Developing Hypoimmunogenic Human iPSC‐Derived Oligodendrocyte Progenitor Cells as an Off‐The‐Shelf Cell Therapy for Myelin Disorders
Abstract Demyelinating disorders are among the most common and debilitating diseases in neurology. Canavan disease (CD) is a lethal demyelinating disease caused by mutation of the aspartoacylase (ASPA) gene, which leads to the accumulation of its substrate N‐acetyl‐l‐aspartate (NAA), and consequentl...
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| Format: | Article |
| Language: | English |
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Wiley
2023-08-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202206910 |
| _version_ | 1797742645524561920 |
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| author | Lizhao Feng Jianfei Chao Peng Ye Qui Luong Guoqiang Sun Wei Liu Qi Cui Sergio Flores Natasha Jackson Afm Nazmul Hoque Shayento Guihua Sun Zhenqing Liu Weidong Hu Yanhong Shi |
| author_facet | Lizhao Feng Jianfei Chao Peng Ye Qui Luong Guoqiang Sun Wei Liu Qi Cui Sergio Flores Natasha Jackson Afm Nazmul Hoque Shayento Guihua Sun Zhenqing Liu Weidong Hu Yanhong Shi |
| author_sort | Lizhao Feng |
| collection | DOAJ |
| description | Abstract Demyelinating disorders are among the most common and debilitating diseases in neurology. Canavan disease (CD) is a lethal demyelinating disease caused by mutation of the aspartoacylase (ASPA) gene, which leads to the accumulation of its substrate N‐acetyl‐l‐aspartate (NAA), and consequently demyelination and vacuolation in the brain. In this study, hypoimmunogenic human induced pluripotent stem cell (iPSC)‐derived oligodendrocyte progenitor cells (OPC) are developed from a healthy donor as an “off‐the‐shelf” cell therapy. Hypoimmunogenic iPSCs are generated through CRISPR/Cas9 editing of the human leukocyte antigen (HLA) molecules in healthy donor‐derived iPSCs and differentiated into OPCs. The OPCs are engrafted into the brains of CD (nur7) mice and exhibit widespread distribution in the brain. The engrafted OPCs mature into oligodendrocytes that express the endogenous wildtype ASPA gene. Consequently, the transplanted mice exhibit elevated human ASPA expression and enzymatic activity and reduced NAA level in the brain. The transplanted OPCs are able to rescue major pathological features of CD, including defective myelination, extensive vacuolation, and motor function deficits. Moreover, the hypoimmunogenic OPCs exhibit low immunogenicity both in vitro and in vivo. The hypoimmunogenic OPCs can be used as “off‐the‐shelf” universal donor cells to treat various CD patients and many other demyelinating disorders, especially autoimmune demyelinating diseases, such as multiple sclerosis. |
| first_indexed | 2024-03-12T14:44:34Z |
| format | Article |
| id | doaj.art-09dd6e46f2554eef892a2a30ee48afbe |
| institution | Directory Open Access Journal |
| issn | 2198-3844 |
| language | English |
| last_indexed | 2024-03-12T14:44:34Z |
| publishDate | 2023-08-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj.art-09dd6e46f2554eef892a2a30ee48afbe2023-08-16T02:23:01ZengWileyAdvanced Science2198-38442023-08-011023n/an/a10.1002/advs.202206910Developing Hypoimmunogenic Human iPSC‐Derived Oligodendrocyte Progenitor Cells as an Off‐The‐Shelf Cell Therapy for Myelin DisordersLizhao Feng0Jianfei Chao1Peng Ye2Qui Luong3Guoqiang Sun4Wei Liu5Qi Cui6Sergio Flores7Natasha Jackson8Afm Nazmul Hoque Shayento9Guihua Sun10Zhenqing Liu11Weidong Hu12Yanhong Shi13Department of Neurodegenerative Diseases Beckman Research Institute of City of Hope 1500 E. Duarte Rd. Duarte CA 91010 USADepartment of Neurodegenerative Diseases Beckman Research Institute of City of Hope 1500 E. Duarte Rd. Duarte CA 91010 USADepartment of Neurodegenerative Diseases Beckman Research Institute of City of Hope 1500 E. Duarte Rd. Duarte CA 91010 USADepartment of Neurodegenerative Diseases Beckman Research Institute of City of Hope 1500 E. Duarte Rd. Duarte CA 91010 USADepartment of Neurodegenerative Diseases Beckman Research Institute of City of Hope 1500 E. Duarte Rd. Duarte CA 91010 USADepartment of Neurodegenerative Diseases Beckman Research Institute of City of Hope 1500 E. Duarte Rd. Duarte CA 91010 USADepartment of Neurodegenerative Diseases