A Rapamycin-Activated Caspase 9-Based Suicide Gene
| العنوان: | A Rapamycin-Activated Caspase 9-Based Suicide Gene |
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| المؤلفون: | Simon Thomas, Martin Pule, Maria Stavrou, Christopher G. Davis, Shaun Cordoba, Shimobi Onuoha, Charlotte Traynor-White, Brian Philip |
| المصدر: | Molecular Therapy |
| سنة النشر: | 2017 |
| مصطلحات موضوعية: | 0301 basic medicine, Cytotoxicity, Immunologic, T-Lymphocytes, Activated Caspase-9, Genetic Vectors, Gene Expression, CD19, Immunophenotyping, 03 medical and health sciences, Mice, Drug Discovery, Genetics, Animals, Humans, cancer, Protein Interaction Domains and Motifs, Molecular Biology, PI3K/AKT/mTOR pathway, Caspase, Cells, Cultured, Pharmacology, Caspase-9, Sirolimus, biology, Chemistry, Genes, Transgenic, Suicide, Suicide gene, Caspase 9, 030104 developmental biology, FKBP, suicide genes, Gene Expression Regulation, CARD domain, Cancer research, biology.protein, Molecular Medicine, Original Article, immunotherapy, Biomarkers |
| الوصف: | Engineered T cell therapies show considerable promise in the treatment of refractory malignancies. Given the ability of engineered T cells to engraft and persist for prolonged periods along with unpredicted toxicities, incorporation of a suicide gene to allow selective depletion after administration is desirable. Rapamycin is a safe and widely available immunosuppressive pharmaceutical that acts by heterodimerization of FKBP12 with the FRB fragment of mTOR. The apical caspase caspase 9 is activated by homodimerization through its CARD domain. We developed a rapamycin-induced caspase 9 suicide gene. First, we showed that caspase 9 could be activated by a two-protein format with replacement of the CARD domain with both FRB and FKBP12. We next identified an optimal compact single-protein rapamycin caspase 9 (rapaCasp9) by fusing both FRB and FKBP12 with the catalytic domain of caspase 9. Functionality of rapaCasp9 when co-expressed with a CD19 CAR was demonstrated in vitro and in vivo. Administration of engineered T cells showed promising results in the treatment of malignancies. The possibility of long-term persistence of these cells, combined with unpredicted toxicities, calls for the incorporation of a suicide gene, allowing selective ablation of these cells. We studied a new suicide gene that is activated by an off-the-shelf pharmaceutical agent. |
| تدمد: | 1525-0024 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::c5b0fd90e5c692ca05c59934bb9aecf3Test https://pubmed.ncbi.nlm.nih.gov/29661681Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....c5b0fd90e5c692ca05c59934bb9aecf3 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15250024 |
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