Custom zinc-finger nucleases for use in human cells
Open accessAbstract
Genome engineering through homologous recombination (HR) is a powerful instrument for studying biological pathways or creating treatment options for genetic disorders. In mammalian cells HR is rare but the creation of targeted DNA double-strand breaks stimulates HR significantly. Here, we present a method to generate, evaluate, and optimize rationally designed endonucleases that promote HR. The DNA-binding domains were synthesized by assembling predefined zinc-finger modules selected by phage display. Attachment of a transcriptional activation domain allowed assessment of DNA binding in reporter assays, while fusion with an endonuclease domain created custom nucleases that were tested for their ability to stimulate HR in episomal and chromosomal gene repair assays. We demonstrate that specificity, expression kinetics, and protein design are crucial parameters for efficient gene repair and that our two-step assay allows one to go quickly from design to testing to successful employment of the custom nucleases in human cells.
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If nuclease action mutates unintended targets that are important for cellular physiology, the treated cells may become dysfunctional or even die.
“For example, if the nuclease action mutates unintended targets that are important for cellular physiology, the treated cells may become dysfunctional or even die [61,62,63].”
From Newer Gene Editing Technologies toward HIV Gene Therapy (2013) · cites this paper as [63]
The fundamental safety concern for using ZFN mediated gene disruption for human therapy is the specificity of gene targeting.
“The fundamental safety concern for using ZFN mediated gene disruption for human therapy is the specificity of gene targeting.”
From Newer Gene Editing Technologies toward HIV Gene Therapy (2013) · cites this paper as [63]
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- Authors
- Alwin, S., Gere, M. B., Guhl, E., Effertz, K., Barbas, C. F., Segal, D. J., Weitzman, M. D., & Cathomen, T.
- Affiliations
- Charité – Universitätsmedizin Berlin (DE)
- Scripps Research Institute (US)
- University of Arizona (US)
- Salk Institute for Biological Studies (US)
- Corresponding author
- Cathomen, Toni
- Venue
- Molecular Therapy
- Publisher
- Elsevier BV
- Published
- 2005-10
- Volume
- 12
- Issue
- 4
- Pages
- 610-617
- ISSN
- 1525-0016 (ISSN-L)
- OpenAlex
- W1999295945
- Cited by
- 165
- References
- 37
- Citations by year
- 2025: 1 · 2024: 1 · 2023: 2 · 2022: 2 · 2021: 3 · 2020: 2 · 2019: 5 · 2018: 1 · 2017: 5 · 2016: 4 · 2015: 7 · 2014: 9 · 2013: 8 · 2012: 19
- FWCI
- 6.40
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Molecular Therapy (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- FreiDok plus (Universitätsbibliothek Freiburg) (submittedVersion)
- Funders
- National Cancer Institute (R21CA103651)
- National Institute of General Medical Sciences (R01GM065059)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Keywords
- zinc finger nucleases, homologous recombination, genome editing, DNA double-strand breaks, phage display, transactivation domain, gene repair, human cells, nuclease specificity, expression kinetics
- MeSH terms
- Base Sequence, Binding Sites, DNA, DNA Nucleotidyltransferases, DNA Repair, DNA-Binding Proteins, Endonucleases, Humans, Molecular Sequence Data, Promoter Regions, Genetic, Recombination, Genetic, Zinc Fingers, Gene Targeting
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