Clinical and Therapeutic Evaluation of the Ten Most Prevalent <i>CRB1</i> Mutations
Mutations in the <i>Crumbs homolog 1</i> (<i>CRB1</i>) gene lead to severe inherited retinal dystrophies (IRDs), accounting for nearly 80,000 cases worldwide. To date, there is no therapeutic option for patients suffering from <i>CRB1</i>-IRDs. Therefore, it is of...
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| Format: | Article |
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MDPI AG
2023-01-01
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| Series: | Biomedicines |
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| Online Access: | https://www.mdpi.com/2227-9059/11/2/385 |
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| author | Bruna Lopes da Costa Masha Kolesnikova Sarah R. Levi Thiago Cabral Stephen H. Tsang Irene H. Maumenee Peter M. J. Quinn |
| author_facet | Bruna Lopes da Costa Masha Kolesnikova Sarah R. Levi Thiago Cabral Stephen H. Tsang Irene H. Maumenee Peter M. J. Quinn |
| author_sort | Bruna Lopes da Costa |
| collection | DOAJ |
| description | Mutations in the <i>Crumbs homolog 1</i> (<i>CRB1</i>) gene lead to severe inherited retinal dystrophies (IRDs), accounting for nearly 80,000 cases worldwide. To date, there is no therapeutic option for patients suffering from <i>CRB1</i>-IRDs. Therefore, it is of great interest to evaluate gene editing strategies capable of correcting <i>CRB1</i> mutations. A retrospective chart review was conducted on ten patients demonstrating one or two of the top ten most prevalent <i>CRB1</i> mutations and receiving care at Columbia University Irving Medical Center, New York, NY, USA. Patient phenotypes were consistent with previously published data for individual <i>CRB1</i> mutations. To identify the optimal gene editing strategy for these ten mutations, base and prime editing designs were evaluated. For base editing, we adopted the use of a near-PAMless Cas9 (SpRY Cas9), whereas for prime editing, we evaluated the canonical NGG and NGA prime editors. We demonstrate that for the correction of c.2843G>A, p.(Cys948Tyr), the most prevalent <i>CRB1</i> mutation, base editing has the potential to generate harmful bystanders. Prime editing, however, avoids these bystanders, highlighting its future potential to halt <i>CRB1</i>-mediated disease progression. Additional studies investigating prime editing for <i>CRB1</i>-IRDs are needed, as well as a thorough analysis of prime editing’s application, efficiency, and safety in the retina. |
| first_indexed | 2024-03-11T09:07:20Z |
| format | Article |
| id | doaj.art-c78a05fb03eb44b2b459a573ecf7b9e7 |
| institution | Directory Open Access Journal |
| issn | 2227-9059 |
| language | English |
| last_indexed | 2024-03-11T09:07:20Z |
| publishDate | 2023-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomedicines |
| spelling | doaj.art-c78a05fb03eb44b2b459a573ecf7b9e72023-11-16T19:17:27ZengMDPI AGBiomedicines2227-90592023-01-0111238510.3390/biomedicines11020385Clinical and Therapeutic Evaluation of the Ten Most Prevalent <i>CRB1</i> MutationsBruna Lopes da Costa0Masha Kolesnikova1Sarah R. Levi2Thiago Cabral3Stephen H. Tsang4Irene H. Maumenee5Peter M. J. Quinn6Department of Biomedical Engineering, Columbia University, New York, NY 10027, USAEdward S. Harkness Eye Institute, Department of Ophthalmology, Columbia University Irving Medical Center/New York-Presbyterian Hospital, New York, NY 10032, USAEdward S. Harkness Eye Institute, Department of Ophthalmology, Columbia University Irving Medical Center/New York-Presbyterian Hospital, New York, NY 10032, USADepartment of Ophthalmology, Federal University of São Paulo, São Paulo 04021-001, SP, BrazilDepartment of Biomedical Engineering, Columbia University, New York, NY 10027, USAEdward S. Harkness Eye Institute, Department of Ophthalmology, Columbia University Irving Medical Center/New York-Presbyterian Hospital, New York, NY 10032, USAEdward S. Harkness Eye Institute, Department of Ophthalmology, Columbia University Irving Medical Center/New York-Presbyterian Hospital, New York, NY 10032, USAMutations in the <i>Crumbs homolog 1</i> (<i>CRB1</i>) gene lead to severe inherited retinal dystrophies (IRDs), accounting for nearly 80,000 cases worldwide. To date, there is no therapeutic option for patients suffering from <i>CRB1</i>-IRDs. Therefore, it is of great interest to evaluate gene editing strategies capable of correcting <i>CRB1</i> mutations. A retrospective chart review was conducted on ten patients demonstrating one or two of the top ten most prevalent <i>CRB1</i> mutations and receiving care at Columbia University Irving Medical Center, New York, NY, USA. Patient phenotypes were consistent with previously published data for individual <i>CRB1</i> mutations. To identify the optimal gene editing strategy for these ten mutations, base and prime editing designs were evaluated. For base editing, we adopted the use of a near-PAMless Cas9 (SpRY Cas9), whereas for prime editing, we evaluated the canonical NGG and NGA prime editors. We demonstrate that for the correction of c.2843G>A, p.(Cys948Tyr), the most prevalent <i>CRB1</i> mutation, base editing has the potential to generate harmful bystanders. Prime editing, however, avoids these bystanders, highlighting its future potential to halt <i>CRB1</i>-mediated disease progression. Additional studies investigating prime editing for <i>CRB1</i>-IRDs are needed, as well as a thorough analysis of prime editing’s application, efficiency, and safety in the retina.https://www.mdpi.com/2227-9059/11/2/385prime editingbase editingCRISPR<i>Crumbs homolog 1</i> (<i>CRB1</i>)inherited retinal disease (IRD)maculopathy |
| spellingShingle | Bruna Lopes da Costa Masha Kolesnikova Sarah R. Levi Thiago Cabral Stephen H. Tsang Irene H. Maumenee Peter M. J. Quinn Clinical and Therapeutic Evaluation of the Ten Most Prevalent <i>CRB1</i> Mutations Biomedicines prime editing base editing CRISPR <i>Crumbs homolog 1</i> (<i>CRB1</i>) inherited retinal disease (IRD) maculopathy |
| title | Clinical and Therapeutic Evaluation of the Ten Most Prevalent <i>CRB1</i> Mutations |
| title_full | Clinical and Therapeutic Evaluation of the Ten Most Prevalent <i>CRB1</i> Mutations |
| title_fullStr | Clinical and Therapeutic Evaluation of the Ten Most Prevalent <i>CRB1</i> Mutations |
| title_full_unstemmed | Clinical and Therapeutic Evaluation of the Ten Most Prevalent <i>CRB1</i> Mutations |
| title_short | Clinical and Therapeutic Evaluation of the Ten Most Prevalent <i>CRB1</i> Mutations |
| title_sort | clinical and therapeutic evaluation of the ten most prevalent i crb1 i mutations |
| topic | prime editing base editing CRISPR <i>Crumbs homolog 1</i> (<i>CRB1</i>) inherited retinal disease (IRD) maculopathy |
| url | https://www.mdpi.com/2227-9059/11/2/385 |
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