Can genome editing transform ocular disease treatment?

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In a recent review published in Experimental & Molecular Medicine, researchers reviewed existing data on the discovery and development of gene-editing technologies and their applications in managing ocular diseases.

Study: Genome editing in the treatment of ocular diseases. Image Credit: GarnaZarina/Shutterstock.comStudy: Genome editing in the treatment of ocular diseases. Image Credit: GarnaZarina/


Gene therapy advances offer a new therapeutic approach for various ocular diseases with genetic or nongenetic etiologies.

The human eye's distinct physiological and anatomical characteristics enable the efficient administration of genetic engineering equipment.

In contrast, advancements in non-invasive imaging and electroretinography enable real-time safety and efficacy monitoring.

About the review

In the present review, researchers presented gene editing methods and their applications in managing ocular diseases.

Introduction to gene editing

Gene-editing technology has become a powerful tool to precisely modify deoxyribonucleic acid (DNA) sequences in living organisms, providing novel avenues for treating various ocular diseases.

The clustered, regularly interspaced short palindromic repeats (CRISPR)-related protein 9 (CRISPR-Cas9) genetic system is the most widely used, given its precision, versatility, and simplicity.

CRISPR-Cas9 comprises single-guide ribonucleic acid (sgRNA), which targets a particular sequence of DNA and Cas9, and cuts the DNA molecule at the target location, giving rise to double-stranded breakages (DSBs). The endogenous machinery uses either of the two mechanisms for break repair: homology-directed repair (HDR) or non-homologous end joining (NHEJ).

Newer technologies like prime and base editors have increased precision and efficacy. Base editors allow accurate nucleotide conversion without causing double-strand breakages within the target deoxyribonucleic acid.

Prime editors provide a robust genome-editing tool for introducing a wide variety of desired changes, including targeted deletions, insertions, and point amino acid substitutions, without double-strand breaks or donor deoxyribonucleic acid templates.

Adenine and cytosine base editors (ABEs and CBEs) make precise nucleotide modifications without causing double-strand breaks. Cytosine base editing results in a cytosine (C)-guanosine (G) to thymine (T)-adenine (A) conversion, while adenine base editing leads to an adenine-thymine to guanosine-cytosine conversion.

In recent years, the fourth-generation CBE (BE4) and phage-assisted non-continuous evolution (PANCE), and continuous evolution (PACE) methods have been applied to improve the efficiency and compatibility of the original ABEs.

Prime-type editors (PEs) use Cas9 nickase (nCas) combined with reverse transcriptase to introduce novel DNA sequences at the targeted locus without causing double-strand breaks.

PE guide RNA (PegRNA), a single-guide RNA comprising the sequence template for reverse transcription, guides nucleotide generation at the targeted locus.

Unlike base editors, prime editors can perform several edits, including insertions, deletions, and all 12 types of single-base substitutions, without relying on DSBs or donor DNA templates and have lower risks of off-target effects and bystander editing than base editing.

Applications of gene editing in managing ocular diseases

The eye is an ideal candidate for gene therapy and genome-editing approaches due to its small size, immune privilege status, compartmentalization, and easy accessibility.

Luxturna, a United States Food and Drug Administration (US FDA)-approved gene therapy treatment for Leber congenital amaurosis (LCA), uses adeno-associated virus (AAV) vectors to deliver a functional RPE65 gene into the retinal pigment epithelium.

Advances in genome-editing technologies, such as CRISPR/Cas9, prime and base editors, hold promise for addressing a broader range of inherited and nongenetic ocular disorders. A recent study demonstrated the potential of herpes simplex virus-1 (HSV-1)-erasing lentiviral particles (HELP) to effectively target two genes of HSV-1 essential for viral replication, UL8, and UL29.

HELP effectively eliminated HSV-1 in human corneal tissue culture without off-target effects, indicating its potential as an effective antiviral therapy for herpetic stromal keratitis (HSK).

CRISPR-Cas9-mediated gene editing can potentially target the collagen type VIII alpha two chain (Col8a2) mutation in the early-onset Fuchs endothelial corneal dystrophy (FECD) mouse model, potentially circumventing the need for transplantation.

A study employed CRISPR-Cas9 and a 100-nucleotide donor template to correct the R124H mutation in primary corneal keratocytes from a granular corneal dystrophy type 2 (GCD2) patient, demonstrating its effectiveness in treating myocilin (MYOC) mutation-related primary open-angle glaucoma (POAG) in patients.

Versatile gene therapy for POAG has been developed, reducing intraocular pressure (IOP) by decreasing aqueous humor production. The CRISPR interference system could also lower TGFβ2 levels and ameliorate ocular hypertension in POAG patients.

Genome-editing therapy with CRISPR-Cas9 has emerged as an alternative approach to treat chronic retinal and choroidal vascular disease, with an antiangiogenic effect comparable to that of aflibercept.

Genome editing has also been used in treating Stargardt disease type 1 (SGTD1), which is caused by deep-intronic variants (DIVs) in the adenine triphosphate binding cassette subfamily A member 4 (ABCA4) gene.

Suprachoroidal injections have been developed as a novel modality for delivering genome-editing tools to the retinal pigment epithelium and retina.


Based on the review findings, genome editing has the potential to revolutionize ocular treatment by allowing precise manipulation of genetic elements. It has been proven versatile in addressing ocular diseases with diverse genetic or nongenetic backgrounds.

The unique characteristics of the eye, immune-privileged status, small size, and compartmentalized structure facilitate efficient delivery and maintenance of genome-edited components without eliciting excessive immune responses.

Regulatory approval is crucial for standardized procedures, comprehensive safety assessments, and long-term follow-up studies.

Journal reference:
Pooja Toshniwal Paharia

Written by

Pooja Toshniwal Paharia

Dr. based clinical-radiological diagnosis and management of oral lesions and conditions and associated maxillofacial disorders.


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