scholarly journals Toward the Treatment of Inherited Diseases of the Retina Using CRISPR-Based Gene Editing

2021 ◽  
Vol 8 ◽  
Author(s):  
Jennifer Hernández-Juárez ◽  
Genaro Rodríguez-Uribe ◽  
Shyamanga Borooah
Keyword(s):  
Gene Editing ◽  
Vision Loss ◽  
Therapeutic Modality ◽  
Leber Congenital Amaurosis ◽  
Inherited Diseases ◽  
Inherited Retinal Dystrophies ◽  
Retinal Dystrophies ◽  
Severe Vision Loss ◽  
Targeted Gene Editing

Inherited retinal dystrophies [IRDs] are a common cause of severe vision loss resulting from pathogenic genetic variants. The eye is an attractive target organ for testing clinical translational approaches in inherited diseases. This has been demonstrated by the approval of the first gene supplementation therapy to treat an autosomal recessive IRD, RPE65-linked Leber congenital amaurosis (type 2), 4 years ago. However, not all diseases are amenable for treatment using gene supplementation therapy, highlighting the need for alternative strategies to overcome the limitations of this supplementation therapeutic modality. Gene editing has become of increasing interest with the discovery of the CRISPR-Cas9 platform. CRISPR-Cas9 offers several advantages over previous gene editing technologies as it facilitates targeted gene editing in an efficient, specific, and modifiable manner. Progress with CRISPR-Cas9 research now means that gene editing is a feasible strategy for the treatment of IRDs. This review will focus on the background of CRISPR-Cas9 and will stress the differences between gene editing using CRISPR-Cas9 and traditional gene supplementation therapy. Additionally, we will review research that has led to the first CRISPR-Cas9 trial for the treatment of CEP290-linked Leber congenital amaurosis (type 10), as well as outline future directions for CRISPR-Cas9 technology in the treatment of IRDs.

Development of a gene-editing approach to restore vision loss in Leber congenital amaurosis type 10

2019 ◽  
Vol 25 (2) ◽  
pp. 229-233 ◽  
Author(s):  
Morgan L. Maeder ◽  
Michael Stefanidakis ◽  
Christopher J. Wilson ◽  
Reshica Baral ◽  
Luis Alberto Barrera ◽  
...  
Keyword(s):  
Gene Editing ◽  
Vision Loss ◽  
Leber Congenital Amaurosis

scholarly journals Expression of Pro-Angiogenic Markers Is Enhanced by Blue Light in Human RPE Cells

Antioxidants ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 1154 ◽  
Author(s):  
Concetta Scimone ◽  
Simona Alibrandi ◽  
Sergio Zaccaria Scalinci ◽  
Edoardo Trovato Battagliola ◽  
Rosalia D’Angelo ◽  
...  
Keyword(s):  
Blue Light ◽  
Vision Loss ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
R Package ◽  
Rpe Cells ◽  
Inherited Retinal Dystrophies ◽  
Retinal Dystrophies ◽  
Increased Risk ◽  
Angiogenic Markers

Inherited retinal dystrophies are characterized by photoreceptor death. Oxidative stress usually occurs, increasing vision loss, and oxidative damage is often reported in retinitis pigmentosa (RP). More than 300 genes have been reported as RP causing. In contrast, choroidal neovascularization (CNV) only occasionally develops in the late stages of RP. We herein study the regulation of RP causative genes that are likely linked to CNV onset under oxidative conditions. We studied how the endogenous adduct N-retinylidene-N-retinylethanolamine (A2E) affects the expression of angiogenic markers in human retinal pigment epithelium (H-RPE) cells and a possible correlation with RP-causing genes. H-RPE cells were exposed to A2E and blue light for 3 and 6h. By transcriptome analysis, genes differentially expressed between A2E-treated cells and untreated ones were detected. The quantification of differential gene expression was performed by the Limma R package. Enrichment pathway analysis by the FunRich tool and gene prioritization by ToppGene allowed us to identify dysregulated genes involved in angiogenesis and linked to RP development. Two RP causative genes, AHR and ROM1, can be associated with an increased risk of CNV development. Genetic analysis of RP patients affected by CNV will confirm this hypothesis.

