Influence of eye pigmentation and light deprivation on inherited retinal dystrophy in the rat

LaVail, Matthew M.; Battelle, Barbara‐Anne

doi:10.1016/0014-4835(75)90080-9

Cited by 292 publications

(204 citation statements)

References 29 publications

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“…In our initial experiment with Ad-Mertk (Table 1, Exp. 1), the appearance of the retina in the inferior hemisphere of the eye, distant from the injection site in the superior hemisphere, was very similar to that of uninjected controls and characteristic of RCS rats at this age (30). The equatorial to peripheral retina had approximately one discontinuous row of PR nuclei in the ONL, highly attenuated RPE, and an intervening OS debris zone containing a number of macrophages ( Fig.…”

Section: Viral-mediated Expression Throughout Experimental Periodmentioning

confidence: 53%

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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.

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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: Viral-mediated Expression Throughout Experimental Periodmentioning

confidence: 53%

“…In the posterior region of the inferior hemisphere, the debris zone was eliminated from some focal regions of degenerated retina (Fig. 2B), as seen in the posterior retina of RCS rats at this age (30). By contrast, the superior hemisphere of treated eyes revealed preservation of PRs (Fig.…”

Section: Viral-mediated Expression Throughout Experimental Periodmentioning

confidence: 73%

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.

Self Cite

264

188

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“…The outer segment zone including rod outer segment and apical debris becomes thicker than in normal rats between days 14 and 20. 6 To analyse the difference between treated RCS rat eyes in comparison to controls, thickness measurements of different layers of the retina were performed on semithin sections. Since the differences were most obvious 8 weeks after injection, all measurements were carried out at this time point.…”

Section: Resultsmentioning

confidence: 99%

“…It has been reported previously that in the RCS rat the disappearance of debris is faster in posterior parts of the retina than in the periphery and it is therefore important to compare equivalent areas throughout the eye in order to assess the overall effect of treatment on the rate of degeneration. 6 Comparison of LNT.SFFV.GFP injected RCS rat retina 4 weeks pi. In LNT.SFFV.GFP treated retinae outer segments, which reach the RPE, could not be found.…”

Section: Long-term Rescue Of Rcs Rats After Gene Therapy M Tschernuttmentioning

confidence: 99%

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Long-term preservation of retinal function in the RCS rat model of retinitis pigmentosa following lentivirus-mediated gene therapy

et al. 2005

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The Royal College of Surgeons (RCS) rat is a wellcharacterized model of autosomal recessive retinitis pigmentosa (RP) due to a defect in the retinal pigment epithelium (RPE). It is homozygous for a null mutation in the gene encoding , a receptor tyrosine kinase found in RPE cells, that is required for phagocytosis of shed photoreceptor outer segments. The absence of Mertk results in accumulation of outer segment debris. This subsequently leads to progressive loss of photoreceptor cells. In order to evaluate the efficacy of lentiviral-mediated gene replacement therapy in the RCS rat, we produced recombinant VSV-G pseudotyped HIV-1-based lentiviruses containing a murine Mertk cDNA driven by a spleen focus forming virus (SFFV) promoter. The vector was subretinally injected into the right eye of 10-dayold RCS rats; the left eye was left untreated as an internal control. Here, we present a detailed assessment of the duration and extent of the morphological rescue and the resulting functional benefits. We examined animals at various time points over a period of 7 months by light and electron microscopy, and electroretinography. We observed correction of the phagocytic defect, slowing of photoreceptor cell loss and preservation of retinal function for up to 7 months. This study demonstrates the potential of gene therapy approaches for the treatment of retinal degenerations caused by defects specific to the RPE and supports the use of lentiviral vectors for the treatment of such disorders. Gene Therapy (2005) 12, 694-701.

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Ganglion cell loss in RCS rat retina: A result of compression of axons by contracting intraretinal vessels linked to the pigment epithelium

et al. 1998

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In the dystrophic Royal College of Surgeons (RCS) rat retina, there is a progressive loss of photoreceptors. As a result, the retinal circulation becomes apposed to the retinal pigment epithelium (RPE) and neovascular formations develop. RPE and inner nuclear layer cells migrate along these vessels towards the retinal ganglion cell (RGC) layer. The retinal layers gradually become disrupted, and some of the RGC axon bundles involute into the retina. These bundles are always associated with blood vessels, and there is evidence of axon damage where they juxtapose. In wholemount preparations of dystrophic retinae (> or =6 months of age), abrupt changes are observed in the trajectory of RGC axon bundles, where they are crossed by circumferential vessels. Degenerative profiles can be seen at these locations. Visualisation of RGCs with Fluoro-gold shows wedge-shaped sectors in the dystrophic retina devoid of labelling, initially in the ventral retina but later spreading dorsally. It is hypothesised that the vessels supplying the neovascular formations contract and pull surface vessels into the retina, thus displacing any axon bundles that lie beneath them into the inner plexiform layer. The contractility may be an intrinsic property of the vessels or it may be conferred by the cells migrating along them. Axonal transport becomes blocked at the points of tension, thereby causing retrograde degeneration of the parent RGCs. Because RGC loss is also a feature of human retinitis pigmentosa, the RCS rat may provide a model to test interventions devised to prevent such loss following photoreceptor degeneration. This model also may be useful for testing methods designed to control blood vessel and matrix formation.

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Influence of eye pigmentation and light deprivation on inherited retinal dystrophy in the rat

Cited by 292 publications

References 29 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

Long-term preservation of retinal function in the RCS rat model of retinitis pigmentosa following lentivirus-mediated gene therapy

Ganglion cell loss in RCS rat retina: A result of compression of axons by contracting intraretinal vessels linked to the pigment epithelium

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