CRISPR/Cas9-mediated targeted gene correction in amyotrophic lateral sclerosis patient iPSCs

• Published in: Protein & cell Vol. 8; no. 5; pp. 365 - 378
• Main Authors: Wang, Lixia, Yi, Fei, Fu, Lina, Yang, Jiping, Wang, Si, Wang, Zhaoxia, Suzuki, Keiichiro, Sun, Liang, Xu, Xiuling, Yu, Yang, Qiao, Jie, Belmonte, Juan Carlos Izpisua, Yang, Ze, Yuan, Yun, Qu, Jing, Liu, Guang-Hui
• Format: Journal Article
• Language: English
• Published: Beijing Higher Education Press 01.05.2017; Springer Nature B.V; Oxford University Press
• Subjects: ALS; Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - genetics; Amyotrophic Lateral Sclerosis - metabolism; Amyotrophic Lateral Sclerosis - therapy; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Line; Clustered Regularly Interspaced Short Palindromic Repeats; CRISPR; CRISPR/Cas9; Developmental Biology; Fibroblasts; gene correction; Genetic Therapy; Genome-Wide Association Study; Genomes; Human Genetics; Humans; Induced Pluripotent Stem Cells - metabolism; Inhibitory postsynaptic potentials; iPSC disease modeling; Life Sciences; Molecular modelling; Motor neurons; Motor task performance; Mutation; Mutation, Missense; Pluripotency; Protein Science; Research Article; Ribonucleic acid; RNA; RNA-Binding Protein FUS - genetics; RNA-Binding Protein FUS - metabolism; Stem Cells; Superoxide dismutase; Superoxide Dismutase-1 - genetics; Superoxide Dismutase-1 - metabolism; ALS; gene correction; CRISPR/Cas9; iPSC disease modeling
• ISSN: 1674-800X; 1674-8018; 1674-8018
• DOI: 10.1007/s13238-017-0397-3

Amyotrophic lateral sclerosis （ALS） is a complex neu- rodegenerative disease with cellular and molecular mechanisms yet to be fully described. Mutations in a number of genes including SOD1 and FUS are associated with familial ALS. Here we report the generation of induced pluripotent stem cells （iPSCs） from fibroblasts of familial ALS patients bearing SOD1＋1A27~c and FUS＋/GISe6A mutations, respectively. We further gener- ated gene corrected ALS iPSCs using CRISPR/Cas9 system. Genome-wide RNA sequencing （RNA-seq） analysis of motor neurons derived from SOD1＋~A272c and corrected iPSCs revealed 899 aberrant transcripts. Our work may shed light on discovery of early biomarkers and pathways dysregulated in ALS, as well as provide a basis for novel therapeutic strategies to treat ALS.