Retinitis Pigmentosa: Clinical Features, Imaging, and Diagnosis

2021 ◽  
pp. 107-112
Keyword(s):  
Retinitis Pigmentosa ◽  
Vision Loss ◽  
Fundus Autofluorescence ◽  
Visual Field Loss ◽  
Clinical Findings ◽  
Autofluorescence Imaging ◽  
Inherited Retinal Dystrophies ◽  
Retinal Dystrophies ◽  
Central Vision Loss ◽  
Progressive Degeneration

Retinitis pigmentosa (RP) is a heterogeneous group of inherited retinal dystrophies characterized by progressive degeneration of rod and cone photoreceptors. The worldwide prevalence of the disease is 1/4000. The earliest symptom in RP is most commonly night blindness, followed by concentric visual field loss. Central vision loss occurs later in life due to cone dysfunction. Photoreceptor responses measured with an electroretinogram are reduced or undetectable. Optical coherence tomography shows a progressive loss of outer retinal layers and fundus autofluorescence imaging reveals alteration autofluorescence in a characteristic pattern. Mutations in more than 80 different genes have been associated with non-syndromic RP. The heterogeneity of RP makes it challenging to describe the clinical findings. The objective of this review is to provide an overview of the clinical characteristics and diagnosis of RP.

scholarly journals Application of CRISPR Tools for Variant Interpretation and Disease Modeling in Inherited Retinal Dystrophies

Genes ◽  
2020 ◽  
Vol 11 (5) ◽  
pp. 473
Author(s):  
Carla Fuster-García ◽  
Belén García-Bohórquez ◽  
Ana Rodríguez-Muñoz ◽  
José M. Millán ◽  
Gema García-García
Keyword(s):  
Vision Loss ◽  
Disease Modeling ◽  
Functional Studies ◽  
Inherited Retinal Dystrophies ◽  
Retinal Dystrophies ◽  
Molecular Imprint ◽  
Large Rearrangements

Inherited retinal dystrophies are an assorted group of rare diseases that collectively account for the major cause of visual impairment of genetic origin worldwide. Besides clinically, these vision loss disorders present a high genetic and allelic heterogeneity. To date, over 250 genes have been associated to retinal dystrophies with reported causative variants of every nature (nonsense, missense, frameshift, splice-site, large rearrangements, and so forth). Except for a fistful of mutations, most of them are private and affect one or few families, making it a challenge to ratify the newly identified candidate genes or the pathogenicity of dubious variants in disease-associated loci. A recurrent option involves altering the gene in in vitro or in vivo systems to contrast the resulting phenotype and molecular imprint. To validate specific mutations, the process must rely on simulating the precise genetic change, which, until recently, proved to be a difficult endeavor. The rise of the CRISPR/Cas9 technology and its adaptation for genetic engineering now offers a resourceful suite of tools to alleviate the process of functional studies. Here we review the implementation of these RNA-programmable Cas9 nucleases in culture-based and animal models to elucidate the role of novel genes and variants in retinal dystrophies.

Leber Congenital Amaurosis

2021 ◽  
pp. 173-184
Keyword(s):  
Vision Loss ◽  
Retinal Dystrophy ◽  
Clinical Findings ◽  
Diverse Group ◽  
Childhood Onset ◽  
Pupillary Reflex ◽  
Leber Congenital Amaurosis ◽  
Disease Spectrum ◽  
Genetic Types ◽  
Retinal Dystrophies

