| First Author | Pang JJ | Year | 2004 |
| Journal | Invest Ophthalmol Vis Sci | Volume | 45 |
| Issue | 13 | Pages | 3486 |
| Mgi Jnum | J:94351 | Mgi Id | MGI:3512521 |
| Citation | Pang JJ, et al. (2004) Gene therapy restores vision in a natural model of RPE65 Leber congenital amaurosis: The rd12 mouse (The Association for Research in Vision & Ophthalmology Annual Meeting Abstracts). Invest Ophthalmol Vis Sci 45(13):3486 |
| abstractText | Full text of Abstract: Gene therapy restores vision in a natural model of RPE65 Leber Congenital Amaurosis: the rdl2 mouse. Jijing Pang1, Bo Chang2, John Heckenlively3, Steven Nusinowitz3,Syed M. M. Noorwez1, J. Hugh McDowell1, Shalesh Kaushal1, Adrian M.M. Timmers1 and William W. Hauswirth1. 1Department of Ophthalmology and Powell Gene Therapy Center, University of Florida, Gainesville, FL 32610; 2The Jackson Laboratory, Bar Harbor, ME 04609; Department of Ophthalmology, Jules Stein Eye Institute, University of California Los Angeles, Los Angeles, CA 90095 Purpose: To test whether AAV-mediated gene delivery can restore the vision in a mouse model with a spontaneous WE65 mutation. Methods: 1 pl of AAV5-CBA-human WE65 vector suspension (3.9 x 10-13th viral particles/ml) was injected subretinally to one eye of rdl2 mice at postnatal day (P) 14 . The partner eye was either not injected or similarly injected with control AAV5-CBA-GFP vector suspension. ERGs were recorded regularly. Seven months later, both eyes were enucleated for histology, immunostaining and retinoid analysis for comparison with age-matched normal C57 BLl6 mice. Results: In AAV5-CBA-hRPE65 treated rd12 eyes, dark adapted ERG waveforms were restored as soon as 1 week after treatment. These restored rod ERGs became stable in amplitude at 3 weeks post-treatment and remained so for 7 months after treatment, the latest time checked. Restored b-wave amplitudes were 60-80% of normal. Treated eyes also maintained normal cone ERGs while they were delayed and exhibited progressive loss in amplitude in partner untreated eyes. By light microscopy, photoreceptor outer segments became shortened, disorganized and contained many voids in untreated rd 12 mice; the outer nuclear layer was about 30% thinner than normal. By transmission electronic microscopy, frequent large lipid-like droplets and vacules accumulated in the RPE cytoplasm. In contrast, treated eyes had nearly normal outer segment morphology and showed only an occassional, small lipid-like droplet in RPE cells. Imrnunostaining with anti-RPE65 antibody showed strong RPE65 expression in the RPE cells of treated rd12 eyes, but no expression in untreated eyes. In treated eyes, the 11-cis retinal and rhodopsin were restored to approximately 50% of normal. Additionally, retinyl esters were dramatically reduced in comparison with untreated eyes or eyes treated with AAV5-CBA-GFP. Reduction in retinyl ester level paralleled the loss of RPE lipid-like droplets. Conclusions: AAV mediated gene therapy can restore a significant fraction of the visual function in this naturally occurring mouse lacking RPE65. This work also shows that a heterologous RPE65 cDNA, the human version, is therapeutic in a nonhuman RPE65 LCA model. Behavioral test is underway. Author Disclosure Block: Jijing Pang, None; John Heckenlively, None; Bo Chang, None; Steven Nusinowitz, None; Syed M. Noorwez, None; J. Hugh McDowell, None; Shalesh Kaushal, None; Adrian M. M. Timmers, None; William W. Hauswirth, AGTC, P Reviewing Codes (Complete): ????? Keyword, Presentation, Grant ID and Clinical Trial (Complete): (1) : 528 gene transfer/gene therapy (2) : 672 retinal degenerations: hereditary (3) : 677 retinal pigment epithelium Presentation Preference : Poster Only Grant Identification : EY11123, EY13729, NS3602, FFB, MVRF, RPB. CR: P Human Clinical Trial : No |
