Prenatal Human Ocular Degeneration Occurs in Leber’s Congenital Amaurosis

Porto, Fernanda Belga Ottoni; Perrault, Isabelle; Hicks, David; Rozet, Jean–Michel; Hanoteau, Noëlle; Hanein, Sylvain; Kaplan, Josseline; Sahel, J

doi:10.1007/978-1-4615-0067-4_8

Cited by 11 publications

(13 citation statements)

References 18 publications

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“…Whereas there is severely impaired vision in all LCA1, there is no consensus about whether there are underlying retinal structure abnormalities in such patients. Some reports describe retinal degeneration (Milam et al, 2003;Porto et al, 2003) and others show normal-appearing, noninvasive, cross-sectional retinal images (Simonelli et al, 2007;Pasadhika et al, 2010). Such studies suggest that there may indeed be loss of rod and cone structure as well as function in some LCA1 patients, and it is important to evaluate gene therapies in an animal model exhibiting degeneration as well as dysfunction.…”

Section: Discussionmentioning

confidence: 99%

“…LCA is a clinically and genetically heterogeneous group of severe, early-onset retinal dystrophies characterized by a reduced or absent electroretinogram (ERG), nystagmus, digito-ocular signs, and apparently normal fundus appearance (Perrault et al, 1999). Among the specific LCA1 studies, there are those that describe retinal degeneration (Milam et al, 2003;Porto et al, 2003) and others suggesting no obvious retinal degeneration (Simonelli et al, 2007;Pasadhika et al, 2010). Until a more thorough analysis of patients with GUCY2D mutations is performed, it is unclear to what extent progressive retinal degeneration is part of the human LCA1 disease phenotype and whether there exists a spectrum of disease expression.…”

Section: Introductionmentioning

confidence: 99%

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AAV-Mediated Gene Therapy in the Guanylate Cyclase (RetGC1/RetGC2) Double Knockout Mouse Model of Leber Congenital Amaurosis

et al. 2013

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Mutations in GUCY2D are associated with recessive Leber congenital amaurosis-1 (LCA1). GUCY2D encodes photoreceptor-specific, retinal guanylate cyclase-1 (RetGC1). Reports of retinal degeneration in LCA1 are conflicting; some describe no obvious degeneration and others report loss of both rods and cones. Proof of concept studies in models representing the spectrum of phenotypes is warranted. We have previously demonstrated adeno-associated virus (AAV)-mediated RetGC1 is therapeutic in GC1ko mice, a model exhibiting loss of cones only. The purpose of this study was to characterize AAV-mediated gene therapy in the RetGC1/RetGC2 double knockout (GCdko) mouse, a model lacking rod and cone function and exhibiting progressive loss of both photoreceptor subclasses. Use of this model also allowed for the evaluation of the functional efficiency of transgenic RetGC1 isozyme. Subretinal delivery of AAV8(Y733F) vector containing the human rhodopsin kinase (hGRK1) promoter driving murine Gucy2e was performed in GCdko mice at various postnatal time points. Treatment resulted in restoration of rod and cone function at all treatment ages and preservation of retinal structure in GCdko mice treated as late as 7 weeks of age. Functional gains and structural preservation were stable for at least 1 year. Treatment also conferred cortical-and subcortical-based visually-guided behavior. Functional efficiency of transgenic RetGC1 was indistinguishable from that of endogenous isozyme in congenic wild-type (WT) mice. This study clearly demonstrates AAV-mediated RetGC1 expression restores function to and preserves structure of rod and cone photoreceptors in a degenerative model of retinal guanylate cyclase deficiency, further supporting development of an AAV-based vector for treatment of LCA1.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

AAV-Mediated Gene Therapy in the Guanylate Cyclase (RetGC1/RetGC2) Double Knockout Mouse Model of Leber Congenital Amaurosis

et al. 2013

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“…First, clinicopathologic observations reported at that time suggested that LCA1 was associated with degeneration of both cones and rods. 37,38 In addition, because it lacked confounding retGC2 activity, this was the only model in which the effects of retGC1 replacement in rods and the functional efficiency of the AAV-delivered enzyme could be precisely determined. In anticipation of possible clinical trials, a thorough clinical characterization of LCA1 was recently performed.…”