Leber Congenital Amaurosis (LCA) is one of the most severe forms of hereditary retinal dystrophies described approximately 150 years ago and is a cause of vision loss early in childhood. Although LCA is characterized by wandering nystagmus, poor pupillary reflex (amaurotic pupils), and undetectable or severely abnormal ERG responses in infancy, there is a milder form called Severe Early Childhood Onset Retinal Dystrophy (SECORD) presenting after infancy usually before the age of five. LCA and SECORD describe a clinically and genetically diverse group of diseases. To date, there are 30 different genes determined to cause LCA/SECORD, and these genes are thought to account for approximately 70-80% of the disease spectrum. In recent years, with the initial successful results reported in treatment with gene therapy, LCA/SECORD has become the focus of new researches. This review summarizes the genetic and pathophysiological basis, different genetic types, and their clinical findings, diagnosis, differential diagnosis, and current developments in the treatment of LCA/SECORD.

scholarly journals Development of an optimized AAV2/5 gene therapy vector for Leber congenital amaurosis owing to defects in RPE65

Gene Therapy ◽  
2016 ◽  
Vol 23 (12) ◽  
pp. 857-862 ◽  
Author(s):  
A Georgiadis ◽  
Y Duran ◽  
J Ribeiro ◽  
L Abelleira-Hervas ◽  
S J Robbie ◽  
...  
Keyword(s):  
Retinal Degeneration ◽  
Early Stage ◽  
Rod Photoreceptor ◽  
Adeno Associated Virus ◽  
Gene Therapy Vector ◽  
Leber Congenital Amaurosis ◽  
Inherited Retinal Dystrophies ◽  
Retinal Dystrophies ◽  
Serotype 5 ◽  
Subretinal Injection

Abstract Leber congenital amaurosis is a group of inherited retinal dystrophies that cause severe sight impairment in childhood; RPE65-deficiency causes impaired rod photoreceptor function from birth and progressive impairment of cone photoreceptor function associated with retinal degeneration. In animal models of RPE65 deficiency, subretinal injection of recombinant adeno-associated virus (AAV) 2/2 vectors carrying RPE65 cDNA improves rod photoreceptor function, and intervention at an early stage of disease provides sustained benefit by protecting cone photoreceptors against retinal degeneration. In affected humans, administration of these vectors has resulted to date in relatively modest improvements in photoreceptor function, even when retinal degeneration is comparatively mild, and the duration of benefit is limited by progressive retinal degeneration. We conclude that the demand for RPE65 in humans is not fully met by current vectors, and predict that a more powerful vector will provide more durable benefit. With this aim we have modified the original AAV2/2 vector to generate AAV2/5-OPTIRPE65. The new configuration consists of an AAV vector serotype 5 carrying an optimized hRPE65 promoter and a codon-optimized hRPE65 gene. In mice, AAV2/5-OPTIRPE65 is at least 300-fold more potent than our original AAV2/2 vector.

scholarly journals Gene editing preserves visual function in a mouse model of retinal degeneration

2019 ◽  
Author(s):  
Paola Vagni ◽  
Laura E. Perlini ◽  
Naïg A. L. Chenais ◽  
Tommaso Marchetti ◽  
Martina Parrini ◽  
...  
Keyword(s):  
Mouse Model ◽  
Retinitis Pigmentosa ◽  
Gene Editing ◽  
Point Mutations ◽  
Loss Of Function ◽  
Inherited Retinal Dystrophies ◽  
Retinal Dystrophies ◽  
Function Point

AbstractInherited retinal dystrophies are a large and heterogeneous group of degenerative diseases caused by mutations in various genes. Given the favourable anatomical and immunological characteristics of the eye, gene therapy holds great potential for their treatment. We used a tailored CRISPR/Cas9-based gene editing system to prevent retinal photoreceptor death in the Rd10 mouse model of retinitis pigmentosa. We tested the gene editing toolin vitroand then usedin vivosubretinal electroporation to deliver it to one of the retinas of mouse pups at different stages of photoreceptor differentiation. Three months after gene editing, the treated eye exhibited a higher visual acuity compared to the untreated eye. Moreover, we observed preservation of light-evoked responses both in explanted retinas and in the visual cortex of treated animals. Our study validates a CRISPR/Cas9-based therapy as a valuable new approach for the treatment of retinitis pigmentosa caused by autosomal recessive loss-of-function point mutations.

