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Therapeutic gene correction for Lesch-Nyhan syndrome using CRISPR-mediated base and prime editing
Lesch-Nyhan syndrome (LNS) is inherited as an X-linked recessive genetic disorder caused by mutations in hypoxanthine-guanine phosphoribosyl transferase 1 (HPRT1). Patients with LNS show various clinical phenotypes, including hyperuricemia, gout, devastating behavioral abnormality, intellectual disa...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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American Society of Gene & Cell Therapy
2023
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9996127/ https://www.ncbi.nlm.nih.gov/pubmed/36910714 http://dx.doi.org/10.1016/j.omtn.2023.02.009 |
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author | Jang, Gayoung Shin, Ha Rim Do, Hyo-Sang Kweon, Jiyeon Hwang, Soojin Kim, Soyoung Heo, Sun Hee Kim, Yongsub Lee, Beom Hee |
author_facet | Jang, Gayoung Shin, Ha Rim Do, Hyo-Sang Kweon, Jiyeon Hwang, Soojin Kim, Soyoung Heo, Sun Hee Kim, Yongsub Lee, Beom Hee |
author_sort | Jang, Gayoung |
collection | PubMed |
description | Lesch-Nyhan syndrome (LNS) is inherited as an X-linked recessive genetic disorder caused by mutations in hypoxanthine-guanine phosphoribosyl transferase 1 (HPRT1). Patients with LNS show various clinical phenotypes, including hyperuricemia, gout, devastating behavioral abnormality, intellectual disability, and self-harm. Although uric acid overproduction can be modulated with the xanthine oxidase inhibitor allopurinol, there exists no treatment for behavioral and neurological manifestations of LNS. In the current study, CRISPR-mediated base editors (BEs) and prime editors (PEs) were utilized to generate LNS-associated disease models and correct the disease models for therapeutic approach. Cytosine BEs (CBEs) were used to induce c.430C>T and c.508C>T mutations in HAP1 cells, and then adenine BEs (ABEs) were used to correct these mutations without DNA cleavage. PEs induced a c.333_334ins(A) mutation, identified in a Korean patient with LNS, in HAP1 cells, which was corrected in turn by PEs. Furthermore, improved PEs corrected the same mutation in LNS patient-derived fibroblasts by up to 14% without any unwanted mutations. These results suggest that CRISPR-mediated BEs and PEs would be suggested as a potential therapeutic strategy of this extremely rare, devastating genetic disease. |
format | Online Article Text |
id | pubmed-9996127 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | American Society of Gene & Cell Therapy |
record_format | MEDLINE/PubMed |
spelling | pubmed-99961272023-03-10 Therapeutic gene correction for Lesch-Nyhan syndrome using CRISPR-mediated base and prime editing Jang, Gayoung Shin, Ha Rim Do, Hyo-Sang Kweon, Jiyeon Hwang, Soojin Kim, Soyoung Heo, Sun Hee Kim, Yongsub Lee, Beom Hee Mol Ther Nucleic Acids Original Article Lesch-Nyhan syndrome (LNS) is inherited as an X-linked recessive genetic disorder caused by mutations in hypoxanthine-guanine phosphoribosyl transferase 1 (HPRT1). Patients with LNS show various clinical phenotypes, including hyperuricemia, gout, devastating behavioral abnormality, intellectual disability, and self-harm. Although uric acid overproduction can be modulated with the xanthine oxidase inhibitor allopurinol, there exists no treatment for behavioral and neurological manifestations of LNS. In the current study, CRISPR-mediated base editors (BEs) and prime editors (PEs) were utilized to generate LNS-associated disease models and correct the disease models for therapeutic approach. Cytosine BEs (CBEs) were used to induce c.430C>T and c.508C>T mutations in HAP1 cells, and then adenine BEs (ABEs) were used to correct these mutations without DNA cleavage. PEs induced a c.333_334ins(A) mutation, identified in a Korean patient with LNS, in HAP1 cells, which was corrected in turn by PEs. Furthermore, improved PEs corrected the same mutation in LNS patient-derived fibroblasts by up to 14% without any unwanted mutations. These results suggest that CRISPR-mediated BEs and PEs would be suggested as a potential therapeutic strategy of this extremely rare, devastating genetic disease. American Society of Gene & Cell Therapy 2023-02-14 /pmc/articles/PMC9996127/ /pubmed/36910714 http://dx.doi.org/10.1016/j.omtn.2023.02.009 Text en © 2023 The Author(s) https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Original Article Jang, Gayoung Shin, Ha Rim Do, Hyo-Sang Kweon, Jiyeon Hwang, Soojin Kim, Soyoung Heo, Sun Hee Kim, Yongsub Lee, Beom Hee Therapeutic gene correction for Lesch-Nyhan syndrome using CRISPR-mediated base and prime editing |
title | Therapeutic gene correction for Lesch-Nyhan syndrome using CRISPR-mediated base and prime editing |
title_full | Therapeutic gene correction for Lesch-Nyhan syndrome using CRISPR-mediated base and prime editing |
title_fullStr | Therapeutic gene correction for Lesch-Nyhan syndrome using CRISPR-mediated base and prime editing |
title_full_unstemmed | Therapeutic gene correction for Lesch-Nyhan syndrome using CRISPR-mediated base and prime editing |
title_short | Therapeutic gene correction for Lesch-Nyhan syndrome using CRISPR-mediated base and prime editing |
title_sort | therapeutic gene correction for lesch-nyhan syndrome using crispr-mediated base and prime editing |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9996127/ https://www.ncbi.nlm.nih.gov/pubmed/36910714 http://dx.doi.org/10.1016/j.omtn.2023.02.009 |
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