Potential CRISPR Base Editing Therapeutic Options in a Sorsby Fundus Dystrophy Patient
TIMP3 mutations are associated with early-onset macular choroidal neovascularisation for which no treatment currently exists. CRISPR base editing, with its ability to irreversibly correct point mutations by chemical modification of nucleobases at DNA level, may be a therapeutic option. We report a b...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-11-01
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| Series: | Genes |
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| Online Access: | https://www.mdpi.com/2073-4425/13/11/2103 |
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| author | Maram E. A. Abdalla Elsayed Maria Kaukonen Peter Kiraly Jasmina Cehajic Kapetanovic Robert E. MacLaren |
| author_facet | Maram E. A. Abdalla Elsayed Maria Kaukonen Peter Kiraly Jasmina Cehajic Kapetanovic Robert E. MacLaren |
| author_sort | Maram E. A. Abdalla Elsayed |
| collection | DOAJ |
| description | TIMP3 mutations are associated with early-onset macular choroidal neovascularisation for which no treatment currently exists. CRISPR base editing, with its ability to irreversibly correct point mutations by chemical modification of nucleobases at DNA level, may be a therapeutic option. We report a bioinformatic analysis of potential therapeutic options in a patient presenting with Sorsby fundus dystrophy. Genetic testing in a 35-year-old gentleman with bilateral macular choroidal neovascularisation revealed the patient to be heterozygous for a TIMP3 variant c.610A>T, p.(Ser204Cys). Using a glycosylase base editor (GBE), another DNA-edit could be introduced that would revert the variant back to wild-type on amino acid level. Alternatively, the mutated residue could be changed to another amino acid that would be better tolerated, and for that, an available ‘NG’-PAM site was found to be available for the SpCas9-based adenine base editor (ABE) that would introduce p.(Ser204Arg). In silico analyses predicted this variant to be non-pathogenic; however, a bystander edit, p.Ile205Thr, would be introduced. This case report highlights the importance of considering genetic testing in young patients with choroidal neovascularisation, particularly within the context of a strong family history of presumed wet age-related macular degeneration, and describes potential therapeutic options. |
| first_indexed | 2024-03-09T18:19:55Z |
| format | Article |
| id | doaj.art-bbd560551e1241a3b35168fccc326f08 |
| institution | Directory Open Access Journal |
| issn | 2073-4425 |
| language | English |
| last_indexed | 2024-03-09T18:19:55Z |
| publishDate | 2022-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Genes |
| spelling | doaj.art-bbd560551e1241a3b35168fccc326f082023-11-24T08:26:21ZengMDPI AGGenes2073-44252022-11-011311210310.3390/genes13112103Potential CRISPR Base Editing Therapeutic Options in a Sorsby Fundus Dystrophy PatientMaram E. A. Abdalla Elsayed0Maria Kaukonen1Peter Kiraly2Jasmina Cehajic Kapetanovic3Robert E. MacLaren4Oxford Eye Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 9DU, UKOxford Eye Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 9DU, UKOxford Eye Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 9DU, UKOxford Eye Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 9DU, UKOxford Eye Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 9DU, UKTIMP3 mutations are associated with early-onset macular choroidal neovascularisation for which no treatment currently exists. CRISPR base editing, with its ability to irreversibly correct point mutations by chemical modification of nucleobases at DNA level, may be a therapeutic option. We report a bioinformatic analysis of potential therapeutic options in a patient presenting with Sorsby fundus dystrophy. Genetic testing in a 35-year-old gentleman with bilateral macular choroidal neovascularisation revealed the patient to be heterozygous for a TIMP3 variant c.610A>T, p.(Ser204Cys). Using a glycosylase base editor (GBE), another DNA-edit could be introduced that would revert the variant back to wild-type on amino acid level. Alternatively, the mutated residue could be changed to another amino acid that would be better tolerated, and for that, an available ‘NG’-PAM site was found to be available for the SpCas9-based adenine base editor (ABE) that would introduce p.(Ser204Arg). In silico analyses predicted this variant to be non-pathogenic; however, a bystander edit, p.Ile205Thr, would be introduced. This case report highlights the importance of considering genetic testing in young patients with choroidal neovascularisation, particularly within the context of a strong family history of presumed wet age-related macular degeneration, and describes potential therapeutic options.https://www.mdpi.com/2073-4425/13/11/2103TIMP3age-related macular degenerationmacular choroidal neovascularisationinherited retinal dystrophygeneticsbase editing |
| spellingShingle | Maram E. A. Abdalla Elsayed Maria Kaukonen Peter Kiraly Jasmina Cehajic Kapetanovic Robert E. MacLaren Potential CRISPR Base Editing Therapeutic Options in a Sorsby Fundus Dystrophy Patient Genes TIMP3 age-related macular degeneration macular choroidal neovascularisation inherited retinal dystrophy genetics base editing |
| title | Potential CRISPR Base Editing Therapeutic Options in a Sorsby Fundus Dystrophy Patient |
| title_full | Potential CRISPR Base Editing Therapeutic Options in a Sorsby Fundus Dystrophy Patient |
| title_fullStr | Potential CRISPR Base Editing Therapeutic Options in a Sorsby Fundus Dystrophy Patient |
| title_full_unstemmed | Potential CRISPR Base Editing Therapeutic Options in a Sorsby Fundus Dystrophy Patient |
| title_short | Potential CRISPR Base Editing Therapeutic Options in a Sorsby Fundus Dystrophy Patient |
| title_sort | potential crispr base editing therapeutic options in a sorsby fundus dystrophy patient |
| topic | TIMP3 age-related macular degeneration macular choroidal neovascularisation inherited retinal dystrophy genetics base editing |
| url | https://www.mdpi.com/2073-4425/13/11/2103 |
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