Beckman Research Institute of City of Hope 1500 E. Duarte Rd. Duarte CA 91010 USADepartment of Neurodegenerative Diseases Beckman Research Institute of City of Hope 1500 E. Duarte Rd. Duarte CA 91010 USADepartment of Neurodegenerative Diseases Beckman Research Institute of City of Hope 1500 E. Duarte Rd. Duarte CA 91010 USADepartment of Neurodegenerative Diseases Beckman Research Institute of City of Hope 1500 E. Duarte Rd. Duarte CA 91010 USADepartment of Neurodegenerative Diseases Beckman Research Institute of City of Hope 1500 E. Duarte Rd. Duarte CA 91010 USADepartment of Neurodegenerative Diseases Beckman Research Institute of City of Hope 1500 E. Duarte Rd. Duarte CA 91010 USADepartment of Neurodegenerative Diseases Beckman Research Institute of City of Hope 1500 E. Duarte Rd. Duarte CA 91010 USADepartment of Neurodegenerative Diseases Beckman Research Institute of City of Hope 1500 E. Duarte Rd. Duarte CA 91010 USAAbstract Demyelinating disorders are among the most common and debilitating diseases in neurology. Canavan disease (CD) is a lethal demyelinating disease caused by mutation of the aspartoacylase (ASPA) gene, which leads to the accumulation of its substrate N‐acetyl‐l‐aspartate (NAA), and consequently demyelination and vacuolation in the brain. In this study, hypoimmunogenic human induced pluripotent stem cell (iPSC)‐derived oligodendrocyte progenitor cells (OPC) are developed from a healthy donor as an “off‐the‐shelf” cell therapy. Hypoimmunogenic iPSCs are generated through CRISPR/Cas9 editing of the human leukocyte antigen (HLA) molecules in healthy donor‐derived iPSCs and differentiated into OPCs. The OPCs are engrafted into the brains of CD (nur7) mice and exhibit widespread distribution in the brain. The engrafted OPCs mature into oligodendrocytes that express the endogenous wildtype ASPA gene. Consequently, the transplanted mice exhibit elevated human ASPA expression and enzymatic activity and reduced NAA level in the brain. The transplanted OPCs are able to rescue major pathological features of CD, including defective myelination, extensive vacuolation, and motor function deficits. Moreover, the hypoimmunogenic OPCs exhibit low immunogenicity both in vitro and in vivo. The hypoimmunogenic OPCs can be used as “off‐the‐shelf” universal donor cells to treat various CD patients and many other demyelinating disorders, especially autoimmune demyelinating diseases, such as multiple sclerosis.https://doi.org/10.1002/advs.202206910allogeneic cell therapyCanavan diseasedemyelinating diseasesiPSCsoff‐the‐shelf cell therapyoligodendrocyte progenitor cells (OPC) |
| spellingShingle | Lizhao Feng Jianfei Chao Peng Ye Qui Luong Guoqiang Sun Wei Liu Qi Cui Sergio Flores Natasha Jackson Afm Nazmul Hoque Shayento Guihua Sun Zhenqing Liu Weidong Hu Yanhong Shi Developing Hypoimmunogenic Human iPSC‐Derived Oligodendrocyte Progenitor Cells as an Off‐The‐Shelf Cell Therapy for Myelin Disorders Advanced Science allogeneic cell therapy Canavan disease demyelinating diseases iPSCs off‐the‐shelf cell therapy oligodendrocyte progenitor cells (OPC) |
| title | Developing Hypoimmunogenic Human iPSC‐Derived Oligodendrocyte Progenitor Cells as an Off‐The‐Shelf Cell Therapy for Myelin Disorders |
| title_full | Developing Hypoimmunogenic Human iPSC‐Derived Oligodendrocyte Progenitor Cells as an Off‐The‐Shelf Cell Therapy for Myelin Disorders |
| title_fullStr | Developing Hypoimmunogenic Human iPSC‐Derived Oligodendrocyte Progenitor Cells as an Off‐The‐Shelf Cell Therapy for Myelin Disorders |
| title_full_unstemmed | Developing Hypoimmunogenic Human iPSC‐Derived Oligodendrocyte Progenitor Cells as an Off‐The‐Shelf Cell Therapy for Myelin Disorders |
| title_short | Developing Hypoimmunogenic Human iPSC‐Derived Oligodendrocyte Progenitor Cells as an Off‐The‐Shelf Cell Therapy for Myelin Disorders |
| title_sort | developing hypoimmunogenic human ipsc derived oligodendrocyte progenitor cells as an off the shelf cell therapy for myelin disorders |
| topic | allogeneic cell therapy Canavan disease demyelinating diseases iPSCs off‐the‐shelf cell therapy oligodendrocyte progenitor cells (OPC) |
| url | https://doi.org/10.1002/advs.202206910 |
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