| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
1From the Vision Science Group, Department of Veterinary Medicine and Surgery, College of Veterinary Medicine, and the 2Department of Ophthalmology, School of Medicine, Mason Eye Institute, University of Missouri-Columbia, Columbia, Missouri; the 3Department of Ophthalmology, Ulleval University Hospital, Oslo, Norway; the 4Department of Pathophysiology of Vision and Neuroophthalmology, University Eye Hospital, Tübingen, Germany; the 5National Eye Institute, National Institutes of Health, Bethesda, Maryland; and the 6Centre for Ophthalmology and Visual Science, University of Western Australia, Nedlands, Australia.
PURPOSE. To assess the efficacy of AAV-mediated gene therapy to restore vision in a large number of RPE65-/- dogs and to determine whether systemic and local side effects are caused by the treatment.
METHODS. Normal RPE65 dog cDNA was subcloned into an rAAV vector under control of a cytomegalovirus promoter, and an AAV.GFP control vector was also produced with the titers 2 x 1012 particles/mL and 2 x 1010 transducing U/mL, respectively. RPE65-/- dogs, aged 4 to 30 months were treated with subretinal injections of the AAV.RPE65 and control vectors, respectively, in each eye, and three 24- to 30-month-old normal control dogs with the latter. Baseline and postoperative systemic and ophthalmic examinations, blood screenings, vision testing, and electroretinography (ERG) were performed. Two RPE65-/- dogs were killed at 3 and 6 months after treatment for morphologic examination of the retinas.
RESULTS. RPE65-/- dogs were practically blind from birth with nonrecordable or low-amplitude ERGs. Construct injections or sham surgeries were performed in 28 eyes; 11 were injected subretinally with the AAV.RPE65 construct. ERGs at 3 months after surgery showed that in the latter eyes, dark-adapted b-wave amplitudes recovered to an average of 28% of normal, and light adapted b-wave amplitudes to 32% of normal. ERG amplitudes were not reduced during a 6- to 9-month follow-up. No systemic side effects were observed, but uveitis developed in nine AAV.RPE65-treated eyes. No uveitis was observed in the eyes treated with the control vector. Immunocytochemistry showed expression of RPE65 in the retinal pigment epithelium (RPE) of AAV.RPE65-treated eyes. Fluorescence microscopy showed expression of green fluorescent protein (GFP) in the RPE and, to a lesser extent, in the neural retinas of AAV.GFP-treated eyes. Ultrastructurally, a reversal of RPE lipid droplet accumulation was observed at the AAV.RPE65 transgene injection site, but not at the site of injection of the control vector.
CONCLUSIONS. In 10 of 11 treated RPE65-/- eyes, gene transfer resulted in development of vision, both subjectively apparent by loss of nystagmus, and objectively recorded by ERG. Structurally, there was reversal of lipid droplet accumulation in the RPE. Uveitis developed in 75% of the transgene-treated eyes, a complication possibly due to an immunopathogenic response to the RPE65 molecule.