scholarly journals NRL S50T mutation and the importance of ‘founder effects’ in inherited retinal dystrophies

2000 ◽  
Vol 8 (10) ◽  
pp. 783-787 ◽  
Author(s):  
David AR Bessant ◽  
Annette M Payne ◽  
Catherine Plant ◽  
Alan C Bird ◽  
Anand Swaroop ◽  
...  
Keyword(s):  
Founder Effects ◽  
Inherited Retinal Dystrophies ◽  
Retinal Dystrophies

scholarly journals Bestrophinopathies: perspectives on clinical disease, Bestrophin-1 function and developing therapies

2021 ◽  
Vol 13 ◽  
pp. 251584142199719
Author(s):  
Simranjeet Singh Grewal ◽  
Joseph J. Smith ◽  
Amanda-Jayne F. Carr
Keyword(s):  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Induced Pluripotent Stem Cell ◽  
Underlying Disease ◽  
Incomplete Penetrance ◽  
Inherited Retinal Dystrophies ◽  
Retinal Dystrophies ◽  
High Acuity ◽  
Induced Pluripotent

Bestrophinopathies are a group of clinically distinct inherited retinal dystrophies that typically affect the macular region, an area synonymous with central high acuity vision. This spectrum of disorders is caused by mutations in bestrophin1 ( BEST1), a protein thought to act as a Ca2+-activated Cl- channel in the retinal pigment epithelium (RPE) of the eye. Although bestrophinopathies are rare, over 250 individual pathological mutations have been identified in the BEST1 gene, with many reported to have various clinical expressivity and incomplete penetrance. With no current clinical treatments available for patients with bestrophinopathies, understanding the role of BEST1 in cells and the pathological pathways underlying disease has become a priority. Induced pluripotent stem cell (iPSC) technology is helping to uncover disease mechanisms and develop treatments for RPE diseases, like bestrophinopathies. Here, we provide a comprehensive review of the pathophysiology of bestrophinopathies and highlight how patient-derived iPSC-RPE are being used to test new genomic therapies in vitro.

scholarly journals Carbon Dot Nanoparticles: Exploring the Potential Use for Gene Delivery in Ophthalmic Diseases

Nanomaterials ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. 935
Author(s):  
Manas R. Biswal ◽  
Sofia Bhatia
Keyword(s):  
Gene Delivery ◽  
Therapeutic Option ◽  
Retinal Dystrophy ◽  
Retinal Cells ◽  
Adeno Associated Virus ◽  
Inherited Retinal Dystrophies ◽  
Retinal Dystrophies ◽  
Efficient Gene ◽  
New Type ◽  
Viral Nanoparticles

Ocular gene therapy offers significant potential for preventing retinal dystrophy in patients with inherited retinal dystrophies (IRD). Adeno-associated virus (AAV) based gene transfer is the most common and successful gene delivery approach to the eye. These days, many studies are using non-viral nanoparticles (NPs) as an alternative therapeutic option because of their unique properties and biocompatibility. Here, we discuss the potential of carbon dots (CDs), a new type of nanocarrier for gene delivery to the retinal cells. The unique physicochemical properties of CDs (such as optical, electronic, and catalytic) make them suitable for biosensing, imaging, drug, and gene delivery applications. Efficient gene delivery to the retinal cells using CDs depends on various factors, such as photoluminescence, quantum yield, biocompatibility, size, and shape. In this review, we focused on different approaches used to synthesize CDs, classify CDs, various pathways for the intake of gene-loaded carbon nanoparticles inside the cell, and multiple studies that worked on transferring nucleic acid in the eye using CDs.

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