A SMN2 splicing modifier rescues the disease phenotypes in an in vitro human spinal muscular atrophy model

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A SMN2 splicing modifier rescues the disease phenotypes in an in vitro human spinal muscular atrophy model
Ye Seul Son; Kwangman Choi; Hana Lee; Ohman Kwon; Kwang Bo Jung; Sunwha Cho; J Baek; B Son; Sung-Min Kang; J Yoon; H Shen; Sangku Lee; J H Oh; H A Lee; Mi Ok LeeHyun Soo ChoCho Rok JungJanghwan KimSungchan ChoMi Young Son
Bibliographic Citation
Stem Cells and Development, vol. 28, no. 7, pp. 438-453
Publication Year
Spinal muscular atrophy (SMA) is caused by the mutation or deletion of the survival motor neuron 1 (SMN1) gene. Only ∼10% of the products of SMN2, a paralogue of SMN1, are functional full-length SMN (SMN-FL) proteins, whereas SMN2 primarily produces alternatively spliced transcripts lacking exon 7. Reduced SMN protein levels in SMA patients lead to progressive degeneration of spinal motor neurons (MNs). In this study, we report an advanced platform based on an SMN2 splicing-targeting approach for SMA drug screening and validation using an SMN2 splicing reporter cell line and an in vitro human SMA model through induced pluripotent stem cell (iPSC) technology. Through drug screening using a robust cell-based luciferase assay to quantitatively measure SMN2 splicing, the small-molecule candidate compound rigosertib was identified as an SMN2 splicing modulator that led to enhanced SMN protein expression. The therapeutic potential of the candidate compound was validated in MN progenitors differentiated from SMA patient-derived iPSCs (SMA iPSC-pMNs) as an in vitro human SMA model, which recapitulated the biochemical and molecular phenotypes of SMA, including lower levels of SMN-FL transcripts and protein, enhanced cell death, and reduced neurite length. The candidate compound exerted strong splicing correction activity for SMN2 and potently alleviated the disease-related phenotypes of SMA iPSC-pMNs by modulating various cellular and molecular abnormalities. Our combined screening platform representing a pMN model of human SMA provides an efficient and reliable drug screening system and is a promising resource for drug evaluation and the exploration of drug modes of action.
spinal muscular atrophymotor neuroninduced pluripotent stem celldisease modelingdrug screeningrigosertib
Mary Ann Liebert, Inc
Appears in Collections:
Division of Research on National Challenges > Stem Cell Convergenece Research Center > 1. Journal Articles
Ochang Branch Institute > Chemical Biology Research Center > 1. Journal Articles
Ochang Branch Institute > Nucleic Acid Therapeutics Research Center > 1. Journal Articles
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