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Acland, Gregory M.; Aguirre, Gustavo D.; Ray, Jharna; Zhang, Qi; Alemán, Tomás S.; Cideciyan, Artur V.; Pearce-Kelling, Susan E.; Anand, Vibha; Zeng, Yong; Maguire, Albert M.; Jacobson, Samuel G.; Hauswirth, William W.; Bennett, Jean

doi:10.1038/88327

Cited by 250 publications

(214 citation statements)

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“…Our study complements the recent remarkable demonstration of restoration of vision in a canine model of an RPE-based disorder by adeno-associated virus mediated transfer of RPE65 (22), as well as an earlier study of mucopolysaccharidosis VII in mice by using an adenovirus vector (21). In these previous studies, the issue of neuronal degeneration could not be addressed because photoreceptor death did not occur during the experimental period.…”

Section: Discussionsupporting

confidence: 64%

“…We therefore chose to address the problem by somatic gene transfer with a viral vector. Viral gene replacement therapy has been used in a number of animal models of retinal degeneration caused by PR (17)(18)(19)(20) or RPE (21,22) defects. Successful complementation of the rdy phenotype would also serve as a model for treatment of individuals with retinitis pigmentosa who harbor MERTK mutations (23) and, more generally, other diseases in which the RPE is dysfunctional, such as age-related macular degeneration.…”

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confidence: 99%

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Correction of the retinal dystrophy phenotype of the RCS rat by viral gene transfer of Mertk

Vollrath

Feng

Duncan

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

264

188

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The Royal College of Surgeons (RCS) rat is a widely studied animal model of retinal degeneration in which the inability of the retinal pigment epithelium (RPE) to phagocytize shed photoreceptor outer segments leads to a progressive loss of rod and cone photoreceptors. We recently used positional cloning to demonstrate that the gene Mertk likely corresponds to the retinal dystrophy (rdy) locus of the RCS rat. In the present study, we sought to determine whether gene transfer of Mertk to a RCS rat retina would result in correction of the RPE phagocytosis defect and preservation of photoreceptors. We used subretinal injection of a recombinant replication-deficient adenovirus encoding rat Mertk to deliver the gene to the eyes of young RCS rats. Electrophysiological assessment of animals 30 days after injection revealed an increased sensitivity of treated eyes to low-intensity light. Histologic and ultrastructural assessment demonstrated substantial sparing of photoreceptors, preservation of outer segment structure, and correction of the RPE phagocytosis defect in areas surrounding the injection site. Our results provide definitive evidence that mutation of Mertk underlies the RCS retinal dystrophy phenotype, and that the phenotype can be corrected by treatment of juvenile animals. To our knowledge, this is the first demonstration of complementation of both a functional cellular defect (phagocytosis) and a photoreceptor degeneration by gene transfer to the RPE. These results, together with the recent discovery of MERTK mutations in individuals with retinitis pigmentosa, emphasize the importance of the RCS rat as a model for gene therapy of diseases that arise from RPE dysfunction.T he Royal College of Surgeons (RCS) rat strain displays an unusual retinal phenotype in which shed photoreceptor (PR) outer segment (OS) debris accumulates in the subretinal space (1). PR disk shedding normally commences at postnatal day (P)12 in the rat (2), and an OS debris layer is readily apparent in the eyes of RCS animals at P20. Genetic chimera studies suggest that the defect is a cell-autonomous function of the RPE, not the PRs (3). Indeed, in vivo (4) and RPE cell culture studies (5) revealed a defect in the ability of RCS RPE to phagocytize shed OS membranes. Despite the RPE-specific nature of the defect, death strikes the PRs first, through the process of apoptosis (6). The time course of PR degeneration is rapid, beginning around P20, with few PR nuclei remaining in the outer nuclear layer (ONL) by P60. Thinning and atrophy of the RPE begins after onset of PR degeneration. The cause of PR cell death is not well understood; the debris zone acting as a diffusion barrier to metabolites (7), disruption of the interphotoreceptor matrix (8), and PR hypoxia due to diminished oxygen diffusion (9) have been proposed as explanations.In contrast to the extensively studied retinal phenotype of the RCS rat, the nature of the genetic defect has remained obscure until recently. Early genetic linkage studies showed that the phenotype is complet...

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Section: Discussionsupporting

confidence: 64%

mentioning

confidence: 99%

Correction of the retinal dystrophy phenotype of the RCS rat by viral gene transfer of Mertk

Vollrath

Feng

Duncan

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

264

188

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“…It should be noted that older animals (Ͼ10 months) begin to exhibit severe retinal degeneration, initially in distinct topographic regions that later become more generalized (22). Fundus photomontages of the left eye of a 6.5-month-old RHO T4R/ϩ RPE65 Ϫ/Ϫ dog, which could not produce the chromophore because of mutation in the RPE65 gene (24,25,44), displayed hyperreflectivity of the tapetal fundus (Fig. 2B1), moderate vascular attenuation, and changes characteristic of outer retinal thinning and mid-stage disease.…”

Section: Resultsmentioning

confidence: 99%

“…RHO T4R/ϩ and RHO T4R/T4R dogs derive their mutant RHO allele from English mastiff dogs affected with autosomal dominant progressive retinal atrophy as described previously (22,23). RPE65 Ϫ/Ϫ and RPE65 ϩ/Ϫ dogs derive their mutant allele, a 4-bp deletion in the canine RPE65 (retinal pigment epithelium protein of 65 kDa) gene, from a briard dog affected with the canine homolog of Leber's congenital amaurosis (24,25). All dogs used in this study were tested to determine their genotype at either or both the RHO (22,23) and RPE65 (25) loci as described previously.…”

