Two therapeutic CRISPR/Cas9 gene editing approaches revert FTD/ALS cellular pathology caused by a C9orf72 repeat expansion mutation in patient derived cells
Two therapeutic CRISPR/Cas9 gene editing approaches revert FTD/ALS cellular pathology caused by a C9orf72 repeat expansion mutation in patient derived cells
Abstract CRISPR gene editing holds promise to cure or arrest genetic disease, if we can find and implement curative edits reliably, safely and effectively. Expansion of a hexanucleotide repeat in C9orf72 is the leading known genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). We evaluated three approaches to editing the mutant C9orf72 gene for their ability to correct pathology in neurons derived from patient iPSCs: excision of the repeat region, excision of the mutant allele, and excision of regulatory region exon 1A. All three approaches normalized RNA abnormalities and TDP-43 pathology, but only repeat excision and mutant allele excision completely eliminated pathologic dipeptide repeats. Our work sheds light on the complex regulation of the C9orf72 gene and suggests that because of sense and anti-sense transcription, silencing a single regulatory region may not reverse all pathology. Our work also provides a roadmap for evaluating CRISPR gene correction using patient iPSCs.
Gill K、Clelland CD、Sckaff M、Birk AM、Aladesuyi Arogundade O、Keough KC、Sachdev A、Ziegle J、Watry HL、Tsai Y-C、Conklin BR
Weill Institute for Neurosciences, University of California San Francisco||Gladstone InstitutesWeill Institute for Neurosciences, University of California San Francisco||Gladstone Institutes||Memory & Aging Center, Department of Neurology, University of California San FranciscoWeill Institute for Neurosciences, University of California San Francisco||Gladstone InstitutesGladstone InstitutesWeill Institute for Neurosciences, University of California San Francisco||Gladstone InstitutesGladstone InstitutesGladstone InstitutesPacific BiosciencesGladstone InstitutesPacific BiosciencesGladstone Institutes||Departments of Medicine, Ophthalmology, and Pharmacology, University of California San Francisco
神经病学、精神病学生物科学研究方法、生物科学研究技术遗传学
Gill K,Clelland CD,Sckaff M,Birk AM,Aladesuyi Arogundade O,Keough KC,Sachdev A,Ziegle J,Watry HL,Tsai Y-C,Conklin BR.Two therapeutic CRISPR/Cas9 gene editing approaches revert FTD/ALS cellular pathology caused by a C9orf72 repeat expansion mutation in patient derived cells[EB/OL].(2025-03-28)[2025-08-02].https://www.biorxiv.org/content/10.1101/2022.05.21.492887.点此复制
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