ArticleStem cells (Dayton, Ohio)2015
Regulated apoptosis of genetically modified hematopoietic stem and progenitor cells via an inducible caspase-9 suicide gene in rhesus macaques.
Article in Stem cells (Dayton, Ohio), 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
25 citing papers in PubMed, 31 citations in OpenAlex.
- Interplay of telomerase non-canonical functions in NK cell resistance to iCasp9-mediated apoptosis.Cell death discovery · 2026Article
- Cytokine-Engineered Chimeric Antigen Receptor-T Cell Therapy: How to Balance the Efficacy and Toxicity.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Review
- Caspase 9-induced apoptosis enables efficient fetal cell ablation and disease modeling.Nature communications · 2025Article
- Emerging approaches for preventing cytokine release syndrome in CAR-T cell therapy.Journal of materials chemistry. B · 2022Review
- Review
- Combinatorial suicide gene strategies for the safety of cell therapies.Frontiers in immunology · 2022Article
- Increased Susceptibility of the CD57International journal of molecular sciences · 2021Article
- Depletion of T cellsFrontiers in immunology · 2021Article
- Next generation chimeric antigen receptor T cells: safety strategies to overcome toxicity.Molecular cancer · 2019Review
- A Cetuximab-Mediated Suicide System in Chimeric Antigen Receptor-Modified Hematopoietic Stem Cells for Cancer Therapy.Human gene therapy · 2019Article
- Chimeric antigen receptor T-cell approaches to HIV cure.Current opinion in HIV and AIDS · 2018Review
- Ex Vivo Selection of Transduced Hematopoietic Stem Cells for Gene Therapy of β-Hemoglobinopathies.Molecular therapy : the journal of the American Society of Gene Therapy · 2018Article
- Exploiting Cell Death Pathways for Inducible Cell Elimination to Modulate Graft-versus-Host-Disease.Biomedicines · 2017Review
- Antitumor effects of a dual-specific lentiviral vector carrying the Escherichia coli purine nucleoside phosphorylase gene.International journal of oncology · 2017Article
- Fail-Safe System against Potential Tumorigenicity after Transplantation of iPSC Derivatives.Stem cell reports · 2017Article
- Rhesus iPSC Safe Harbor Gene-Editing Platform for Stable Expression of Transgenes in Differentiated Cells of All Germ Layers.Molecular therapy : the journal of the American Society of Gene Therapy · 2017Article
- Improving the safety of T-Cell therapies using an inducible caspase-9 gene.Experimental hematology · 2016Review
- Genome editing and the next generation of antiviral therapy.Human genetics · 2016Review
- Serial Activation of the Inducible Caspase 9 Safety Switch After Human Stem Cell Transplantation.Molecular therapy : the journal of the American Society of Gene Therapy · 2016Article
- Escape Mutations, Ganciclovir Resistance, and Teratoma Formation in Human iPSCs Expressing an HSVtk Suicide Gene.Molecular therapy. Nucleic acids · 2016Article
Corrections and comments
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Authors and funding
10 authors at 4 institutions in 1 country.
Funding
Abstract
The high risk of insertional oncogenesis reported in clinical trials using integrating retroviral vectors to genetically modify hematopoietic stem and progenitor cells (HSPCs) requires the development of safety strategies to minimize risks associated with novel cell and gene therapies. The ability to ablate genetically modified cells in vivo is desirable, should an abnormal clone emerge. Inclusion of "suicide genes" in vectors to facilitate targeted ablation of vector-containing abnormal clones in vivo is one potential safety approach. We tested whether the inclusion of the "inducible Caspase-9" (iCasp9) suicide gene in a gamma-retroviral vector facilitated efficient elimination of vector-containing HSPCs and their hematopoietic progeny in vivo long-term, in an autologous non-human primate transplantation model. Following stable engraftment of iCasp9 expressing hematopoietic cells in rhesus macaques, administration of AP1903, a chemical inducer of dimerization able to activate iCasp9, specifically eliminated vector-containing cells in all hematopoietic lineages long-term, suggesting activity at the HSPC level. Between 75% and 94% of vector-containing cells were eliminated by well-tolerated AP1903 dosing, but lack of complete ablation was linked to lower iCasp9 expression in residual cells. Further investigation of resistance mechanisms demonstrated upregulation of Bcl-2 in hematopoietic cell lines transduced with the vector and resistant to AP1903 ablation. These results demonstrate both the potential and the limitations of safety approaches using iCasp9 to HSPC-targeted gene therapy settings, in a model with great relevance to clinical development.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.