Histopathologic study of X-linked cone-rod dystrophy (CORDX1) caused by a mutation in the RPGR exon ORF15

Demirci, F. Yesim; Gupta, Nisha; Radak, Amy L.; Rigatti, Brian W.; Mah, Tammy S.; Milam, Ann H.; Gorin, Michael B.

doi:10.1016/j.ajo.2004.08.041

Cited by 15 publications

(15 citation statements)

References 7 publications

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“…sph.uth.tmc.edu/RetNet/). Also concurrent involvement of cones and rods occurs in some forms of X-linked retinitis pigmentosa (XLRP) caused by mutations in the retinitis pigmentosa (RP) GTPase regulator (RPGR) gene, 5,6 and it is the early and severe cone involvement that causes the marked visual impairment. 7 In many other retinal diseases, however, cones are affected secondarily.…”

Section: Introductionmentioning

confidence: 99%

Targeting gene expression to cones with human cone opsin promoters in recombinant AAV

et al. 2008

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Specific cone-directed therapy is of high priority in the treatment of human hereditary retinal diseases. However, not much information exists about the specific targeting of photoreceptor subclasses. Three versions of the human red cone opsin promoter (PR0.5, 3LCR-PR0.5 and PR2.1), and the human blue cone opsin promoter HB569, were evaluated for their specificity and robustness in targeting green fluorescent protein (GFP) gene expression to subclasses of cones in the canine retina when used in recombinant adeno-associated viral vectors of serotype 5. The vectors were administered by subretinal injection. The promoter PR2.1 led to most effective and specific expression of GFP in the long-and medium-wavelength-absorbing cones (L/M cones) of normal and diseased retinas. The PR0.5 promoter was not effective. Adding three copies of the 35-bp LCR in front of PR0.5 lead to weak GFP expression in L/M cones. The HB569 promoter was not specific, and GFP was expressed in a few L/M cones, some rods and the retinal pigment epithelium. These results suggest that L/M cones, the predominant class of cone photoreceptors in the retinas of dogs and most mammalian species can be successfully targeted using the human red cone opsin promoter.

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Section: Introductionmentioning

confidence: 99%

Targeting gene expression to cones with human cone opsin promoters in recombinant AAV

et al. 2008

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“…The additional RPGR screening was performed to exclude other genetic causes. To the best of our knowledge, this gene is the only known causal gene for XL-CRD to date [7]. The study was approved by the Medical Ethics Committee of Erasmus Medical Center, and adhered to the tenets of the Declaration of Helsinki.…”

Section: Methodsmentioning

confidence: 99%

Cone-rod dystrophy can be a manifestation of Danon disease

Thiadens

Slingerland

Florijn

et al. 2012

Graefes Arch Clin Exp Ophthalmol

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BackgroundDanon disease is a neuromuscular disorder with variable expression in the eye. We describe a family with Danon disease and cone-rod dystrophy (CRD).MethodsAffected males of one family with Danon were invited for an extensive ophthalmologic examination, including color vision testing, fundus photography, Goldmann perimetry, full-field electroretinogram (ERG), and SD-OCT. Previous ophthalmologic data were retrieved from medical charts. The LAMP2 and RPGR gene were analyzed by direct sequencing.ResultsTwo siblings had no ocular phenotype. The third sibling and a cousin developed CRD leading to legal blindness. Visual acuity deteriorated progressively over time, color vision was severely disturbed, and ERG showed reduced photopic and scotopic responses. SD-OCT revealed thinning of the photoreceptor and RPE layer. Visual fields demonstrated central scotoma. The causal mutation was p.Gly384Arg in LAMP2; no mutations were found in RPGR.ConclusionsThis is the first description of CRD in Danon disease. The retinal phenotype was a late onset but severe dystrophy characterized by loss of photoreceptors and RPE cells. With this report, we highlight the importance of a comprehensive ophthalmologic examination in the clinical work-up of Danon disease.

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“…The dog diseases are mainly rod > cone degenerations, and there was efficacy in treating both the severe XLPRA2 with central retinal degeneration and the less severe XLPRA1 with central retinal preservation using vectors that targeted both rods and cones. Not included in the canine disease spectrum, however, are certain human RPGR-XLRP phenotypes, such as mild cone > rod or cone dystrophies (25,26,(43)(44)(45). Some patients can show very limited or even normal rod function, and cone-targeting strategies must be developed for these subtypes.…”

Section: Discussionmentioning

confidence: 99%

Gene therapy rescues photoreceptor blindness in dogs and paves the way for treating human X-linked retinitis pigmentosa

Beltran

Cideciyan

Lewin

et al. 2012

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

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Hereditary retinal blindness is caused by mutations in genes expressed in photoreceptors or retinal pigment epithelium. Gene therapy in mouse and dog models of a primary retinal pigment epithelium disease has already been translated to human clinical trials with encouraging results. Treatment for common primary photoreceptor blindness, however, has not yet moved from proof of concept to the clinic. We evaluated gene augmentation therapy in two blinding canine photoreceptor diseases that model the common X-linked form of retinitis pigmentosa caused by mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene, which encodes a photoreceptor ciliary protein, and provide evidence that the therapy is effective. After subretinal injections of adeno-associated virus-2/5-vectored human RPGR with human IRBP or GRK1 promoters, in vivo imaging showed preserved photoreceptor nuclei and inner/ outer segments that were limited to treated areas. Both rod and cone photoreceptor function were greater in treated (three of four) than in control eyes. Histopathology indicated normal photoreceptor structure and reversal of opsin mislocalization in treated areas expressing human RPGR protein in rods and cones. Postreceptoral remodeling was also corrected: there was reversal of bipolar cell dendrite retraction evident with bipolar cell markers and preservation of outer plexiform layer thickness. Efficacy of gene therapy in these large animal models of X-linked retinitis pigmentosa provides a path for translation to human treatment.retina | retinal degeneration P hotoreceptors function cooperatively with the retinal pigment epithelium (RPE) to optimize photon catch and generate signals that are transmitted to higher vision centers and perceived as a visual image. Disruption of the visual process in the retinal photoreceptors can result in blindness. Genetic defects in the retina cause substantial numbers of sight-impairing disorders by a multitude of mechanisms (1, 2). These genetic diseases were classically considered incurable, but the past few years have witnessed a new era of retinal therapeutics in which successful gene therapy of an animal model of one blinding human disease (3) was followed by stepwise translation to the clinic. The RPE65 form of Leber congenital amaurosis, due to a biochemical blockade of the retinoid cycle in the RPE, was the first and remains the only blinding genetic disease to be successfully treated in humans (reviewed in ref. 4).The next level of challenge is to initiate treatment for the majority of blinding retinal disorders in which the genetic flaws are primarily in the photoreceptors. Successful targeting of therapeutic vectors to mutant photoreceptors would be required to restore function and preserve structure. Among photoreceptor dystrophies, the X-linked forms of retinitis pigmentosa (XLRP) are one of the most common causes of severe vision loss (5). More than 25 y ago, the genetic loci were identified (6), and discovery of the underlying gene defects followed (7,8). Mutations in the reti...

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Histopathologic study of X-linked cone-rod dystrophy (CORDX1) caused by a mutation in the RPGR exon ORF15

Cited by 15 publications

References 7 publications

Targeting gene expression to cones with human cone opsin promoters in recombinant AAV

Targeting gene expression to cones with human cone opsin promoters in recombinant AAV

Cone-rod dystrophy can be a manifestation of Danon disease

Gene therapy rescues photoreceptor blindness in dogs and paves the way for treating human X-linked retinitis pigmentosa

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