Section: Methodsmentioning

confidence: 99%

A Naturally Occurring Mutation of the Opsin Gene (T4R) in Dogs Affects Glycosylation and Stability of the G Protein-coupled Receptor

Zhu

Jang

Jastrzębska

et al. 2004

Journal of Biological Chemistry

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Rho (rhodopsin; opsin plus 11-cis-retinal) is a prototypical G protein-coupled receptor responsible for the capture of a photon in retinal photoreceptor cells. A large number of mutations in the opsin gene associated with autosomal dominant retinitis pigmentosa have been identified. The naturally occurring T4R opsin mutation in the English mastiff dog leads to a progressive retinal degeneration that closely resembles human retinitis pigmentosa caused by the T4K mutation in the opsin gene. Using genetic approaches and biochemical assays, we explored the properties of the T4R mutant protein. Employing immunoaffinity-purified Rho from affected RHO T4R/T4R dog retina, we found that the mutation abolished glycosylation at Asn 2 , whereas glycosylation at Asn 15 was unaffected, and the mutant opsin localized normally to the rod outer segments. Moreover, we found that T4R Rho* lost its chromophore faster as measured by the decay of meta-rhodopsin II and that it was less resistant to heat denaturation. Detergent-solubilized T4R opsin regenerated poorly and interacted abnormally with the G protein transducin (G t ). Structurally, the mutation affected mainly the "plug" at the intradiscal (extracellular) side of Rho, which is possibly responsible for protecting the chromophore from the access of bulk water. The T4R mutation may represent a novel molecular mechanism of degeneration where the unliganded form of the mutant opsin exerts a detrimental effect by losing its structural integrity.

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“…47 and 56) can now be extended to a large animal. The temporal, functional, and structural progression of disease in the canine model offers an ideal time window of opportunity for gene therapy (16,57). Affected dogs are clinically normal for at least several months before retinal degeneration develops, but at this stage retinal dysfunction can be clearly monitored by dark adaptometry.…”

Section: Discussionmentioning

confidence: 99%

Naturally occurring rhodopsin mutation in the dog causes retinal dysfunction and degeneration mimicking human dominant retinitis pigmentosa

Kijas

Cideciyan

Alemán

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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109

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Rhodopsin is the G protein-coupled receptor that is activated by light and initiates the transduction cascade leading to night (rod) vision. Naturally occurring pathogenic rhodopsin (RHO) mutations have been previously identified only in humans and are a common cause of dominantly inherited blindness from retinal degeneration. We identified English Mastiff dogs with a naturally occurring dominant retinal degeneration and determined the cause to be a point mutation in the RHO gene (Thr4Arg). Dogs with this mutant allele manifest a retinal phenotype that closely mimics that in humans with RHO mutations. The phenotypic features shared by dog and man include a dramatically slowed time course of recovery of rod photoreceptor function after light exposure and a distinctive topographic pattern to the retinal degeneration. The canine disease offers opportunities to explore the basis of prolonged photoreceptor recovery after light in RHO mutations and determine whether there are links between the dysfunction and apoptotic retinal cell death. The RHO mutant dog also becomes the large animal needed for preclinical trials of therapies for a major subset of human retinopathies. R hodopsin, the visual pigment of rod photoreceptors, is one of many G protein-coupled receptors involved in human disease (1-3). Numerous rhodopsin gene (RHO) mutations (mostly point mutations) cause retinitis pigmentosa (RP), a blinding human retinal degeneration (see RetNet, http:͞͞ www.sph.uth.tmc.edu͞Retnet͞; refs. 4 and 5). RP caused by RHO mutations exhibits two different phenotypes (4, 5). One is an early-onset disorder with rapid loss of rods uniformly across the retina. The second has a protracted natural history of vision loss and puzzling features: rod vision can be normal early in life, and degeneration slowly spreads from a disease focus in one retinal region. Furthermore, and independent of disease stage, there is abnormally slow recovery of rod vision after bright light exposure. Variation in severity of this second phenotype may indicate that epigenetic factors play an important role in its progression (5-7) and suggests that it may be particularly amenable to preventive or ameliorative therapies.Other than in humans, naturally occurring disease-causing RHO mutations have not been identified previously in mammals. Genetically engineered animals and mutagenized flies have been the mainstay for in vivo research and treatment attempts in the past decade (reviewed in ref. 8).Naturally occurring hereditary retinal degenerations in dogs, termed progressive retinal atrophies (PRAs), are widespread and have provided several models of autosomal recessive and X-linked RP (9-13). We have now identified an autosomal dominant form of PRA, one that closely resembles the second human phenotype described above. This model should advance understanding of the pathophysiology of the disease and therapies for this major subset of dominant RP. Materials and MethodsRhodopsin Gene Sequence Analysis. Mutation analysis by comparative sequencing of the five c...

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Cited by 250 publications

References 0 publications

Correction of the retinal dystrophy phenotype of the RCS rat by viral gene transfer of Mertk

Correction of the retinal dystrophy phenotype of the RCS rat by viral gene transfer of Mertk

A Naturally Occurring Mutation of the Opsin Gene (T4R) in Dogs Affects Glycosylation and Stability of the G Protein-coupled Receptor

Naturally occurring rhodopsin mutation in the dog causes retinal dysfunction and degeneration mimicking human dominant retinitis pigmentosa

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