Differential Macular Morphology in Patients withRPE65-,CEP290-,GUCY2D-, andAIPL1-Related Leber Congenital Amaurosis

Pasadhika, Sirichai; Fishman, Gerald A.; Stone, Edwin M.; Lindeman, Martin; Zelkha, Ruth; López, Irma; Koenekoop, Robert K.; Shahidi, Mahnaz

doi:10.1167/iovs.09-3734

Cited by 92 publications

(104 citation statements)

References 26 publications

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“…One study reported the post-mortem retinal findings in a child with GUCY2D mutation and another study reported the optical coherence study findings in three patients with LCA1. 42,46 Milam et al 46 reported a lack of cone labeling using anti red-green cone opsin, which may resemble the lack of zpr1 staining in our report. Additional findings in zebrafish reported here include morphologically visible outer-segment loss of both rods and cones, compatible with the human finding of rods and cones without outer segments.…”

Section: Discussionsupporting

confidence: 81%

“…LCA1 patients present in infancy with severely impaired vision and extinguished ERG despite a normal fundus and retained photoreceptors in both their macular and peripheral retina for decades. [39][40][41][42] There is relatively better maintenance of retinal structure in LCA1 patients than that seen in other forms of the disease. 42 Taken together, this suggests an important role for the zebrafish as an animal model on which rapid visual screening and retinal histology may offer a unique advantage in the study of GC1 disease through both gene knockdown or future studies of dominant gene supplementation.…”

Section: Discussionmentioning

confidence: 98%

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Gucy2f zebrafish knockdown – a model for Gucy2d-related leber congenital amaurosis

et al. 2012

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Mutations in retinal-specific guanylate cyclase (Gucy2d) are associated with Leber congenital amaurosis-1 (LCA1). Zebrafish offer unique advantages relative to rodents, including their excellent color vision, precocious retinal development, robust visual testing strategies, low cost, relatively easy transgenesis and shortened experimental times. In this study we will demonstrate the feasibility of using gene-targeting in the zebrafish as a model for the photoreceptor-specific GUCY2D-related LCA1, by reporting the visual phenotype and retinal histology resulting from Gucy2f knockdown. Gucy2f zebrafish LCA-orthologous cDNA was identified and isolated by PCR amplification. Its expression pattern was determined by whole-mount in-situ hybridization and its function was studied by gene knockdown using two different morpholino-modified oligos (MO), one that blocks translation of Gucy2f and one that blocks splicing of Gucy2f. Visual function was assessed with an optomotor assay on 6-days-postfertilization larvae, and by analyzing changes in retinal histology. Gucy2f knockdown resulted in significantly lower vision as measured by the optomotor response compared with uninjected and control MO-injected zebrafish larvae. Histological changes in the Gucy2f-knockdown larvae included loss and shortening of cone and rod outer segments. A zebrafish model of Gucy2f-related LCA1 displays early visual dysfunction and photoreceptor layer dystrophy. This study serves as proof of concept for the use of zebrafish as a simple, inexpensive model with excellent vision on which further study of LCA-related genes is possible. Keywords: leber congenital amaurosis; animal model; GUCY2D; optomotor assay INTRODUCTION Leber congenital amaurosis (LCA) is a family of severe, early-onset, autosomal-recessive forms of pediatric blindness. LCA has been linked to more than 16 genes, often exhibiting clinical heterogeneity. 1,2 LCA1 is caused by mutations in the gene GUCY2D, which encodes the retinal Gucy2d-1 (GC1) and accounts for B20% of all cases of LCA. 3 LCA2 is caused by mutations in the RPE65 gene, which is expressed in the retinal pigment epithelium. Breakthrough research has demonstrated visual improvement following gene therapy trials in humans with LCA2. 4,5 Human trials relied on a decade of proof-of-concept studies in canine and rodent models. 6-8 Unlike LCA2, in which gene therapy is aimed at correcting an RPE defect, searching for gene therapy for LCA1 will involve an attempt at treating the photoreceptors. European Journal of Human GeneticsResearch in inherited retinal disease relies heavily on animal models, commonly mammals such as mice and dogs. These animal models have significant advantages, including the availability of knockout technology. Two specific drawbacks slow the applicability of rodent or canine models for study of relatively rare genetic diseases such as LCA and other retinal dystrophies. The first difficulty is the high cost and length of time required to create a new knockout line; thus, it is applicable only for comm...

