From Bench to Bed: The Current Genome Editing Therapies for Glaucoma

He, Meihui; Rong, Rong; Ji, Dan; Xia, Xiaobo

doi:10.3389/fcell.2022.879957

Cited by 8 publications

(4 citation statements)

References 110 publications

(98 reference statements)

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“…It is noteworthy, however, that the application of gene editing therapies is still limited because of safety concerns regarding off-target effects and oncogenesis (Ref. 71 ). Still, gene editing research is quickly advancing with more clinical trials underway, which might address these limitations and ease the clinical translation of this technology.…”

Section: Glaucomamentioning

confidence: 99%

AAV-mediated gene therapies for glaucoma and uveitis: are we there yet?

Castro,

Steel,

Layton

2024

Expert Rev. Mol. Med.

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Glaucoma and uveitis are non-vascular ocular diseases which are among the leading causes of blindness and visual loss. These conditions have distinct characteristics and mechanisms but share a multifactorial and complex nature, making their management challenging and burdensome for patients and clinicians. Furthermore, the lack of symptoms in the early stages of glaucoma and the diverse aetiology of uveitis hinder timely and accurate diagnoses, which are a cause of poor visual outcomes under both conditions. Although current treatment is effective in most cases, it is often associated with low patient adherence and adverse events, which directly impact the overall therapeutic success. Therefore, long-lasting alternatives with improved safety and efficacy are needed. Gene therapy, particularly utilising adeno-associated virus (AAV) vectors, has emerged as a promising approach to address unmet needs in these diseases. Engineered capsids with enhanced tropism and lower immunogenicity have been proposed, along with constructs designed for targeted and controlled expression. Additionally, several pathways implicated in the pathogenesis of these conditions have been targeted with single or multigene expression cassettes, gene editing and silencing approaches. This review discusses strategies employed in AAV-based gene therapies for glaucoma and non-infectious uveitis and provides an overview of current progress and future directions.

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Section: Glaucomamentioning

confidence: 99%

AAV-mediated gene therapies for glaucoma and uveitis: are we there yet?

Castro,

Steel,

Layton

2024

Expert Rev. Mol. Med.

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“…Among available viral vector systems, the adeno-associated virus (AAV) vector has emerged as a preferable tool for targeting RGCs. The ability of AAV vectors to transduce distinct retinal cell types depends on the virus serotype, the route of vector administration, and the age of the host [76,77]. DNA-and RNA-based technologies are also of great benefit for modifying gene expression.…”

Section: Therapeutic Approaches In Glaucoma Researchmentioning

confidence: 99%

“…DNA-and RNA-based technologies are also of great benefit for modifying gene expression. DNA plasmids or oligonucleotides are easy to work with and can be readily injected into eyes, but they are not easily taken up by cells, which may result in just slight protection of axotomized RGCs owing to limited transfection efficiency [77]. Small interference RNA (siRNA) has been successfully delivered to RGCs via injection into the superior colliculus; however, the highly invasive nature of this approach limits its clinical application [78].…”

Section: Therapeutic Approaches In Glaucoma Researchmentioning

confidence: 99%

Revisiting Retinal Degeneration Hallmarks: Insights from Molecular Markers and Therapy Perspectives

Rosa,

Disner,

Pinto

et al. 2023

IJMS

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Visual impairment and blindness are a growing public health problem as they reduce the life quality of millions of people. The management and treatment of these diseases represent scientific and therapeutic challenges because different cellular and molecular actors involved in the pathophysiology are still being identified. Visual system components, particularly retinal cells, are extremely sensitive to genetic or metabolic alterations, and immune responses activated by local insults contribute to biological events, culminating in vision loss and irreversible blindness. Several ocular diseases are linked to retinal cell loss, and some of them, such as retinitis pigmentosa, age-related macular degeneration, glaucoma, and diabetic retinopathy, are characterized by pathophysiological hallmarks that represent possibilities to study and develop novel treatments for retinal cell degeneration. Here, we present a compilation of revisited information on retinal degeneration, including pathophysiological and molecular features and biochemical hallmarks, and possible research directions for novel treatments to assist as a guide for innovative research. The knowledge expansion upon the mechanistic bases of the pathobiology of eye diseases, including information on complex interactions of genetic predisposition, chronic inflammation, and environmental and aging-related factors, will prompt the identification of new therapeutic strategies.

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“…Gonioscopy can reveal that the angle has an immature appearance of arrested development with a high flat iris insertion, with peripheral scalloping and circumferential iris vessels [ 9 ]. Elevated IOP can consequently cause loss of retinal ganglion cells (RGCs) and a progressive optic neuropathy [ 4 , 10 – 12 ], however optic disc cupping can be reversible with treatment [ 13 ]. Globally, the incidence rate of PCG is approximately 1–80 cases per 100,000 live births [ 10 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

Increasing the diagnostic yield of childhood glaucoma cases recruited into the 100,000 Genomes Project

Al-Saei,

Malka,

Owen

et al. 2024

BMC Genomics

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Childhood glaucoma (CG) encompasses a heterogeneous group of genetic eye disorders that is responsible for approximately 5% of childhood blindness worldwide. Understanding the molecular aetiology is key to improving diagnosis, prognosis and unlocking the potential for optimising clinical management. In this study, we investigated 86 CG cases from 78 unrelated families of diverse ethnic backgrounds, recruited into the Genomics England 100,000 Genomes Project (GE100KGP) rare disease cohort, to improve the genetic diagnostic yield. Using the Genomics England/Genomic Medicine Centres (GE/GMC) diagnostic pipeline, 13 unrelated families were solved (13/78, 17%). Further interrogation using an expanded gene panel yielded a molecular diagnosis in 7 more unrelated families (7/78, 9%). This analysis effectively raises the total number of solved CG families in the GE100KGP to 26% (20/78 families). Twenty-five percent (5/20) of the solved families had primary congenital glaucoma (PCG), while 75% (15/20) had secondary CG; 53% of this group had non-acquired ocular anomalies (including iris hypoplasia, megalocornea, ectopia pupillae, retinal dystrophy, and refractive errors) and 47% had non-acquired systemic diseases such as cardiac abnormalities, hearing impairment, and developmental delay. CYP1B1 was the most frequently implicated gene, accounting for 55% (11/20) of the solved families. We identified two novel likely pathogenic variants in the TEK gene, in addition to one novel pathogenic copy number variant (CNV) in FOXC1. Variants that passed undetected in the GE100KGP diagnostic pipeline were likely due to limitations of the tiering process, the use of smaller gene panels during analysis, and the prioritisation of coding SNVs and indels over larger structural variants, CNVs, and non-coding variants.

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From Bench to Bed: The Current Genome Editing Therapies for Glaucoma

Cited by 8 publications

References 110 publications

AAV-mediated gene therapies for glaucoma and uveitis: are we there yet?

AAV-mediated gene therapies for glaucoma and uveitis: are we there yet?

Revisiting Retinal Degeneration Hallmarks: Insights from Molecular Markers and Therapy Perspectives

Increasing the diagnostic yield of childhood glaucoma cases recruited into the 100,000 Genomes Project

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