The Enigma of CRB1 and CRB1 Retinopathies

Ray, Thomas A.; Cochran, Kelly; Kay, Jeremy N.

doi:10.1007/978-3-030-27378-1_41

Cited by 8 publications

(12 citation statements)

References 27 publications

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“… 10 CRB1 is located in the cell membrane of Müller cells and has a role in protein scaffold. 11 LRAT and RPE65 are located in retinal pigment epithelium (RPE) cells and are involved in the visual cycle. 12 The retinal location of the proteins encoded by the genes that will be discussed in this review are depicted in figure 1 .…”

Section: Introductionmentioning

confidence: 99%

Leber congenital amaurosis/early-onset severe retinal dystrophy: current management and clinical trials

et al. 2021

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Leber congenital amaurosis (LCA) is a severe congenital/early-onset retinal dystrophy. Given its monogenic nature and the immunological and anatomical privileges of the eye, LCA has been particularly targeted by cutting-edge research. In this review, we describe the current management of LCA, and highlight the clinical trials that are on-going and planned. RPE65-related LCA pivotal trials, which culminated in the first Food and Drug Administration-approved and European Medicines Agency-approved ocular gene therapy, have paved the way for a new era of genetic treatments in ophthalmology. At present, multiple clinical trials are available worldwide applying different techniques, aiming to achieve better outcomes and include more genes and variants. Genetic therapy is not only implementing gene supplementation by the use of adeno-associated viral vectors, but also clustered regularly interspaced short palindromic repeats (CRISPR)-mediated gene editing and post-transcriptional regulation through antisense oligonucleotides. Pharmacological approaches intending to decrease photoreceptor degeneration by supplementing 11-cis-retinal and cell therapy’s aim to replace the retinal pigment epithelium, providing a trophic and metabolic retinal structure, are also under investigation. Furthermore, optoelectric devices and optogenetics are also an option for patients with residual visual pathway. After more than 10 years since the first patient with LCA received gene therapy, we also discuss future challenges, such as the overlap between different techniques and the long-term durability of efficacy. The next 5 years are likely to be key to whether genetic therapies will achieve their full promise, and whether stem cell/cellular therapies will break through into clinical trial evaluation.

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Section: Introductionmentioning

confidence: 99%

Leber congenital amaurosis/early-onset severe retinal dystrophy: current management and clinical trials

et al. 2021

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“…Most forms of CRB1 retinal disease are progressive in humans [1–6]. To examine whether progressive changes occurred with age in the modifier strains, histological analysis was repeated at 12 months of age (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Inherited retinal dystrophies associated with variants of the apicobasal polarity gene CRB1 exhibit a perplexing diversity of disease phenotypes (reviewed in [1][2][3][4][5][6]), including Leber congenital amaurosis (LCA8, MIM 613835), early-onset rod-cone dystrophy, juvenile-or adultonset retinitis pigmentosa (RP) with or without paraarteriolar preservation of the retinal pigment epithelium (RP12, MIM 600105), cone-rod dystrophy, RP with Coats-like exudative vasculopathy (retinal telangiectasia), hypermetropia, keratoconus, foveal retinoschisis and cystic or retinoschisis-like maculopathy and macular dystrophy, and pigmented paravenous chorioretinal atrophy (PPCRA, MIM 172870). This variability in disease onset, progression, severity, topography, and specific pathological features makes it difficult to advise patients about therapeutic options and key quality of life issues, and to identify suitable patients for participation in prospective clinical trials [7].…”

Section: Introductionmentioning

confidence: 99%

“…Alleles may differ in their effect on protein levels, stability, or function, and variants affecting specific protein domains might be associated with distinct CRB1-disease subtypes. Although most efforts to establish genotype-phenotype correlations have met with limited success to date [1][2][3][4][5][6], some recent clinical studies indicate potential correlations [7], [24], [25]. The correlation of disease-causing missense substitutions in the extracellular domains of Drosophila Crb with variable cellular and retinal degeneration phenotypes [26] and the recent identification of a novel photoreceptor-specific isoform, CRB1-B, in human and mouse retinas [21], may provide new perspectives for understanding these allele-specific effects.…”

