Developing Hypoimmunogenic Human iPSC‐Derived Oligodendrocyte Progenitor Cells as an Off‐The‐Shelf Cell Therapy for Myelin Disorders

• Published in: Advanced science 2023-08, Vol.10 (23), p.e2206910-n/a
• Main Authors: Feng, Lizhao, Chao, Jianfei, Ye, Peng, Luong, Qui, Sun, Guoqiang, Liu, Wei, Cui, Qi, Flores, Sergio, Jackson, Natasha, Shayento, Afm Nazmul Hoque, Sun, Guihua, Liu, Zhenqing, Hu, Weidong, Shi, Yanhong
• Format: Article
• Language: English
• Subjects: allogeneic cell therapy; Antigens; Brain; Canavan disease; Cloning; Cytotoxicity; demyelinating diseases; Enzymes; Flow cytometry; Genes; Genetic engineering; iPSCs; Lymphocytes; Mutation; off‐the‐shelf cell therapy; oligodendrocyte progenitor cells (OPC); Patients; Proteins; Stem cells; Transcription factors; universal donor
• ISSN: 2198-3844; 2198-3844
• DOI: 10.1002/advs.202206910

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. Canavan disease (CD) is a demyelinating disorder caused by mutation of the ASPA gene. Human hypoimmunogenic oligodendrocyte progenitor cells (OPCs) are generated with the wildtype ASPA gene. These cells exhibit low immunogenicity in vitro and in vivo. In a CD mouse model, the engrafted OPCs mature into oligodendrocytes to express endogenous ASPA, repair myelination, and rescue main pathologies of CD.