Gene Insertion Into Genomic Safe Harbors for Human Gene Therapy
Open accessAbstract
Genomic safe harbors (GSHs) are sites in the genome able to accommodate the integration of new genetic material in a manner that ensures that the newly inserted genetic elements: (i) function predictably and (ii) do not cause alterations of the host genome posing a risk to the host cell or organism. GSHs are thus ideal sites for transgene insertion whose use can empower functional genetics studies in basic research and therapeutic applications in human gene therapy. Currently, no fully validated GSHs exist in the human genome. Here, we review our formerly proposed GSH criteria and discuss additional considerations on extending these criteria, on strategies for the identification and validation of GSHs, as well as future prospects on GSH targeting for therapeutic applications. In view of recent advances in genome biology, gene targeting technologies, and regenerative medicine, gene insertion into GSHs can potentially catalyze nearly all applications in human gene therapy.
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Constitutive expression of Cas9 and gRNA from lentiviral vectors increases the risk of off-target effects.
“Moreover, the constitutive expression of both Cas9 protein and gRNA increases the risk of off‐target effects (Lino et al., 2018; Papapetrou & Schambach, 2016).”
From CRISPR/Cas9 Ribonucleoprotein Nucleofection for Genome Editing in Primary Human Keratinocytes: Knockouts, Deletions, and Homology‐Directed Repair Mutagenesis (2024) · cites this paper as Papapetrou & Schambach, 2016
The genomic safe harbors section discusses risks from lentiviral vector integration, including disruption of nearby genes, but not off-target effects caused by constitutive Cas9 and gRNA expression. The section on targeting predetermined safe harbors names CRISPR-Cas9 as a targeting tool without addressing that risk. Searches for constitutive Cas9/gRNA expression and prolonged expression causing off-target cleavage found no supporting passage in our copy. (LLM, conf=0.76)
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References 71 · Cited by 238
Research works printed but not linked: 1
- [60]60. Wakitani, S, Takaoka, K, Hattori, T, Miyazawa, N, Iwanaga, T, Takeda, S et al. (2003). Embryonic stem cells injected into the mouse knee joint form teratomas and subsequently destroy the joint. Rheumatology (Oxford) 42 : 162-165.
- Authors
- Papapetrou, E. P., & Schambach, A.
- Affiliations
- Tisch Cancer Institute (US)
- Boston Children's Hospital (US)
- Corresponding author
- Papapetrou, Eirini P
- Venue
- Molecular Therapy
- Publisher
- Elsevier BV
- Published
- 2016-04
- Volume
- 24
- Issue
- 4
- Pages
- 678-684
- ISSN
- 1525-0016 (ISSN-L)
- PMC
- PMC4886940
- OpenAlex
- W2335459725
- Cited by
- 238
- References
- 71
- Citations by year
- 2026: 17 · 2025: 22 · 2024: 28 · 2023: 24 · 2022: 30 · 2021: 36 · 2020: 38 · 2019: 21 · 2018: 10 · 2017: 8 · 2016: 4
- FWCI
- 1.92
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Molecular Therapy (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Damon Runyon Cancer Research Foundation
- Lawrence Ellison Foundation
- Seventh Framework Programme
- European Commission
- Deutsche Forschungsgemeinschaft (SFB738)
- National Institutes of Health (R00 DK087923, R01 HL121570)
- Bundesministerium für Bildung und Forschung
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Animal Genetics and Reproduction
- Keywords
- human gene therapy, transgene integration, gene targeting, insertion site selection, chromosomal integration, regenerative medicine, functional genetics
- MeSH terms
- Humans, Genetic Therapy, Genome, Human, Mutagenesis, Insertional, Transgenes
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