Leber congenital amaurosis due to RPE65 mutations and its treatment with gene therapy

Cideciyan, Artur V.

doi:10.1016/j.preteyeres.2010.04.002

Cited by 221 publications

(199 citation statements)

References 199 publications

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“…In human clinical trials to date, AAV-vectored gene therapy for the RPE65 form of Leber congenital amaurosis (LCA) has shown improvement of some aspects of vision (36,37), but there is recent evidence in patients from two of the ongoing trials that such intervention has not been able to stem the progression rate of retinal degeneration (16,38,39). In naturally occurring canine models, both of RPE65-LCA and others, gene therapy has produced similar results: intervention after the onset of photoreceptor degeneration has not been able to modify the natural history of the disease (16) or to restore visual function unless adjunctive treatments are done (40).…”

Section: Discussionmentioning

confidence: 99%

Successful arrest of photoreceptor and vision loss expands the therapeutic window of retinal gene therapy to later stages of disease

Beltran

Cideciyan

Iwabe

et al. 2015

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

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Inherited retinal degenerations cause progressive loss of photoreceptor neurons with eventual blindness. Corrective or neuroprotective gene therapies under development could be delivered at a predegeneration stage to prevent the onset of disease, as well as at intermediate-degeneration stages to slow the rate of progression. Most preclinical gene therapy successes to date have been as predegeneration interventions. In many animal models, as well as in human studies, to date, retinal gene therapy administered well after the onset of degeneration was not able to modify the rate of progression even when successfully reversing dysfunction. We evaluated consequences of gene therapy delivered at intermediate stages of disease in a canine model of X-linked retinitis pigmentosa (XLRP) caused by a mutation in the Retinitis Pigmentosa GTPase Regulator (RPGR) gene. Spatiotemporal natural history of disease was defined and therapeutic dose selected based on predegeneration results. Then interventions were timed at earlier and later phases of intermediate-stage disease, and photoreceptor degeneration monitored with noninvasive imaging, electrophysiological function, and visual behavior for more than 2 y. All parameters showed substantial and significant arrest of the progressive time course of disease with treatment, which resulted in long-term improved retinal function and visual behavior compared with control eyes. Histology confirmed that the human RPGR transgene was stably expressed in photoreceptors and associated with improved structural preservation of rods, cones, and ON bipolar cells together with correction of opsin mislocalization. These findings in a clinically relevant large animal model demonstrate the long-term efficacy of RPGR gene augmentation and substantially broaden the therapeutic window for intervention in patients with RPGR-XLRP.

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Section: Discussionmentioning

confidence: 99%

Successful arrest of photoreceptor and vision loss expands the therapeutic window of retinal gene therapy to later stages of disease

Beltran

Cideciyan

Iwabe

et al. 2015

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

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“…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][7][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.…”

Section: Introductionmentioning

confidence: 99%

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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“…One of the key components of the visual cycle is the retinoid isomerase encoded by the RPEspecific protein 65 kDa (RPE65) gene (2). Mutations in RPE65 cause Leber congenital amaurosis (LCA), a severe childhood blindness (3). RPE65-associated LCA (RPE65-LCA) is a complex disease in which vision loss results from two pathological mechanisms-dysfunction and degeneration of photoreceptors (3)(4)(5)(6).…”

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confidence: 99%

“…Mutations in RPE65 cause Leber congenital amaurosis (LCA), a severe childhood blindness (3). RPE65-associated LCA (RPE65-LCA) is a complex disease in which vision loss results from two pathological mechanisms-dysfunction and degeneration of photoreceptors (3)(4)(5)(6). RPE65-LCA has been proclaimed to be the first successfully treated inherited retinopathy using gene augmentation therapy (7)(8)(9)(10), and the treatment has resulted in substantial improvement in vision that endures at least 3 y (11).…”

mentioning

confidence: 99%

“…Gene therapy experiments that have evaluated photoreceptor degeneration have been performed mainly in mouse and dog models treated at young ages (12)(13)(14)(15)(16)(17)(18) and have implied that at least a subset of photoreceptors could be rescued from degeneration. However, accumulating evidence has suggested that human RPE65-LCA, which can show degeneration prenatally or within the first years of life (19,20), is better modeled at the more advanced disease stages in older animals (3,21).…”

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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.

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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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Leber congenital amaurosis due to RPE65 mutations and its treatment with gene therapy

Cited by 221 publications

References 199 publications

Successful arrest of photoreceptor and vision loss expands the therapeutic window of retinal gene therapy to later stages of disease

Successful arrest of photoreceptor and vision loss expands the therapeutic window of retinal gene therapy to later stages of disease

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

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