ArticleHuman molecular genetics2020
Correction of amyotrophic lateral sclerosis related phenotypes in induced pluripotent stem cell-derived motor neurons carrying a hexanucleotide expansion mutation in C9orf72 by CRISPR/Cas9 genome editing using homology-directed repair.
Article in Human molecular genetics, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 51 papers.
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Who cites it
51 citing papers in PubMed, 71 citations in OpenAlex.
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- A tabletop blast device for the study of the long-term consequences of traumatic brain injury on brain organoids.Cell reports methods · 2025Article
- CRISPR Technology in Disease Management: An Updated Review of Clinical Translation and Therapeutic Potential.Cell proliferation · 2025Article
- Neuronal activity-dependent gene dysregulation inAmerican journal of physiology. Cell physiology · 2025Article
- CRISPR in Neurodegenerative Diseases Treatment: An Alternative Approach to Current Therapies.Genes · 2025Review
- Therapeutic Approaches for C9ORF72-Related ALS: Current Strategies and Future Horizons.International journal of molecular sciences · 2025Review
- Targeting GeneInternational journal of molecular sciences · 2025Review
- Targets and Gene Therapy of ALS (Part 1).International journal of molecular sciences · 2025Review
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- High-throughput screen of 100 000 small molecules in C9ORF72 ALS neurons identifies spliceosome modulators that mobilize G4C2 repeat RNA into nuclear export and repeat associated non-canonical translation.Nucleic acids research · 2025Article
- Drug repurposing in amyotrophic lateral sclerosis (ALS).Expert opinion on drug discovery · 2025Review
- Exploring epigenetic modifications as potential biomarkers and therapeutic targets in amyotrophic lateral sclerosis.Journal of neurology · 2025Review
- A high-fidelity CRISPR-Cas13 system improves abnormalities associated with C9ORF72-linked ALS/FTD.Nature communications · 2025Article
- CRISPR-Cas technologies in neurodegenerative disorders: mechanistic insights, therapeutic potential, and translational challenges.Frontiers in neurology · 2025Review
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- In vivo and ex vivo gene therapy for neurodegenerative diseases: a promise for disease modification.Naunyn-Schmiedeberg's archives of pharmacology · 2024Review
- Poly-GR repeats associated with ALS/FTD geneScience signaling · 2024Article
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Authors and funding
11 authors at 4 institutions in 2 countries.
Funding
Abstract
The G4C2 hexanucleotide repeat expansion (HRE) in C9orf72 is the commonest cause of familial amyotrophic lateral sclerosis (ALS). A number of different methods have been used to generate isogenic control lines using clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 and non-homologous end-joining by deleting the repeat region, with the risk of creating indels and genomic instability. In this study, we demonstrate complete correction of an induced pluripotent stem cell (iPSC) line derived from a C9orf72-HRE positive ALS/frontotemporal dementia patient using CRISPR/Cas9 genome editing and homology-directed repair (HDR), resulting in replacement of the excised region with a donor template carrying the wild-type repeat size to maintain the genetic architecture of the locus. The isogenic correction of the C9orf72 HRE restored normal gene expression and methylation at the C9orf72 locus, reduced intron retention in the edited lines and abolished pathological phenotypes associated with the C9orf72 HRE expansion in iPSC-derived motor neurons (iPSMNs). RNA sequencing of the mutant line identified 2220 differentially expressed genes compared with its isogenic control. Enrichment analysis demonstrated an over-representation of ALS relevant pathways, including calcium ion dependent exocytosis, synaptic transport and the Kyoto Encyclopedia of Genes and Genomes ALS pathway, as well as new targets of potential relevance to ALS pathophysiology. Complete correction of the C9orf72 HRE in iPSMNs by CRISPR/Cas9-mediated HDR provides an ideal model to study the earliest effects of the hexanucleotide expansion on cellular homeostasis and the key pathways implicated in ALS pathophysiology.
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