SUPT4H1-edited stem cell therapy rescues neuronal dysfunction in a mouse model for Huntington’s disease
Abstract Huntington’s disease (HD) is a severe inherited neurological disorder caused by a CAG repeat expansion in the huntingtin gene (HTT), leading to the accumulation of mutant huntingtin with polyglutamine repeats. Despite its severity, there is no cure for this debilitating disease. HTT lowerin...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2022-01-01
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| Series: | npj Regenerative Medicine |
| Online Access: | https://doi.org/10.1038/s41536-021-00198-0 |
| _version_ | 1819261460595867648 |
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| author | Hyun Jung Park Areum Han Ji Yeon Kim Jiwoo Choi Hee Sook Bae Gyu-bon Cho Hyejung Shin Eun ji Shin Kang-in Lee Seokjoong Kim Jae Young Lee Jihwan Song |
| author_facet | Hyun Jung Park Areum Han Ji Yeon Kim Jiwoo Choi Hee Sook Bae Gyu-bon Cho Hyejung Shin Eun ji Shin Kang-in Lee Seokjoong Kim Jae Young Lee Jihwan Song |
| author_sort | Hyun Jung Park |
| collection | DOAJ |
| description | Abstract Huntington’s disease (HD) is a severe inherited neurological disorder caused by a CAG repeat expansion in the huntingtin gene (HTT), leading to the accumulation of mutant huntingtin with polyglutamine repeats. Despite its severity, there is no cure for this debilitating disease. HTT lowering strategies, including antisense oligonucleotides (ASO) showed promising results very recently. Attempts to develop stem cell-based therapeutics have shown efficacy in preclinical HD models. Using an HD patient’s autologous cells, which have genetic defects, may hamper therapeutic efficacy due to mutant HTT. Pretreating these cells to reduce mutant HTT expression and transcription may improve the transplanted cells’ therapeutic efficacy. To investigate this, we targeted the SUPT4H1 gene that selectively supports the transcription of long trinucleotide repeats. Transplanting SUPT4H1-edited HD-induced pluripotent stem cell-derived neural precursor cells (iPSC-NPCs) into the YAC128 HD transgenic mouse model improved motor function compared to unedited HD iPSC-NPCs. Immunohistochemical analysis revealed reduced mutant HTT expression without compensating wild-type HTT expression. Further, SUPT4H1 editing increased neuronal and decreased reactive astrocyte differentiation in HD iPSC-NPCs compared to the unedited HD iPSC-NPCs. This suggests that ex vivo editing of SUPT4H1 can reduce mutant HTT expression and provide a therapeutic gene editing strategy for autologous stem cell transplantation in HD. |
| first_indexed | 2024-12-23T19:42:09Z |
| format | Article |
| id | doaj.art-7c96b11192d44adebf96d70eac327bd7 |
| institution | Directory Open Access Journal |
| issn | 2057-3995 |
| language | English |
| last_indexed | 2024-12-23T19:42:09Z |
| publishDate | 2022-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Regenerative Medicine |
| spelling | doaj.art-7c96b11192d44adebf96d70eac327bd72022-12-21T17:33:38ZengNature Portfolionpj Regenerative Medicine2057-39952022-01-017111110.1038/s41536-021-00198-0SUPT4H1-edited stem cell therapy rescues neuronal dysfunction in a mouse model for Huntington’s diseaseHyun Jung Park0Areum Han1Ji Yeon Kim2Jiwoo Choi3Hee Sook Bae4Gyu-bon Cho5Hyejung Shin6Eun ji Shin7Kang-in Lee8Seokjoong Kim9Jae Young Lee10Jihwan Song11Department of Biomedical Science, CHA Stem Cell Institute, CHA University, 335 Pangyo-ro, Bundang-guDepartment of Biomedical Science, CHA Stem Cell Institute, CHA University, 335 Pangyo-ro, Bundang-guDepartment of Biomedical Science, CHA Stem Cell Institute, CHA University, 335 Pangyo-ro, Bundang-guDepartment of Biomedical Science, CHA Stem Cell Institute, CHA University, 335 Pangyo-ro, Bundang-guToolgen Inc., 219 Gasan Digital 1-ro, Geumcheon-guToolgen Inc., 219 Gasan Digital 1-ro, Geumcheon-guToolgen Inc., 219 Gasan Digital 1-ro, Geumcheon-guToolgen Inc., 219 Gasan Digital 1-ro, Geumcheon-guToolgen Inc., 219 Gasan Digital 1-ro, Geumcheon-guToolgen Inc., 219 Gasan Digital 1-ro, Geumcheon-guToolgen Inc., 219 Gasan Digital 1-ro, Geumcheon-guDepartment of Biomedical Science, CHA Stem Cell Institute, CHA University, 335 Pangyo-ro, Bundang-guAbstract Huntington’s disease (HD) is a severe inherited neurological disorder caused by a CAG repeat expansion in the huntingtin gene (HTT), leading to the accumulation of mutant huntingtin with polyglutamine repeats. Despite its severity, there is no cure for this debilitating disease. HTT lowering strategies, including antisense oligonucleotides (ASO) showed promising results very recently. Attempts to develop stem cell-based therapeutics have shown efficacy in preclinical HD models. Using an HD patient’s autologous cells, which have genetic defects, may hamper therapeutic efficacy due to mutant HTT. Pretreating these cells to reduce mutant HTT expression and transcription may improve the transplanted cells’ therapeutic efficacy. To investigate this, we targeted the SUPT4H1 gene that selectively supports the transcription of long trinucleotide repeats. Transplanting SUPT4H1-edited HD-induced pluripotent stem cell-derived neural precursor cells (iPSC-NPCs) into the YAC128 HD transgenic mouse model improved motor function compared to unedited HD iPSC-NPCs. Immunohistochemical analysis revealed reduced mutant HTT expression without compensating wild-type HTT expression. Further, SUPT4H1 editing increased neuronal and decreased reactive astrocyte differentiation in HD iPSC-NPCs compared to the unedited HD iPSC-NPCs. This suggests that ex vivo editing of SUPT4H1 can reduce mutant HTT expression and provide a therapeutic gene editing strategy for autologous stem cell transplantation in HD.https://doi.org/10.1038/s41536-021-00198-0 |
| spellingShingle | Hyun Jung Park Areum Han Ji Yeon Kim Jiwoo Choi Hee Sook Bae Gyu-bon Cho Hyejung Shin Eun ji Shin Kang-in Lee Seokjoong Kim Jae Young Lee Jihwan Song SUPT4H1-edited stem cell therapy rescues neuronal dysfunction in a mouse model for Huntington’s disease npj Regenerative Medicine |
| title | SUPT4H1-edited stem cell therapy rescues neuronal dysfunction in a mouse model for Huntington’s disease |
| title_full | SUPT4H1-edited stem cell therapy rescues neuronal dysfunction in a mouse model for Huntington’s disease |
| title_fullStr | SUPT4H1-edited stem cell therapy rescues neuronal dysfunction in a mouse model for Huntington’s disease |
| title_full_unstemmed | SUPT4H1-edited stem cell therapy rescues neuronal dysfunction in a mouse model for Huntington’s disease |
| title_short | SUPT4H1-edited stem cell therapy rescues neuronal dysfunction in a mouse model for Huntington’s disease |
| title_sort | supt4h1 edited stem cell therapy rescues neuronal dysfunction in a mouse model for huntington s disease |
| url | https://doi.org/10.1038/s41536-021-00198-0 |
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