Examining the Potential of CRISPR Base Editing for Inherited Retinal Diseases


A substantial proportion of patients with inherited retinal disease could be treated with base editing, while therapeutic strategies that focus on common variants could be used to treat a large number of patients with the disease, according to study results.

A substantial proportion of patients with inherited retinal disease (IRD) could be treated with base editing, while therapeutic strategies that focus on common variants could be used to treat a large number of patients with the disease, according to study results published in JAMA Ophthalmology.

“Monogenic inherited retinal degeneration (IRD) is associated with pathogenic variants in genes associated with outer retinal cells, and patients with the disease experience substantial visual loss,” the authors explained. Although adeno-associated viral (AAV) vectors are popular for retinal gene therapy, the genes implicated in common recessively inherited IRDs are not easily treated with AAV because coding sequences often exceed the kilobase capacity of an AAV vector.

However, patients with IRD associated with the retinoid isomerohydrolase gene, RPE65, can now undergo therapy to treat the disease by providing a normal copy of the relevant gene. This method is currently being tested in clinical trials for additional genes.

One potential therapeutic alternative to AAV for these large genes might be the use of gene editing to correct the endogenous genetic sequence, the researchers wrote. “Tools such as the clustered regularly interspaced short palindrome repeats (CRISPR)–associated protein 9 (Cas9) system enable the precise and efficient alteration of nucleic acids.”

Base editors, as a class of gene editing tool that directly create point variants at specified loci in DNA or RNA, are capable of repairing all 4 transition variants in DNA and correcting 2 genomic transition variants in RNA. In addition, unlike other gene correction methods, base editing “does not require the creation of double-stranded breaks in DNA or require a donor template of DNA for repair.”

To determine the proportion of patients with a recessive IRD gene and a pathogenic variant correctable with base editing, and to investigate the prevalence of common target variants, the researchers analyzed data from the Leiden Open Variation Database (LOVD) and from patients with IRD in the United Kingdom and United States.

All individuals with biallelic pathogenic variants of genes associated with IRD identified by the Oxford University Hospitals Medical Genetics Laboratories, the LOVD, and previously published studies between July 2013 and December 2019 were included in the analysis.

The 6 most commonly occurring recessive genes, identified from a total cohort of 6986 patients with IRD, were ABCA4, USH2A, MYO7A, EYS, CEP290, and CDH23, which cumulatively accounted for 35% of all patients with an IRD in the studies.

Overall, 12,369 alleles from LOVD and 179 patients who received diagnoses via the genetic services of the Oxford Hospital Laboratories were included in final analyses.

The researchers found:

  • Editable variants accounted for 53% of all pathogenic variants in the candidate genes contained in LOVD; variants G>A (23.1%) and C>T (18.1%) were the most prevalent types, with fewer T>C (7.0%) and A>G (4.8%) variants
  • The proportion of pathogenic alleles that were editable varied by gene (63.1% of alleles in ABCA4, 62.7% in CDH23, 53.8% in MYO7A, 41.6% in CEP290, 37.3% in USH2A, and 22.2% in EYS)
  • The 5 most common editable pathogenic variants of each gene accounted for a mean (SD) of 19.1% (9.5%) of all pathogenic alleles within each gene
  • 136 of 179 patients (76.0%) had at least 1 editable allele
  • 53 of 107 patients (49.5%) with biallelic pathogenic variants in ABCA4 and 16 of 56 patients (28.6%) with biallelic pathogenic variants in USH2A had 1 of the 5 most common editable alleles

As many patients with IRD are heterozygous, “correction of only one of these alleles should theoretically be sufficient to ameliorate the condition in many cases,” the researchers wrote. Thus, patients were classified as having editable variants if they had at least 1 editable allele.

Guide RNA is required for each individual variant when using base editing strategies. “Although many heterogenous private variants occur in each gene, analysis of the LOVD data indicates that targeting the 5 most common editable variants allows for approximately one-fifth of pathogenic variants in each gene to be targeted,” the authors noted.

Due to data limitations, researchers were unable to take into account sampling biases and differences in the population prevalence of certain variables or genes, marking a limitation to the study. The analyses also only considered definitively pathogenic variants and not variants of unknown significance in IRD.

“The study’s findings support the conclusion that base editing is a promising tool with many potential therapeutic targets, in an increasing array of gene editing techniques that might be developed for patients with inherited retinal disease due to variants in large genes that are not readily treatable with AAV gene therapy,” the researchers concluded.


Fry LE, McClements ME, MacLaren RE. Analysis of pathogenic variants correctable with CRISPR base editing among patients with recessive inherited retinal degeneration. JAMA Ophthalmol. Published online January 28, 2021. doi:10.1001/jamaophthalmol.2020.6418

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