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Cited by 9CRISPR and Genetic EngineeringRetinal Development and DisordersVirus-based gene therapy research

High-Efficiency CRISPR/Cas9-Mediated Correction of a Homozygous Mutation in Achromatopsia-Patient-Derived iPSCs

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Siles, Laura, Gaudó, Paula, Pomares, Esther·2023·International Journal of Molecular Sciences
DOI 10.3390/ijms24043655PMC PMC9964936
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Abstract

Achromatopsia is an autosomal recessive disorder, in which cone photoreceptors undergo progressive degeneration, causing color blindness and poor visual acuity, among other significant eye affectations. It belongs to a group of inherited retinal dystrophies that currently have no treatment. Although functional improvements have been reported in several ongoing gene therapy studies, more efforts and research should be carried out to enhance their clinical application. In recent years, genome editing has arisen as one of the most promising tools for personalized medicine. In this study, we aimed to correct a homozygous PDE6C pathogenic variant in hiPSCs derived from a patient affected by achromatopsia through CRISPR/Cas9 and TALENs technologies. Here, we demonstrate high efficiency in gene editing by CRISPR/Cas9 but not with TALENs approximation. Despite a few of the edited clones displaying heterozygous on-target defects, the proportion of corrected clones with a potentially restored wild-type PDE6C protein was more than half of the total clones analyzed. In addition, none of them presented off-target aberrations. These results significantly contribute to advances in single-nucleotide gene editing and the development of future strategies for the treatment of achromatopsia.

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  • All predicted off-target sites located within exonic regions or intronic regions in close proximity to exons were analyzed by Sanger sequencing.

    “All predicted off-target sites located within exonic regions or intronic regions in close proximity to exons were analyzed by Sanger sequencing, following the same criteria as previously reported studies [36,40,41].”

    From Precise CRISPR/Cas9 and Cas12 Correction Using Lipoplexes in Retinal Models Derived from Patients with Inherited Retinal Dystrophies (2026) · cites this paper as [41]

    Results §2.5 says the authors Sanger-sequenced all predicted intronic off-targets with three mismatches; none of the predicted off-targets with three mismatches were exonic. Materials and Methods §4.6 likewise describes sequencing intronic sites, but does not identify proximity to exons as a selection criterion. The cited paper therefore supports the intronic sequencing practice, not the stated criterion in full. (LLM, conf=0.86)

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Cited by

Sorted by citations

Authors
Siles, L., Gaudó, P., & Pomares, E.
Affiliations
Instituto de Microcirugía Ocular (ES)
Corresponding author
Pomares, Esther
ORCID
Pomares, Esther
Venue
International Journal of Molecular Sciences
Publisher
MDPI AG
Published
2023-02-11
Volume
24
Issue
4
Pages
3655
ISSN
1422-0067 (ISSN-L)
DOI
10.3390/ijms24043655
PMC
PMC9964936
OpenAlex
W4320493001
Cited by
9
References
3
Citations by year
2026: 3 · 2025: 2 · 2024: 2 · 2023: 2
FWCI
0.80
Type
journal article
Language
en
Open access
Licence
Locations
  • International Journal of Molecular Sciences (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • private donation (Fi-201401, LCF/PR/PR17/11120006)
  • Fundació Bancària“la Caixa” (Fi-201401, LCF/PR/PR17/11120006)
  • Fundació de Recerca de l’Institut de Microcirurgia Ocular de Barcelona, Spain (Fi-201401, LCF/PR/PR17/11120006)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
Keywords
achromatopsia, PDE6C, CRISPR/Cas9, TALEN, induced pluripotent stem cells, genome editing, inherited retinal disease, cone photoreceptor degeneration, off-target effects, homozygous mutation, gene therapy
MeSH terms
Transcription Activator-Like Effector Nucleases, Gene Editing, Color Vision Defects, Humans, Mutation, Induced Pluripotent Stem Cells, CRISPR-Cas Systems

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