The changing landscape of gene editing in hematopoietic stem cells: a step towards Cas9 clinical translation
Open accessAbstract
Purpose of review: Since the discovery two decades ago that programmable endonucleases can be engineered to modify human cells at single nucleotide resolution, the concept of genome editing was born. Now these technologies are being applied to therapeutically relevant cell types, including hematopoietic stem cells (HSC), which possess the power to repopulate an entire blood and immune system. The purpose of this review is to discuss the changing landscape of genome editing in hematopoietic stem cells (GE-HSC) from the discovery stage to the preclinical stage, with the imminent goal of clinical translation for the treatment of serious genetic diseases of the blood and immune system. Recent findings: With the discovery that the RNA-programmable (sgRNA) clustered regularly interspace short palindromic repeats (CRISPR)-Cas9 nuclease (Cas9/sgRNA) systems can be easily used to precisely modify the human genome in 2012, a genome-editing revolution of hematopoietic stem cells (HSC) has bloomed. We have observed that over the last 2 years, academic institutions and small biotech companies are developing HSC-based Cas9/sgRNA genome-editing curative strategies to treat monogenic disorders, including β-hemoglobinopathies and primary immunodeficiencies. We will focus on recent publications (within the past 2 years) that employ different genome-editing strategies to ‘hijack’ the cell's endogenous double-strand repair pathways to confer a disease-specific therapeutic advantage. Summary: The number of genome-editing strategies in HSCs that could offer therapeutic potential for diseases of the blood and immune system have dramatically risen over the past 2 years. The HSC-based genome-editing field is primed to enter clinical trials in the subsequent years. We will summarize the major advancements for the development of novel autologous GE-HSC cell and gene therapy strategies for hematopoietic diseases that are candidates for curative allogeneic bone marrow transplantation.
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It explains that supplying a homologous donor during break repair allows homologous recombination to introduce precise edits, from single-base changes to large cassette insertions.
“If a homologous donor DNA template is provided during the DSB repair, the homologous recombination (HR) repair pathway can generate more precise changes to the target DNA, including single nucleotide changes to insertion of large gene cassettes8,9.”
From A high-fidelity Cas9 mutant delivered as a ribonucleoprotein complex enables efficient gene editing in human hematopoietic stem and progenitor cells (2018) · cites this paper as [9]
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- Authors
- Dever, D. P., & Porteus, M. H.
- Affiliations
- Stanford Medicine (US)
- Corresponding author
- Porteus, Matthew H.
- Venue
- Current Opinion in Hematology
- Published
- 2017-11
- Volume
- 24
- Issue
- 6
- Pages
- 481-488
- ISSN
- 1065-6251 (ISSN-L)
- 1531-7048
- PMC
- PMC5766279
- OpenAlex
- W2745866632
- Semantic Scholar
- 7926b047577245a5054733a2ab18afdfb9b81814
- Cited by
- 62
- References
- 41
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 2 · 2023: 1 · 2022: 7 · 2021: 16 · 2020: 14 · 2019: 10 · 2018: 4 · 2017: 2
- FWCI
- 0.77
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Current Opinion in Hematology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (5r01ai120766-02)
- National Institute of Allergy and Infectious Diseases (R01-AI120766, R01AI097320)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Health Sciences › Medicine › Oncology › CAR-T cell therapy research
- Keywords
- hematopoietic stem cells, CRISPR/Cas9, genome editing, gene therapy, clinical translation, β-hemoglobinopathies, primary immunodeficiency, autologous cell therapy, allogeneic bone marrow transplantation, DNA double-strand break repair
- MeSH terms
- Gene Editing, Hematopoietic Stem Cells, Humans, Genetic Diseases, Inborn, CRISPR-Cas Systems
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