-associated virus-2-based RPE65 gene replacement therapy to treat three young adults with RPE65-LCA and measured their vision before and up to 90 days after the intervention. All three patients showed a statistically significant increase in visual sensitivity at 30 days after treatment localized to retinal areas that had received the vector. There were no changes in the effect between 30 and 90 days. Both cone- and rod-photoreceptor-based vision could be demonstrated in treated areas. For cones, there were increases of up to 1.7 log units (i.e., 50 fold); and for rods, there were gains of up to 4.8 log units (i.e., 63,000 fold). To assess what fraction of full vision potential was restored by gene therapy, we related the degree of light sensitivity to the level of remaining photoreceptors within the treatment area. We found that the intervention could overcome nearly all of the loss of light sensitivity resulting from the biochemical blockade. However, this reconstituted retinoid cycle was not completely normal. Resensitization kinetics of the newly treated rods were remarkably slow and required 8 h or more for the attainment of full sensitivity, compared with <1 h in normal eyes. Cone-sensitivity recovery time was rapid. These results demonstrate dramatic, albeit imperfect, recovery of rod- and cone-photoreceptor-based vision after RPE65 gene therapy.
Details
- Title: Subtitle
- Human gene therapy for RPE65 isomerase deficiency activates the retinoid cycle of vision but with slow rod kinetics
- Creators
- Artur V Cideciyan - Scheie Eye Institute, Department of Ophthalmology, University of Pennsylvania, Philadelphia, PA 19104, USA. cideciya@mail.med.upenn.eduTomas S AlemanSanford L BoyeSharon B SchwartzShalesh KaushalAlejandro J RomanJi-Jing PangAlexander SumarokaElizabeth A M WindsorJames M WilsonTerence R FlotteGerald A FishmanElise HeonEdwin M StoneBarry J ByrneSamuel G JacobsonWilliam W Hauswirth
- Resource Type
- Journal article
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, Vol.105(39), pp.15112-15117
- DOI
- 10.1073/pnas.0807027105
- PMID
- 18809924
- PMCID
- PMC2567501
- NLM abbreviation
- Proc Natl Acad Sci U S A
- ISSN
- 0027-8424
- eISSN
- 1091-6490
- Publisher
- United States
- Grant note
- R01 EY013385 / NEI NIH HHS R01 EY011123 / NEI NIH HHS U10 EY017280 / NEI NIH HHS P30 EY008571 / NEI NIH HHS P01 HL059412 / NHLBI NIH HHS U10 EY013729 / NEI NIH HHS
- Language
- English
- Date published
- 09/30/2008
- Academic Unit
- Iowa Neuroscience Institute; Ophthalmology and Visual Sciences
- Record Identifier
- 9983980001002771
Metrics
23 Record Views