Section: Introductionmentioning

confidence: 99%

“…For example, mutations in genes encoding proteins that may directly or indirectly interact with CRB1 might mediate different pathogenic effects. In support of this hypothesis, distinct and variable disease phenotypes have been observed among individuals with identical CRB1 alleles, suggesting the existence of genetic modifiers [2][3][4], [6], [7], [27][28][29].…”

Section: Introductionmentioning

confidence: 99%

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Identification of Arhgef12 and Prkci as Genetic Modifiers of Retinal Dysplasia in the Crb1^rd8 Mouse Model

Weatherly

Collin

Charette

et al. 2021

Preprint

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Mutations in the apicobasal polarity gene CRB1 lead to diverse retinal diseases, such as Leber congenital amaurosis, cone-rod dystrophy, retinitis pigmentosa (with and without Coats-like vasculopathy), foveal retinoschisis, macular dystrophy, and pigmented paravenous chorioretinal atrophy. Limited correlation between disease phenotypes and CRB1 alleles, and evidence that patients sharing the same alleles often present with different disease features, suggest that genetic modifiers contribute to clinical variation. Similarly, the retinal phenotype of mice bearing the Crb1 retinal degeneration 8 (rd8) allele varies with genetic background. Here, we initiated a sensitized chemical mutagenesis screen in B6.Cg-Crb1rd8/Pjn, a strain with a mild clinical presentation, to identify genetic modifiers that cause a more severe disease phenotype. Two models from this screen, Tvrm266 and Tvrm323, exhibited increased retinal dysplasia. Genetic mapping with high-throughput exome and candidate-gene sequencing identified causative mutations in Arhgef12 and Prkci, respectively. Epistasis analysis of both strains indicated that the increased dysplastic phenotype required homozygosity of the Crb1rd8 allele. Retinal dysplastic lesions in Tvrm266 mice were smaller and caused less photoreceptor degeneration than those in Tvrm323 mice, which developed an early, large diffuse lesion phenotype. In both models at one month of age, Müller glia and microglia mislocalization at dysplastic lesions was similar to that in B6.Cg-Crb1rd8/Pjn mice, while photoreceptor cell mislocalization was more extensive. External limiting membrane disruption was comparable in Tvrm266 and B6.Cg-Crb1rd8/Pjn mice but milder in Tvrm323 mice. Immunohistological analysis of mice at postnatal day 0 indicated a normal distribution of mitotic cells in Tvrm266 and Tvrm323 mice, suggesting normal early development. Aberrant electroretinography responses were observed in both models but functional decline was significant only in Tvrm323 mice. These results identify Arhgef12 and Prkci as modifier genes that differentially shape Crb1-associated retinal disease, which may be relevant to understanding clinical variability and underlying disease mechanisms.

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Imaging endpoints for clinical trials in MacTel type 2

Pauleikhoff

Pauleikhoff²,

Chew

2021

Eye

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The Enigma of CRB1 and CRB1 Retinopathies

Cited by 8 publications

References 27 publications

Leber congenital amaurosis/early-onset severe retinal dystrophy: current management and clinical trials

Leber congenital amaurosis/early-onset severe retinal dystrophy: current management and clinical trials

Identification of Arhgef12 and Prkci as Genetic Modifiers of Retinal Dysplasia in the Crb1^rd8 Mouse Model

Imaging endpoints for clinical trials in MacTel type 2

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The Enigma of CRB1 and CRB1 Retinopathies

Cited by 8 publications

References 27 publications

Leber congenital amaurosis/early-onset severe retinal dystrophy: current management and clinical trials

Leber congenital amaurosis/early-onset severe retinal dystrophy: current management and clinical trials

Identification of Arhgef12 and Prkci as Genetic Modifiers of Retinal Dysplasia in the Crb1rd8 Mouse Model

Imaging endpoints for clinical trials in MacTel type 2

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Product

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Identification of Arhgef12 and Prkci as Genetic Modifiers of Retinal Dysplasia in the Crb1^rd8 Mouse Model