This article has been cited by other articles:
|
|
 |
|
  S. G. Jacobson, T. S. Aleman, A. V. Cideciyan, A. J. Roman, A. Sumaroka, E. A. M. Windsor, S. B. Schwartz, E. Heon, and E. M. Stone Defining the Residual Vision in Leber Congenital Amaurosis Caused by RPE65 Mutations Invest. Ophthalmol. Vis. Sci., May 1, 2009; 50(5): 2368 - 2375. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Lorenz, E. Poliakov, M. Schambeck, C. Friedburg, M. N. Preising, and T. M. Redmond A Comprehensive Clinical and Biochemical Functional Study of a Novel RPE65 Hypomorphic Mutation Invest. Ophthalmol. Vis. Sci., December 1, 2008; 49(12): 5235 - 5242. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. G. Jacobson, A. V. Cideciyan, T. S. Aleman, A. Sumaroka, E. A. M. Windsor, S. B. Schwartz, E. Heon, and E. M. Stone Photoreceptor Layer Topography in Children with Leber Congenital Amaurosis Caused by RPE65 Mutations Invest. Ophthalmol. Vis. Sci., October 1, 2008; 49(10): 4573 - 4577. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. V. Cideciyan, T. S. Aleman, S. L. Boye, S. B. Schwartz, S. Kaushal, A. J. Roman, J.-j. Pang, A. Sumaroka, E. A. M. Windsor, J. M. Wilson, et al. Human gene therapy for RPE65 isomerase deficiency activates the retinoid cycle of vision but with slow rod kinetics PNAS, September 30, 2008; 105(39): 15112 - 15117. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. M. Gearhart, C. C. Gearhart, and S. M. Petersen-Jones A Novel Method for Objective Vision Testing in Canine Models of Inherited Retinal Disease Invest. Ophthalmol. Vis. Sci., August 1, 2008; 49(8): 3568 - 3576. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. W.B. Bainbridge, A. J. Smith, S. S. Barker, S. Robbie, R. Henderson, K. Balaggan, A. Viswanathan, G. E. Holder, A. Stockman, N. Tyler, et al. Effect of Gene Therapy on Visual Function in Leber's Congenital Amaurosis N. Engl. J. Med., May 22, 2008; 358(21): 2231 - 2239. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Samardzija, J. von Lintig, N. Tanimoto, V. Oberhauser, M. Thiersch, C. E. Reme, M. Seeliger, C. Grimm, and A. Wenzel R91W mutation in Rpe65 leads to milder early-onset retinal dystrophy due to the generation of low levels of 11-cis-retinal Hum. Mol. Genet., January 15, 2008; 17(2): 281 - 292. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Allocca, C. Mussolino, M. Garcia-Hoyos, D. Sanges, C. Iodice, M. Petrillo, L. H. Vandenberghe, J. M. Wilson, V. Marigo, E. M. Surace, et al. Novel Adeno-Associated Virus Serotypes Efficiently Transduce Murine Photoreceptors J. Virol., October 15, 2007; 81(20): 11372 - 11380. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. C. Khani, B. S. Pawlyk, O. V. Bulgakov, E. Kasperek, J. E. Young, M. Adamian, X. Sun, A. J. Smith, R. R. Ali, and T. Li AAV-Mediated Expression Targeting of Rod and Cone Photoreceptors with a Human Rhodopsin Kinase Promoter Invest. Ophthalmol. Vis. Sci., September 1, 2007; 48(9): 3954 - 3961. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Menotti-Raymond, V. A. David, A. A. Schaffer, R. Stephens, D. Wells, R. Kumar-Singh, S. J. O'Brien, and K. Narfstrom Mutation in CEP290 Discovered for Cat Model of Human Retinal Degeneration J. Hered., May 16, 2007; (2007) esm019v1. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. G. Jacobson, A. V. Cideciyan, T. S. Aleman, A. Sumaroka, S. B. Schwartz, E. A. M. Windsor, A. J. Roman, E. Heon, E. M. Stone, and D. A. Thompson RDH12 and RPE65, Visual Cycle Genes Causing Leber Congenital Amaurosis, Differ in Disease Expression Invest. Ophthalmol. Vis. Sci., January 1, 2007; 48(1): 332 - 338. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Padnick-Silver, J. J. K. Derwent, E. Giuliano, K. Narfstrom, and R. A. Linsenmeier Retinal oxygenation and oxygen metabolism in abyssinian cats with a hereditary retinal degeneration. Invest. Ophthalmol. Vis. Sci., August 1, 2006; 47(8): 3683 - 3689. