RNA-Targeting CRISPR/CasRx system relieves disease symptoms in Huntington’s disease models
Abstract Background HD is a devastating neurodegenerative disorder caused by the expansion of CAG repeats in the HTT. Silencing the expression of mutated proteins is a therapeutic direction to rescue HD patients, and recent advances in gene editing technology such as CRISPR/CasRx have opened up new...
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BMC
2025-01-01
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| Series: | Molecular Neurodegeneration |
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| Online Access: | https://doi.org/10.1186/s13024-024-00794-w |
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| author | Yingqi Lin Caijuan Li Yizhi Chen Jiale Gao Jiawei Li Chunhui Huang Zhaoming Liu Wei Wang Xiao Zheng Xichen Song Jianhao Wu Jiaxi Wu Oscar Junhong Luo Zhuchi Tu Shihua Li Xiao-Jiang Li Liangxue Lai Sen Yan |
| author_facet | Yingqi Lin Caijuan Li Yizhi Chen Jiale Gao Jiawei Li Chunhui Huang Zhaoming Liu Wei Wang Xiao Zheng Xichen Song Jianhao Wu Jiaxi Wu Oscar Junhong Luo Zhuchi Tu Shihua Li Xiao-Jiang Li Liangxue Lai Sen Yan |
| author_sort | Yingqi Lin |
| collection | DOAJ |
| description | Abstract Background HD is a devastating neurodegenerative disorder caused by the expansion of CAG repeats in the HTT. Silencing the expression of mutated proteins is a therapeutic direction to rescue HD patients, and recent advances in gene editing technology such as CRISPR/CasRx have opened up new avenues for therapeutic intervention. Methods The CRISPR/CasRx system was employed to target human HTT exon 1, resulting in an efficient knockdown of HTT mRNA. This therapeutic effect was substantiated in various models: HEK 293 T cell, the HD 140Q-KI mouse, and the HD-KI pig model. The efficiency of the knockdown was analyzed through Western blot and RT-qPCR. Additionally, neuropathological changes were examined using Western blot, immunostaining, and RNA sequencing. The impact on motor abilities was assessed via behavioral experiments, providing a comprehensive evaluation of the treatment's effectiveness. Results CRISPR/CasRx system can significantly reduce HTT mRNA levels across various models, including HEK 293 T cells, HD 140Q-KI mice at various disease stages, and HD-KI pigs, and resulted in decreased expression of mHTT. Utilizing the CRISPR/CasRx system to knock down HTT RNA has shown to ameliorate gliosis in HD 140Q-KI mice and delay neurodegeneration in HD pigs. Conclusions These findings highlight the effectiveness of the RNA-targeting CRISPR/CasRx as a potential therapeutic strategy for HD. Furthermore, the success of this approach provides valuable insights and novel avenues for the treatment of other genetic disorders caused by gene mutations. |
| format | Article |
| id | doaj-art-d8f5d04ee87b4113ae3be0c85ae9730f |
| institution | Kabale University |
| issn | 1750-1326 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
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| series | Molecular Neurodegeneration |
| spelling | doaj-art-d8f5d04ee87b4113ae3be0c85ae9730f2025-01-19T12:38:40ZengBMCMolecular Neurodegeneration1750-13262025-01-0120112410.1186/s13024-024-00794-wRNA-Targeting CRISPR/CasRx system relieves disease symptoms in Huntington’s disease modelsYingqi Lin0Caijuan Li1Yizhi Chen2Jiale Gao3Jiawei Li4Chunhui Huang5Zhaoming Liu6Wei Wang7Xiao Zheng8Xichen Song9Jianhao Wu10Jiaxi Wu11Oscar Junhong Luo12Zhuchi Tu13Shihua Li14Xiao-Jiang Li15Liangxue Lai16Sen Yan17Guangdong Key Laboratory of Non-Human Primate Research, Key Laboratory of CNS Regeneration (Ministry of Education), School of Medicine, GHM Institute of CNS Regeneration, Jinan UniversityGuangdong Key Laboratory of Non-Human Primate Research, Key Laboratory of CNS Regeneration (Ministry of Education), School of Medicine, GHM Institute of CNS Regeneration, Jinan UniversityGuangdong Key Laboratory of Non-Human Primate Research, Key Laboratory of CNS Regeneration (Ministry of Education), School of Medicine, GHM Institute of CNS Regeneration, Jinan UniversityGuangdong Key Laboratory of Non-Human Primate Research, Key Laboratory of CNS Regeneration (Ministry of Education), School of Medicine, GHM Institute of CNS Regeneration, Jinan UniversityGuangdong Key Laboratory of Non-Human Primate Research, Key Laboratory of CNS Regeneration (Ministry of Education), School of Medicine, GHM Institute of CNS Regeneration, Jinan UniversityGuangdong Key Laboratory of Non-Human Primate Research, Key Laboratory of CNS Regeneration (Ministry of Education), School of Medicine, GHM Institute of CNS Regeneration, Jinan UniversityChina-New Zealand Joint Laboratory On Biomedicine and Health, CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou, Institutes of Biomedicine and Health , Chinese Academy