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...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-03-01
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| Series: | Molecular Therapy: Nucleic Acids |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S216225312300029X |
| _version_ | 1811161880943656960 |
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| author | Gayoung Jang Ha Rim Shin Hyo-Sang Do Jiyeon Kweon Soojin Hwang Soyoung Kim Sun Hee Heo Yongsub Kim Beom Hee Lee |
| author_facet | Gayoung Jang Ha Rim Shin Hyo-Sang Do Jiyeon Kweon Soojin Hwang Soyoung Kim Sun Hee Heo Yongsub Kim Beom Hee Lee |
| author_sort | Gayoung Jang |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-04-10T06:22:14Z |
| format | Article |
| id | doaj.art-eb6665589bc6414aa635932aaa3cb0f1 |
| institution | Directory Open Access Journal |
| issn | 2162-2531 |
| language | English |
| last_indexed | 2024-04-10T06:22:14Z |
| publishDate | 2023-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Nucleic Acids |
| spelling | doaj.art-eb6665589bc6414aa635932aaa3cb0f12023-03-02T04:59:16ZengElsevierMolecular Therapy: Nucleic Acids2162-25312023-03-0131586595Therapeutic gene correction for Lesch-Nyhan syndrome using CRISPR-mediated base and prime editingGayoung Jang0Ha Rim Shin1Hyo-Sang Do2Jiyeon Kweon3Soojin Hwang4Soyoung Kim5Sun Hee Heo6Yongsub Kim7Beom Hee Lee8Department of Biomedical Sciences, Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; Stem Cell Immunomodulation Research Center, University of Ulsan College of Medicine, Seoul, Republic of KoreaDepartment of Biomedical Sciences, Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; Stem Cell Immunomodulation Research Center, University of Ulsan College of Medicine, Seoul, Republic of KoreaAsan Institute for Life Sciences, Asan Medical Center, Seoul, Republic of KoreaDepartment of Biomedical Sciences, Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of KoreaDepartment of Pediatrics, Asan Medical Center Children’s Hospital, University of Ulsan College of Medicine, Seoul, Republic of KoreaAsan Institute for Life Sciences, Asan Medical Center, Seoul, Republic of KoreaAsan Institute for Life Sciences, Asan Medical Center, Seoul, Republic of KoreaDepartment of Biomedical Sciences, Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; Stem Cell Immunomodulation Research Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; Corresponding author. Yongsub Kim, Department of Biomedical Sciences, Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.Department of Pediatrics, Asan Medical Center Children’s Hospital, University of Ulsan College of Medicine, Seoul, Republic of Korea; Medical Genetics Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; Corresponding author. Beom Hee Lee, Department of Pediatrics, Asan Medical Center Children’s Hospital, University of Ulsan College of Medicine, Seoul, Republic of Korea.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.http://www.sciencedirect.com/science/article/pii/S216225312300029XMT: RNA/DNA EditingLesch-Nyhan syndromeLNSHPRT1, CRISPR-Casgene correctionbase editing |
| spellingShingle | Gayoung Jang Ha Rim Shin Hyo-Sang Do Jiyeon Kweon Soojin Hwang Soyoung Kim Sun Hee Heo Yongsub Kim Beom Hee Lee Therapeutic gene correction for Lesch-Nyhan syndrome using CRISPR-mediated base and prime editing Molecular Therapy: Nucleic Acids MT: RNA/DNA Editing Lesch-Nyhan syndrome LNS HPRT1, CRISPR-Cas gene correction base 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 | MT: RNA/DNA Editing Lesch-Nyhan syndrome LNS HPRT1, CRISPR-Cas gene correction base editing |
| url | http://www.sciencedirect.com/science/article/pii/S216225312300029X |
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