ArticleMolecular genetics & genomic medicine2019
Precise CCM1 gene correction and inactivation in patient-derived endothelial cells: Modeling Knudson's two-hit hypothesis in vitro.
Article in Molecular genetics & genomic medicine, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed, 14 citations in OpenAlex.
- Human stem cell models in cerebral cavernous malformations.Stem cell research & therapy · 2026Review
- Familial Cerebral Cavernous Malformations: Pathophysiology, Genetics, Biomarkers, and Treatment Perspectives.Journal of neurochemistry · 2026Review
- High-throughput differentiation of human blood vessel organoids reveals overlapping and distinct functions of the cerebral cavernous malformation proteins.Angiogenesis · 2025Article
- Endothelial Differentiation ofInternational journal of molecular sciences · 2023Article
- Modern Brain Arteriovenous Malformation Models: A Review.Stroke (Hoboken, N.J.) · 2022Review
- Bringing CCM into a dish: cell culture models for cerebral cavernous malformations.Medizinische Genetik : Mitteilungsblatt des Berufsverbandes Medizinische Genetik e.V · 2021Article
- Inactivation of Cerebral Cavernous Malformation Genes Results in Accumulation of von Willebrand Factor and Redistribution of Weibel-Palade Bodies in Endothelial Cells.Frontiers in molecular biosciences · 2021Article
- Postzygotic mosaicism in cerebral cavernous malformation.Journal of medical genetics · 2020Article
- Precise CCM1 gene correction and inactivation in patient-derived endothelial cells: Modeling Knudson's two-hit hypothesis in vitro.Molecular genetics & genomic medicine · 2019Article
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Authors and funding
5 authors at 1 institution in 1 country.
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No grant is acknowledged in the PubMed record.
Abstract
backgroundThe CRISPR/Cas9 system has opened new perspectives to study the molecular basis of cerebral cavernous malformations (CCMs) in personalized disease models. However, precise genome editing in endothelial and other hard-to-transfect cells remains challenging.
methodsIn a proof-of-principle study, we first isolated blood outgrowth endothelial cells (BOECs) from a CCM1 mutation carrier with multiple CCMs. In a CRISPR/Cas9 gene correction approach, a high-fidelity Cas9 variant was then transfected into patient-derived BOECs using a ribonucleoprotein complex and a single-strand DNA oligonucleotide. In addition, patient-specific CCM1 knockout clones were expanded after CRISPR/Cas9 gene inactivation.
resultsDeep sequencing demonstrated correction of the mutant allele in nearly 33% of all cells whereas no CRISPR/Cas9-induced mutations in predicted off-target loci were identified. Corrected BOECs could be cultured in cell mixtures but demonstrated impaired clonal survival. In contrast, CCM1-deficient BOECs displayed increased resistance to stress-induced apoptotic cell death and could be clonally expanded to high passages. When cultured together, CCM1-deficient BOECs largely replaced corrected as well as heterozygous BOECs.
conclusionWe here demonstrate that a non-viral CRISPR/Cas9 approach can not only be used for gene knockout but also for precise gene correction in hard-to-transfect endothelial cells (ECs). Comparing patient-derived isogenic CCM1
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