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Terrada, S. Fisson, Y. De Kozak, M. Kaddouri, P. Lehoang, D. Klatzmann, B. L. Salomon, and B. Bodaghi Regulatory T cells control uveoretinitis induced by pathogenic Th1 cells reacting to a specific retinal neoantigen. J. Immunol., June 15, 2006; 176(12): 7171 - 7179. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Yoshioka, T. Abe, R. Wakusawa, T. Moriya, S. Mochizuki, Y. Saigo, T. Saito, H. Murata, Y. Tokita, T. Iseya, et al. Recombinant AAV-Transduced Iris Pigment Epithelial Cell Transplantation May Transfer Vector to Native RPE but Suppress Systemic Dissemination Invest. Ophthalmol. Vis. Sci., February 1, 2006; 47(2): 745 - 752. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. S. Pawlyk, A. J. Smith, P. K. Buch, M. Adamian, D.-H. Hong, M. A. Sandberg, R. R. Ali, and T. Li Gene Replacement Therapy Rescues Photoreceptor Degeneration in a Murine Model of Leber Congenital Amaurosis Lacking RPGRIP Invest. Ophthalmol. Vis. Sci., September 1, 2005; 46(9): 3039 - 3045. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Aguirre-Hernandez and D. R. Sargan Evaluation of Candidate Genes in the Absence of Positional Information: A Poor Bet on a Blind Dog! J. Hered., September 1, 2005; 96(5): 475 - 484. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. W. Chalberg, H. L. Genise, D. Vollrath, and M. P. Calos {phi}C31 Integrase Confers Genomic Integration and Long-Term Transgene Expression in Rat Retina Invest. Ophthalmol. Vis. Sci., June 1, 2005; 46(6): 2140 - 2146. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Moosajee Genes and the eye J R Soc Med, May 1, 2005; 98(5): 206 - 207. [Full Text] [PDF]
|
|
|
|
|
|
S. G. Jacobson, T. S. Aleman, A. V. Cideciyan, A. Sumaroka, S. B. Schwartz, E. A. M. Windsor, E. I. Traboulsi, E. Heon, S. J. Pittler, A. H. Milam, et al. Identifying photoreceptors in blind eyes caused by RPE65 mutations: Prerequisite for human gene therapy success PNAS, April 26, 2005; 102(17): 6177 - 6182. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Le Meur, M. Weber, Y. Pereon, A. Mendes-Madeira, D. Nivard, J.-Y. Deschamps, P. Moullier, and F. Rolling Postsurgical Assessment and Long-term Safety of Recombinant Adeno-Associated Virus-Mediated Gene Transfer Into the Retinas of Dogs and Primates Arch Ophthalmol, April 1, 2005; 123(4): 500 - 506. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Hojo, T. Abe, E. Sugano, Y. Yoshioka, Y. Saigo, H. Tomita, R. Wakusawa, and M. Tamai Photoreceptor Protection by Iris Pigment Epithelial Transplantation Transduced with AAV-Mediated Brain-Derived Neurotrophic Factor Gene Invest. Ophthalmol. Vis. Sci., October 1, 2004; 45(10): 3721 - 3726. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. R. Kim, N. Fishkin, J. Kong, K. Nakanishi, R. Allikmets, and J. R. Sparrow Rpe65 Leu450Met variant is associated with reduced levels of the retinal pigment epithelium lipofuscin fluorophores A2E and iso-A2E PNAS, August 10, 2004; 101(32): 11668 - 11672. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. L. McHenry, Y. Liu, W. Feng, A. R. Nair, K. L. Feathers, X. Ding, A. Gal, D. Vollrath, P. A. Sieving, and D. A. Thompson MERTK Arginine-844-Cysteine in a Patient with Severe Rod-Cone Dystrophy: Loss of Mutant Protein Function in Transfected Cells Invest. Ophthalmol. Vis. Sci., May 1, 2004; 45(5): 1456 - 1463. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. L. Mata, W. N. Moghrabi, J. S. Lee, T. V. Bui, R. A. Radu, J. Horwitz, and G. H. Travis Rpe65 Is a Retinyl Ester Binding Protein That Presents Insoluble Substrate to the Isomerase in Retinal Pigment Epithelial Cells J. Biol. Chem., January 2, 2004; 279(1): 635 - 643. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Nour, A. B. Quiambao, M. R. Al-Ubaidi, and M. I. Naash Absence of Functional and Structural Abnormalities Associated with Expression of EGFP in the Retina Invest. Ophthalmol. Vis. Sci., January 1, 2004; 45(1): 15 - 22. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
