Disease Course of Patients with X-linked Retinitis Pigmentosa due to<i>RPGR</i>Gene Mutations

Sandberg, Michael A.; Rosner, Bernard; Weigel-DiFranco, Carol; Dryja, Thaddeus P.; Berson, Eliot L.

doi:10.1167/iovs.06-0971

Cited by 134 publications

(159 citation statements)

References 15 publications

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“…18 Despite a broad overlap in phenotype between RP patients with RPGR mutations, previous study showed that patients with mutation in exons 1-14 had a smaller visual filed area, lower ERG amplitude and lost ERG amplitude 50% greater than those with ORF15 mutations. 37,38 In contrast to these studies, subject 4 with ORF11 mutation had milder AO-SLO features, in terms of both quantity and quality, along with better ERG amplitude than subjects 1 and 5 who had ORF15 mutations, even subject 4 was older and high myopia. Although this result showed that the AO-SLO finding well matched with ERG, proving sensitivity of AO-SLO.…”

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confidence: 69%

Cellular imaging demonstrates genetic mosaicism in heterozygous carriers of an X-linked ciliopathy gene

Hong

et al. 2013

Eur J Hum Genet

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X-linked retinitis pigmentosa (XLRP) is the least common genetic type of retinitis pigmentosa; however, it has extremely devastating consequences to patients' activities of daily living. RPGR and RP2 genes expressed in the photoreceptor sensory cilia are predominantly implicated in XLRP; however, the interpretation of genetic mutations and their correlation with clinical phenotypes remain unknown, and the role of these genes in photoreceptor cilia function is not completely elucidated. Therefore, we evaluated structural characteristics in five female obligate carriers of XLRP by using state-of-the-art non-invasive imaging methods, including adaptive optics (AO) scanning laser ophthalmoscopy (SLO). In all five carriers examined, qualitative and quantitative analyses by AO SLO imaging revealed a mosaic pattern of cone disruption, even in the absence of visual symptoms, normal visual acuity and normal macular thickness, on optical coherence tomography and mildly subnormal full-field cone electroretinographic findings. As the technique is sensitive to the level of a single cone, the ability to visualize the cone cells in vivo should be especially useful in other retinal diseases. In addition, further investigation of XLRP carriers may yield insight into how cone structures change over time and ultimately enable understanding of the role of RPGR and RP2 in cone cell survival. European Journal of Human Genetics (2013Genetics ( ) 21, 1240Genetics ( -1248 doi:10.1038/ejhg.2013; published online 27 February 2013Keywords: X-linked retinitis pigmentosa carrier; photoreceptor layer; adaptive optics scanning laser ophthalmoscopy INTRODUCTIONIdentification of X-linked retinitis pigmentosa (XLRP) carriers is challenging and has serious implications for genetic counseling. Female XLRP carriers usually have normal, or close to normal, visual acuity, but often show some degree of fundus changes, including sectorial or peripheral pigmentary deposits and a tapetal-like reflex (TLR), 1 as well as abnormal fundus. Many previous studies have detailed the prevalence of abnormal fundus photography, 1,2 vitreous fluorophotometry, 3 infrared (IR) reflectance images, 1,2 electroretinographic (ERG), 4,5 psychophysical 6 and flicker-fusion 7 findings in such carriers. More recently, several studies have investigated XLRP carriers with advanced devices, including FAF, 8 multifocal ERG 9 and OCT 10,11 to reveal clinical phenotypes of XLRP. Most XLRP carriers can be identified on the basis of fundus findings and ERG changes; however, 10-30% of carriers show no abnormal ERG or fundus finding. 1,4,5,9 Although XLRP is the least common genetic type of RP, accounting for 6-17% of familial retinitis pigmentosa cases, it is extremely devastating. 1,12,13 In the first or second decade of life, affected individuals experience a decrease in peripheral and night vision, and the disease often leads to partial or complete blindness in the fourth or fifth decade of life. 14 In contrast to the severe retinal degeneration in affected men, female carriers of t...

