Rescue of the disease-associated phenotype in CRISPR-corrected hiPSCs as a therapeutic approach for inherited retinal dystrophies
Inherited retinal dystrophies (IRDs), such as retinitis pigmentosa and Stargardt disease, are a group of rare diseases caused by mutations in more than 300 genes that currently have no treatment in most cases. They commonly trigger blindness and other ocular affectations due to retinal cell degenera...
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Elsevier
2025-03-01
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| Series: | Molecular Therapy: Nucleic Acids |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2162253125000368 |
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| author | Laura Siles Esther Pomares |
| author_facet | Laura Siles Esther Pomares |
| author_sort | Laura Siles |
| collection | DOAJ |
| description | Inherited retinal dystrophies (IRDs), such as retinitis pigmentosa and Stargardt disease, are a group of rare diseases caused by mutations in more than 300 genes that currently have no treatment in most cases. They commonly trigger blindness and other ocular affectations due to retinal cell degeneration. Gene editing has emerged as a promising and powerful strategy for the development of IRD therapies, allowing the permanent correction of pathogenic variants. Using clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 and transcription activator-like effector nucleases (TALEN) gene-editing tools, we precisely corrected seven hiPS cell lines derived from IRD patients carrying mutations in ABCA4, BEST1, PDE6A, PDE6C, RHO, or USH2A. Homozygous mutations and point insertions/deletions resulted in the highest homology-directed repair efficiencies, with at least half of the clones repaired properly without off-target effects. Strikingly, correction of a heterozygous pathogenic variant was achieved using the wild-type allele of the patient as the template for DNA repair. These results suggest the unexpected potential application of CRISPR as a donor template-free strategy for single-nucleotide modifications. Additionally, the corrected clones exhibited a reversion of the disease-associated phenotype in retinal cellular models. These data strengthen the study and application of gene editing-based approaches for IRD treatment. |
| format | Article |
| id | doaj-art-c0a768f6149f43c4abc9a217bd14d9fa |
| institution | DOAJ |
| issn | 2162-2531 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Nucleic Acids |
| spelling | doaj-art-c0a768f6149f43c4abc9a217bd14d9fa2025-08-20T03:11:06ZengElsevierMolecular Therapy: Nucleic Acids2162-25312025-03-0136110248210.1016/j.omtn.2025.102482Rescue of the disease-associated phenotype in CRISPR-corrected hiPSCs as a therapeutic approach for inherited retinal dystrophiesLaura Siles0Esther Pomares1Departament de Genètica, Institut de Microcirurgia Ocular, IMO Grupo Miranza, 08035 Barcelona, SpainDepartament de Genètica, Institut de Microcirurgia Ocular, IMO Grupo Miranza, 08035 Barcelona, Spain; Corresponding author: Esther Pomares, Departament de Genètica, Institut de Microcirurgia Ocular, IMO Grupo Miranza, 08035 Barcelona, Spain.Inherited retinal dystrophies (IRDs), such as retinitis pigmentosa and Stargardt disease, are a group of rare diseases caused by mutations in more than 300 genes that currently have no treatment in most cases. They commonly trigger blindness and other ocular affectations due to retinal cell degeneration. Gene editing has emerged as a promising and powerful strategy for the development of IRD therapies, allowing the permanent correction of pathogenic variants. Using clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 and transcription activator-like effector nucleases (TALEN) gene-editing tools, we precisely corrected seven hiPS cell lines derived from IRD patients carrying mutations in ABCA4, BEST1, PDE6A, PDE6C, RHO, or USH2A. Homozygous mutations and point insertions/deletions resulted in the highest homology-directed repair efficiencies, with at least half of the clones repaired properly without off-target effects. Strikingly, correction of a heterozygous pathogenic variant was achieved using the wild-type allele of the patient as the template for DNA repair. These results suggest the unexpected potential application of CRISPR as a donor template-free strategy for single-nucleotide modifications. Additionally, the corrected clones exhibited a reversion of the disease-associated phenotype in retinal cellular models. These data strengthen the study and application of gene editing-based approaches for IRD treatment.http://www.sciencedirect.com/science/article/pii/S2162253125000368MT: RNA/DNA Editinginherited retinal dystrophiesgene editingsister chromatidCRISPRTALEN |
| spellingShingle | Laura Siles Esther Pomares Rescue of the disease-associated phenotype in CRISPR-corrected hiPSCs as a therapeutic approach for inherited retinal dystrophies Molecular Therapy: Nucleic Acids MT: RNA/DNA Editing inherited retinal dystrophies gene editing sister chromatid CRISPR TALEN |
| title | Rescue of the disease-associated phenotype in CRISPR-corrected hiPSCs as a therapeutic approach for inherited retinal dystrophies |
| title_full | Rescue of the disease-associated phenotype in CRISPR-corrected hiPSCs as a therapeutic approach for inherited retinal dystrophies |
| title_fullStr | Rescue of the disease-associated phenotype in CRISPR-corrected hiPSCs as a therapeutic approach for inherited retinal dystrophies |
| title_full_unstemmed | Rescue of the disease-associated phenotype in CRISPR-corrected hiPSCs as a therapeutic approach for inherited retinal dystrophies |
| title_short | Rescue of the disease-associated phenotype in CRISPR-corrected hiPSCs as a therapeutic approach for inherited retinal dystrophies |
| title_sort | rescue of the disease associated phenotype in crispr corrected hipscs as a therapeutic approach for inherited retinal dystrophies |
| topic | MT: RNA/DNA Editing inherited retinal dystrophies gene editing sister chromatid CRISPR TALEN |
| url | http://www.sciencedirect.com/science/article/pii/S2162253125000368 |
| work_keys_str_mv | AT laurasiles rescueofthediseaseassociatedphenotypeincrisprcorrectedhipscsasatherapeuticapproachforinheritedretinaldystrophies AT estherpomares rescueofthediseaseassociatedphenotypeincrisprcorrectedhipscsasatherapeuticapproachforinheritedretinaldystrophies |