Section: Introductionmentioning

confidence: 99%

Gene Therapy Fully Restores Vision to the All-Cone Nrl^−/−Gucy2e^−/− Mouse Model of Leber Congenital Amaurosis-1

et al. 2015

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Mutations in GUCY2D are the cause of Leber congenital amaurosis type 1 (LCA1). GUCY2D encodes retinal guanylate cyclase-1 (retGC1), a protein expressed exclusively in outer segments of photoreceptors and essential for timely recovery from photoexcitation. Recent clinical data show that, despite a high degree of visual disturbance stemming from a loss of cone function, LCA1 patients retain normal photoreceptor architecture, except for foveal cone outer segment abnormalities and, in some patients, foveal cone loss. These results point to the cone-rich central retina as a target for GUCY2D replacement. LCA1 gene replacement studies thus far have been conducted in rod-dominant models (mouse) or with vectors and organisms lacking clinical translatability. Here we investigate gene replacement in the Nrl Gucy2e-/ -mouse, an all-cone model deficient in retGC1. We show that AAV-retGC1 treatment fully restores cone function, cone-mediated visual behavior, and guanylate cyclase activity, and preserves cones in treated Nrl -/ -Gucy2e -/ -mice over the long-term. A novel finding was that retinal function could be restored to levels above that in Nrl -/ -controls, contrasting results in other models of retGC1 deficiency. We attribute this to increased cyclase activity in treated Nrl -/ -Gucy2e -/ -mice relative to Nrl -/ -controls. Thus, Nrl -/ -Gucy2e -/ -mice possess an expanded dynamic range in ERG response to gene replacement relative to other models. Lastly, we show that a candidate clinical vector, AAV5-GRK1-GUCY2D, when delivered to adult Nrl -/ -Gucy2e -/ -mice, restores retinal function that persists for at least 6 months. Our results provide strong support for clinical application of a gene therapy targeted to the cone-rich, central retina of LCA1 patients.

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“…Reports on the extent of photoreceptor degeneration associated with this disease have been conflicting. 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%

“…First, before its 2013 clinical characterization (Jacobson et al 2013), multiple reports described that both cone/rod structure and cone/rod function were compromised in LCA1 Porto et al 2003), suggesting that the best model of this disease was one in which both photoreceptor subclasses were nonfunctional/degenerative. Although the GC1KO mouse is useful for evaluating therapeutic benefit to cones (Boye et al 2010Mihelec et al 2011), residual rod function and preservation of rod structure in this model complicates the ability to evaluate rod therapy.…”

Section: Gc1/gc2 Double Knockout (Gcdko) Mousementioning

confidence: 99%

Leber Congenital Amaurosis Caused by Mutations in GUCY2D

Boye

2014

Cold Spring Harbor Perspectives in Medicine

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Prenatal Human Ocular Degeneration Occurs in Leber’s Congenital Amaurosis

Cited by 11 publications

References 18 publications

AAV-Mediated Gene Therapy in the Guanylate Cyclase (RetGC1/RetGC2) Double Knockout Mouse Model of Leber Congenital Amaurosis

AAV-Mediated Gene Therapy in the Guanylate Cyclase (RetGC1/RetGC2) Double Knockout Mouse Model of Leber Congenital Amaurosis

Gene Therapy Fully Restores Vision to the All-Cone Nrl^−/−Gucy2e^−/− Mouse Model of Leber Congenital Amaurosis-1

Leber Congenital Amaurosis Caused by Mutations in GUCY2D

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Prenatal Human Ocular Degeneration Occurs in Leber’s Congenital Amaurosis

Cited by 11 publications

References 18 publications

AAV-Mediated Gene Therapy in the Guanylate Cyclase (RetGC1/RetGC2) Double Knockout Mouse Model of Leber Congenital Amaurosis

AAV-Mediated Gene Therapy in the Guanylate Cyclase (RetGC1/RetGC2) Double Knockout Mouse Model of Leber Congenital Amaurosis

Gene Therapy Fully Restores Vision to the All-Cone Nrl−/−Gucy2e−/− Mouse Model of Leber Congenital Amaurosis-1

Leber Congenital Amaurosis Caused by Mutations in GUCY2D

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Gene Therapy Fully Restores Vision to the All-Cone Nrl^−/−Gucy2e^−/− Mouse Model of Leber Congenital Amaurosis-1