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confidence: 69%

Cellular imaging demonstrates genetic mosaicism in heterozygous carriers of an X-linked ciliopathy gene

Hong

et al. 2013

Eur J Hum Genet

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“…4,5 Males carrying RPGR mutations typically show signs of night blindness and restriction of visual fields in their first or second decade of life, and the disease often progresses to nearly complete vision loss in the fourth or fifth decade. [6][7][8] Female carriers are usually not affected, but can occasionally exhibit electroretinogram (ERG) defects. 6,9,10 The RPGR gene uses alternative splicing sites and polyadenylation signals producing multiple transcript variants.…”

Section: Introductionmentioning

confidence: 99%

Stability and Safety of an AAV Vector for Treating RPGR-ORF15 X-Linked Retinitis Pigmentosa

et al. 2015

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Our collaborative successful gene replacement therapy using AAV vectors expressing a variant of human RPGR-ORF15 in two canine models provided therapeutic proof of concept for translation into human treatment. The ORF15 sequence contained within this AAV vector, however, has ORF15 DNA sequence variations compared to the published sequence that are likely due to its unusual composition of repetitive purine nucleotides. This mutability is a concern for AAV vector production and safety when contemplating a human trial. In this study, we establish the safety profile of AAV-hIRBP-hRPGR and AAV-hGRK1-hRPGR vectors used in the initial canine proof-of-principle experiments by demonstrating hRPGR-ORF15 sequence stability during all phases of manipulation, from plasmid propagation to vector production to its stability in vivo after subretinal administration to animals. We also evaluate potential toxicity in vivo by investigating protein expression, retinal structure and function, and vector biodistribution. Expression of hRPGR is detected in the inner segments and synaptic terminals of photoreceptors and is restricted to the connecting cilium when the vector is further diluted. Treated eyes exhibit no toxicity as assessed by retinal histopathology, immunocytochemistry, optical coherence tomography, fundoscopy, electroretinogram, and vector biodistribution. Therefore, the hRPGR-ORF15 variant in our AAV vectors appears to be a more stable form than the endogenous hRPGR cDNA when propagated in vitro. Its safety profile presented here in combination with its proven efficacy supports future gene therapy clinical trials. INTRODUCTIONRetinitis pigmentosa (RP) is a common form of genetically heterogeneous, inherited retinal diseases characterized by progressive degeneration of rod and cone photoreceptor cells and affects 1 in 4000 individuals.1,2 The X-linked form of RP (XLRP), comprising an estimated 15% of total RP cases, is among the most severe forms.3 Mutations in the gene coding for RP GTPase regulator (RPGR) cause XLRP and account for over 70% of cases.

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“…Furthermore, in the present study, there was no attempt to target the very central retina; the extracentral subretinal approach as used in the dogs would be the advisable strategy for early phase human clinical trials on the basis of the current observations. However, many RPGR patients show continued survival of foveal cones and impaired but useful visual acuity in late disease stages (15). Because subfoveal injections of viral vector constructs have been shown to cause loss of diseased foveal cones (50), an alternate means of therapeutic gene delivery should be considered.…”

Section: Discussionmentioning

confidence: 99%

“…Males affected with RPGR-XLRP typically have night blindness in their first decade of life followed by reduction of their visual field and loss of visual acuity. By the end of their fourth decade, most patients are legally blind (14)(15)(16).…”

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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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Disease Course of Patients with X-linked Retinitis Pigmentosa due toRPGRGene Mutations

Abstract: Patients with X-linked retinitis pigmentosa due to RPGR mutations lose visual acuity and visual field more rapidly than do patients with dominant retinitis pigmentosa due to RHO mutations.

Cited by 134 publications

References 15 publications

Cellular imaging demonstrates genetic mosaicism in heterozygous carriers of an X-linked ciliopathy gene

Cellular imaging demonstrates genetic mosaicism in heterozygous carriers of an X-linked ciliopathy gene

Stability and Safety of an AAV Vector for Treating RPGR-ORF15 X-Linked Retinitis Pigmentosa

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

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