ArticleStem cell research & therapy2021
In vitro genome editing rescues parkinsonism phenotypes in induced pluripotent stem cells-derived dopaminergic neurons carrying LRRK2 p.G2019S mutation.
Article in Stem cell research & therapy, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 32 citations in OpenAlex.
- Review
- CRISPR-Cas9 Therapeutics in Early Clinical Development: Delivery and Molecular Diagnostics.Cells · 2026Review
- Human pluripotent stem cell engineering with CRISPR-Cas9 for Parkinson's disease.Experimental & molecular medicine · 2026Review
- Dopamine and cortical neurons with different Parkinsonian mutations show variation in lysosomal and mitochondrial dysfunction.NPJ Parkinson's disease · 2025Article
- Clinical translation of human iPSC technologies: advances, safety concerns, and future directions.Frontiers in cell and developmental biology · 2025Review
- Expanding the CRISPR/Cas toolkit: applications in proteomics and theranostics.Frontiers in bioengineering and biotechnology · 2025Review
- Recent Research Trends in Stem Cells Using CRISPR/Cas-Based Genome Editing Methods.International journal of stem cells · 2024Review
- Association of antihypertensives and Parkinson's disease in a primary care population matched for underlying diagnosis.PloS one · 2024Article
- Enhancing Our Understanding of Cell Types, Differentiation, and Disease Through Enhancers: An Interview with César Daniel Meléndez-Ramírez, MS.The Yale journal of biology and medicine · 2023Article
- Recent Advances in CRISPR/Cas9 Delivery Approaches for Therapeutic Gene Editing of Stem Cells.Stem cell reviews and reports · 2023Review
- What did CRISPR-Cas9 accomplish in its first 10 years?Biochemia medica · 2023Article
- Revealing invisible cell phenotypes with conditional generative modeling.Nature communications · 2023Article
- Whole genomic analysis reveals atypical non-homologous off-target large structural variants induced by CRISPR-Cas9-mediated genome editing.Nature communications · 2023Article
- LRRK2 Knockout Confers Resistance in HEK-293 Cells to Rotenone-Induced Oxidative Stress, Mitochondrial Damage, and Apoptosis.International journal of molecular sciences · 2023Article
- Gene editing with 'pencil' rather than 'scissors' in human pluripotent stem cells.Stem cell research & therapy · 2023Review
- Overexpression of Parkin in the Neuronal Progenitor Cells from a Patient with Parkinson's Disease Shifts the Transcriptome Towards the Normal State.Molecular neurobiology · 2023Article
- Seeing Neurodegeneration in a New Light Using Genetically Encoded Fluorescent Biosensors and iPSCs.International journal of molecular sciences · 2023Review
- Advances in Gene Therapy Techniques to TreatBiomolecules · 2022Review
- Review
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Authors and funding
17 authors at 4 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundThe c.G6055A (p.G2019S) mutation in leucine-rich repeat kinase 2 (LRRK2) is the most prevalent genetic cause of Parkinson's disease (PD). CRISPR/Cas9-mediated genome editing by homology-directed repair (HDR) has been applied to correct the mutation but may create small insertions and deletions (indels) due to double-strand DNA breaks. Adenine base editors (ABEs) could convert targeted A·T to G·C in genomic DNA without double-strand breaks. However, the correction efficiency of ABE in LRRK2 c.G6055A (p.G2019S) mutation remains unknown yet. This study aimed to compare the mutation correction efficiencies and off-target effects between HDR and ABEs in induced pluripotent stem cells (iPSCs) carrying LRRK2 c.G6055A (p.G2019S) mutation.
methodsA set of mutation-corrected isogenic lines by editing the LRRK2 c.G6055A (p.G2019S) mutation in a PD patient-derived iPSC line using HDR or ABE were established. The mutation correction efficacies, off-target effects, and indels between HDR and ABE were compared. Comparative transcriptomic and proteomic analyses between the LRRK2 p.G2019S iPSCs and isogenic control cells were performed to identify novel molecular targets involved in LRRK2-parkinsonism pathways.
resultsABE had a higher correction rate (13/53 clones, 24.5%) than HDR (3/47 clones, 6.4%). Twenty-seven HDR clones (57.4%), but no ABE clones, had deletions, though 14 ABE clones (26.4%) had off-target mutations. The corrected isogenic iPSC-derived dopaminergic neurons exhibited reduced LRRK2 kinase activity, decreased phospho-α-synuclein expression, and mitigated neurite shrinkage and apoptosis. Comparative transcriptomic and proteomic analysis identified different gene expression patterns in energy metabolism, protein degradation, and peroxisome proliferator-activated receptor pathways between the mutant and isogenic control cells.
conclusionsThe results of this study envision that ABE could directly correct the pathogenic mutation in iPSCs for reversing disease-related phenotypes in neuropathology and exploring novel pathophysiological targets in PD.
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