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Section: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 98%

Gucy2f zebrafish knockdown – a model for Gucy2d-related leber congenital amaurosis

et al. 2012

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“…The progression rate in RPE65-mutant dogs averaged −0.33 log 10 /y, corresponding to −0.05 log 10 /human y. Thus, both murine and canine models show an extended period (up to 25% of their lifespan) with a retinawide dysfunction-only phase that does not seem to have an equivalent in human RPE65-LCA at any age observed to date (6,(19)(20)(21)(22)(23)(24)(43)(44)(45). Human RPE65-LCA is best modeled in older animals clearly displaying the dysfunction as well as degeneration phases of RPE65 disease.…”

Section: Discussionmentioning

confidence: 93%

“…Rpe65 −/− mice show an onset of degeneration near 3-4 mo (4, 42) and a degeneration rate averaging −0.22 log 10 /y (21). Assuming an allometric relationship between rates of neurodegeneration and maximum lifespan (33), the Rpe65 −/− mouse disease is much slower than human disease (6,(19)(20)(21)(22)(23)(24)(43)(44)(45), with an onset that is equivalent to 9-12 human y and a rate that corresponds to −0.006 log 10 /human y. RPE65-mutant dogs were also known to have slow photoreceptor degeneration (5,29,30,32), but the details of spatiotemporal progression were unknown. Our results showed that the onset of degeneration ranges from 5 to 8 y depending on retinal location.…”

Section: Discussionmentioning

confidence: 99%

Human retinal gene therapy for Leber congenital amaurosis shows advancing retinal degeneration despite enduring visual improvement

Cideciyan

Jacobson

Beltran

et al. 2013

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

384

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Leber congenital amaurosis (LCA) associated with retinal pigment epithelium-specific protein 65 kDa (RPE65) mutations is a severe hereditary blindness resulting from both dysfunction and degeneration of photoreceptors. Clinical trials with gene augmentation therapy have shown partial reversal of the dysfunction, but the effects on the degeneration are not known. We evaluated the consequences of gene therapy on retinal degeneration in patients with RPE65-LCA and its canine model. In untreated RPE65-LCA patients, there was dysfunction and degeneration of photoreceptors, even at the earliest ages. Examined serially over years, the outer photoreceptor nuclear layer showed progressive thinning. Treated RPE65-LCA showed substantial visual improvement in the short term and no detectable decline from this new level over the long term. However, retinal degeneration continued to progress unabated. In RPE65-mutant dogs, the first one-quarter of their lifespan showed only dysfunction, and there was normal outer photoreceptor nuclear layer thickness retina-wide. Dogs treated during the earlier dysfunction-only stage showed improved visual function and dramatic protection of treated photoreceptors from degeneration when measured 5-11 y later. Dogs treated later during the combined dysfunction and degeneration stage also showed visual function improvement, but photoreceptor loss continued unabated, the same as in human RPE65-LCA. The results suggest that, in RPE65 disease treatment, protection from visual function deterioration cannot be assumed to imply protection from degeneration. The effects of gene augmentation therapy are complex and suggest a need for a combinatorial strategy in RPE65-LCA to not only improve function in the short term but also slow retinal degeneration in the long term.neurodegeneration | outer nuclear layer | retinal structure

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“…Histopathological analysis of two postmortem retinas (a 26-wk-old preterm abortus and a 12-yr-old donor) revealed signs of photoreceptor degeneration in both rods and cones Porto et al 2003). Later studies using state of the art, in-life imaging (i.e., optical coherence tomography) revealed no obvious degeneration in patients as old as 53 years of age (Simonelli et al 2007;Pasadhika et al 2010).…”

Section: Patient Characterizationmentioning

confidence: 95%

Leber Congenital Amaurosis Caused by Mutations in GUCY2D

Boye

2014

Cold Spring Harbor Perspectives in Medicine

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Differential Macular Morphology in Patients withRPE65-,CEP290-,GUCY2D-, andAIPL1-Related Leber Congenital Amaurosis

Abstract: Variations of macular microstructures were observed among LCA patients with different genotypes. Disorganization of retinal lamellar structure was generally age related. Preservation of retinal microanatomic structures may not be associated with better visual acuity.

Cited by 92 publications

References 26 publications

Gucy2f zebrafish knockdown – a model for Gucy2d-related leber congenital amaurosis

Gucy2f zebrafish knockdown – a model for Gucy2d-related leber congenital amaurosis

Human retinal gene therapy for Leber congenital amaurosis shows advancing retinal degeneration despite enduring visual improvement

Leber Congenital Amaurosis Caused by Mutations in GUCY2D

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