of SciencesGuangdong Key Laboratory of Non-Human Primate Research, Key Laboratory of CNS Regeneration (Ministry of Education), School of Medicine, GHM Institute of CNS Regeneration, Jinan UniversityGuangdong Key Laboratory of Non-Human Primate Research, Key Laboratory of CNS Regeneration (Ministry of Education), School of Medicine, GHM Institute of CNS Regeneration, Jinan UniversityGuangdong Key Laboratory of Non-Human Primate Research, Key Laboratory of CNS Regeneration (Ministry of Education), School of Medicine, GHM Institute of CNS Regeneration, Jinan UniversityGuangdong Key Laboratory of Non-Human Primate Research, Key Laboratory of CNS Regeneration (Ministry of Education), School of Medicine, GHM Institute of CNS Regeneration, Jinan UniversityGuangdong Key Laboratory of Non-Human Primate Research, Key Laboratory of CNS Regeneration (Ministry of Education), School of Medicine, GHM Institute of CNS Regeneration, Jinan UniversityDepartment of Systems Biomedical Sciences, School of Medicine, Jinan UniversityGuangdong Key Laboratory of Non-Human Primate Research, Key Laboratory of CNS Regeneration (Ministry of Education), School of Medicine, GHM Institute of CNS Regeneration, Jinan UniversityGuangdong Key Laboratory of Non-Human Primate Research, Key Laboratory of CNS Regeneration (Ministry of Education), School of Medicine, GHM Institute of CNS Regeneration, Jinan UniversityGuangdong Key Laboratory of Non-Human Primate Research, Key Laboratory of CNS Regeneration (Ministry of Education), School of Medicine, GHM Institute of CNS Regeneration, Jinan UniversityChina-New Zealand Joint Laboratory On Biomedicine and Health, CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou, Institutes of Biomedicine and Health , Chinese Academy of SciencesGuangdong Key Laboratory of Non-Human Primate Research, Key Laboratory of CNS Regeneration (Ministry of Education), School of Medicine, GHM Institute of CNS Regeneration, Jinan UniversityAbstract Background HD is a devastating neurodegenerative disorder caused by the expansion of CAG repeats in the HTT. Silencing the expression of mutated proteins is a therapeutic direction to rescue HD patients, and recent advances in gene editing technology such as CRISPR/CasRx have opened up new avenues for therapeutic intervention. Methods The CRISPR/CasRx system was employed to target human HTT exon 1, resulting in an efficient knockdown of HTT mRNA. This therapeutic effect was substantiated in various models: HEK 293 T cell, the HD 140Q-KI mouse, and the HD-KI pig model. The efficiency of the knockdown was analyzed through Western blot and RT-qPCR. Additionally, neuropathological changes were examined using Western blot, immunostaining, and RNA sequencing. The impact on motor abilities was assessed via behavioral experiments, providing a comprehensive evaluation of the treatment's effectiveness. Results CRISPR/CasRx system can significantly reduce HTT mRNA levels across various models, including HEK 293 T cells, HD 140Q-KI mice at various disease stages, and HD-KI pigs, and resulted in decreased expression of mHTT. Utilizing the CRISPR/CasRx system to knock down HTT RNA has shown to ameliorate gliosis in HD 140Q-KI mice and delay neurodegeneration in HD pigs. Conclusions These findings highlight the effectiveness of the RNA-targeting CRISPR/CasRx as a potential therapeutic strategy for HD. Furthermore, the success of this approach provides valuable insights and novel avenues for the treatment of other genetic disorders caused by gene mutations.https://doi.org/10.1186/s13024-024-00794-wCRISPR/CasRxHuntington's diseaseHTTHD-KI pig |
| spellingShingle | Yingqi Lin Caijuan Li Yizhi Chen Jiale Gao Jiawei Li Chunhui Huang Zhaoming Liu Wei Wang Xiao Zheng Xichen Song Jianhao Wu Jiaxi Wu Oscar Junhong Luo Zhuchi Tu Shihua Li Xiao-Jiang Li Liangxue Lai Sen Yan RNA-Targeting CRISPR/CasRx system relieves disease symptoms in Huntington’s disease models Molecular Neurodegeneration CRISPR/CasRx Huntington's disease HTT HD-KI pig |
| title | RNA-Targeting CRISPR/CasRx system relieves disease symptoms in Huntington’s disease models |
| title_full | RNA-Targeting CRISPR/CasRx system relieves disease symptoms in Huntington’s disease models |
| title_fullStr | RNA-Targeting CRISPR/CasRx system relieves disease symptoms in Huntington’s disease models |
| title_full_unstemmed | RNA-Targeting CRISPR/CasRx system relieves disease symptoms in Huntington’s disease models |
| title_short | RNA-Targeting CRISPR/CasRx system relieves disease symptoms in Huntington’s disease models |
| title_sort | rna targeting crispr casrx system relieves disease symptoms in huntington s disease models |
| topic | CRISPR/CasRx Huntington's disease HTT HD-KI pig |
| url | https://doi.org/10.1186/s13024-024-00794-w |
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