Leber congenital amaurosis: Clinical correlations with genotypes, gene therapy trials update, and future directions

Chung, Daniel C.; Traboulsi, Elias I.

doi:10.1016/j.jaapos.2009.10.004

Cited by 98 publications

(69 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…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: 99%

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

et al. 2012

View full text Add to dashboard Cite

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...

show abstract

Section: Discussionmentioning

confidence: 99%

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

et al. 2012

View full text Add to dashboard Cite

show abstract

“…Several types of IRD, such as Leber congenital amaurosis (LCA), cause vision loss in infancy or childhood (Weleber 2002;Michaelides et al 2006;Chung and Traboulsi 2009). More than 200 different types of IRDs have been identified across all age groups by clinical and genetic studies, making IRDs one of the most genetically diverse groups of inherited disorders (Hsiau et al 2007;RetNet 2014).…”

mentioning

confidence: 99%

The Status ofRPE65Gene Therapy Trials: Safety and Efficacy

Pierce

Bennett

2015

Cold Spring Harb Perspect Med

131

View full text Add to dashboard Cite

Several groups have reported the results of clinical trials of gene augmentation therapy for Leber congenital amaurosis (LCA) because of mutations in the RPE65 gene. These studies have used subretinal injection of adeno-associated virus (AAV) vectors to deliver the human RPE65 cDNA to the retinal pigment epithelial (RPE) cells of the treated eyes. In all of the studies reported to date, this approach has been shown to be both safe and effective. The successful clinical trials of gene augmentation therapy for retinal degeneration caused by mutations in the RPE65 gene sets the stage for broad application of gene therapy to treat retinal degenerative disorders.

show abstract

“…LCA1 patients present within the first year of life and are routinely described as having reduced visual acuity, reduced or nonrecordable electroretinogram (ERG) responses, nystagmus, digito-ocular signs, and apparently normal fundus (Perrault et al 1999;Chung and Traboulsi 2009). Reports on the extent of photoreceptor degeneration associated with this disease have been conflicting.…”

Section: Patient Characterizationmentioning

confidence: 99%

Leber Congenital Amaurosis Caused by Mutations in GUCY2D

Boye

2014

Cold Spring Harbor Perspectives in Medicine

View full text Add to dashboard Cite

Leber congenital amaurosis: Clinical correlations with genotypes, gene therapy trials update, and future directions

Cited by 98 publications

References 40 publications

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

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

The Status ofRPE65Gene Therapy Trials: Safety and Efficacy

Leber Congenital Amaurosis Caused by Mutations in GUCY2D

Contact Info

Product

Resources

About