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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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Autores principales: Elsayed, Maram E. A. Abdalla, Kaukonen, Maria, Kiraly, Peter, Kapetanovic, Jasmina Cehajic, MacLaren, Robert E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9690532/
https://www.ncbi.nlm.nih.gov/pubmed/36421778
http://dx.doi.org/10.3390/genes13112103
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author Elsayed, Maram E. A. Abdalla
Kaukonen, Maria
Kiraly, Peter
Kapetanovic, Jasmina Cehajic
MacLaren, Robert E.
author_facet Elsayed, Maram E. A. Abdalla
Kaukonen, Maria
Kiraly, Peter
Kapetanovic, Jasmina Cehajic
MacLaren, Robert E.
author_sort Elsayed, Maram E. A. Abdalla
collection PubMed
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.
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spelling pubmed-96905322022-11-25 Potential CRISPR Base Editing Therapeutic Options in a Sorsby Fundus Dystrophy Patient Elsayed, Maram E. A. Abdalla Kaukonen, Maria Kiraly, Peter Kapetanovic, Jasmina Cehajic MacLaren, Robert E. Genes (Basel) Article 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. MDPI 2022-11-12 /pmc/articles/PMC9690532/ /pubmed/36421778 http://dx.doi.org/10.3390/genes13112103 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Elsayed, Maram E. A. Abdalla
Kaukonen, Maria
Kiraly, Peter
Kapetanovic, Jasmina Cehajic
MacLaren, Robert E.
Potential CRISPR Base Editing Therapeutic Options in a Sorsby Fundus Dystrophy Patient
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 Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9690532/
https://www.ncbi.nlm.nih.gov/pubmed/36421778
http://dx.doi.org/10.3390/genes13112103
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