دورية أكاديمية
Cytoreductive conditioning intensity predicts clonal diversity in ADA-SCID retroviral gene therapy patients.
| العنوان: | Cytoreductive conditioning intensity predicts clonal diversity in ADA-SCID retroviral gene therapy patients. |
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| المؤلفون: | Cooper AR; Department of Microbiology, Immunology and Molecular Genetics and.; Molecular Biology Interdepartmental PhD Program, University of California, Los Angeles, Los Angeles, CA., Lill GR; Department of Microbiology, Immunology and Molecular Genetics and., Shaw K; Department of Microbiology, Immunology and Molecular Genetics and., Carbonaro-Sarracino DA; Department of Microbiology, Immunology and Molecular Genetics and., Davila A; Department of Microbiology, Immunology and Molecular Genetics and., Sokolic R; Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD; and., Candotti F; Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD; and., Pellegrini M; Department of Molecular, Cellular and Developmental Biology., Kohn DB; Department of Microbiology, Immunology and Molecular Genetics and.; Molecular Biology Institute, and.; Eli & Edythe Broad Center of Regenerative Medicine & Stem Cell Research, University of California, Los Angeles, Los Angeles, CA. |
| المصدر: | Blood [Blood] 2017 May 11; Vol. 129 (19), pp. 2624-2635. Date of Electronic Publication: 2017 Mar 28. |
| نوع المنشور: | Clinical Trial; Journal Article; Research Support, Non-U.S. Gov't; Research Support, N.I.H., Extramural |
| اللغة: | English |
| بيانات الدورية: | Publisher: Elsevier Country of Publication: United States NLM ID: 7603509 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1528-0020 (Electronic) Linking ISSN: 00064971 NLM ISO Abbreviation: Blood Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 2021- : [New York] : Elsevier Original Publication: New York, Grune & Stratton [etc.] |
| مواضيع طبية MeSH: | Adenosine Deaminase/*deficiency , Agammaglobulinemia/*genetics , Agammaglobulinemia/*therapy , Antineoplastic Agents, Alkylating/*therapeutic use , Busulfan/*therapeutic use , Gammaretrovirus/*genetics , Genetic Therapy/*methods , Genetic Vectors/*therapeutic use , Severe Combined Immunodeficiency/*genetics , Severe Combined Immunodeficiency/*therapy, Adaptor Proteins, Signal Transducing/genetics ; Adenosine Deaminase/genetics ; Agammaglobulinemia/pathology ; Child ; DNA-Binding Proteins/genetics ; Genetic Vectors/genetics ; Humans ; LIM Domain Proteins/genetics ; MDS1 and EVI1 Complex Locus Protein ; Proto-Oncogene Proteins/genetics ; Proto-Oncogenes/genetics ; Severe Combined Immunodeficiency/pathology ; T-Lymphocytes/cytology ; T-Lymphocytes/drug effects ; T-Lymphocytes/metabolism ; T-Lymphocytes/pathology ; Transcription Factors/genetics |
| مستخلص: | Retroviral gene therapy has proved efficacious for multiple genetic diseases of the hematopoietic system, but roughly half of clinical gene therapy trial protocols using gammaretroviral vectors have reported leukemias in some of the patients treated. In dramatic contrast, 39 adenosine deaminase-deficient severe combined immunodeficiency (ADA-SCID) patients have been treated with 4 distinct gammaretroviral vectors without oncogenic consequence. We investigated clonal dynamics and diversity in a cohort of 15 ADA-SCID children treated with gammaretroviral vectors and found clear evidence of genotoxicity, indicated by numerous common integration sites near proto-oncogenes and by increased abundance of clones with integrations near MECOM and LMO2 These clones showed stable behavior over multiple years and never expanded to the point of dominance or dysplasia. One patient developed a benign clonal dominance that could not be attributed to insertional mutagenesis and instead likely resulted from expansion of a transduced natural killer clone in response to chronic Epstein-Barr virus viremia. Clonal diversity and T-cell repertoire, measured by vector integration site sequencing and T-cell receptor β-chain rearrangement sequencing, correlated significantly with the amount of busulfan preconditioning delivered to patients and to CD34 + cell dose. These data, in combination with results of other ADA-SCID gene therapy trials, suggest that disease background may be a crucial factor in leukemogenic potential of retroviral gene therapy and underscore the importance of cytoreductive conditioning in this type of gene therapy approach. |
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| معلومات مُعتمدة: | M01 RR000043 United States RR NCRR NIH HHS; M01 RR000865 United States RR NCRR NIH HHS; R01 FD003005 United States FD FDA HHS; T32 GM007185 United States GM NIGMS NIH HHS |
| المشرفين على المادة: | 0 (Adaptor Proteins, Signal Transducing) 0 (Antineoplastic Agents, Alkylating) 0 (DNA-Binding Proteins) 0 (LIM Domain Proteins) 0 (LMO2 protein, human) 0 (MDS1 and EVI1 Complex Locus Protein) 0 (MECOM protein, human) 0 (Proto-Oncogene Proteins) 0 (Transcription Factors) EC 3.5.4.4 (Adenosine Deaminase) G1LN9045DK (Busulfan) |
| SCR Disease Name: | Severe combined immunodeficiency due to adenosine deaminase deficiency |
| تواريخ الأحداث: | Date Created: 20170330 Date Completed: 20170908 Latest Revision: 20210202 |
| رمز التحديث: | 20231215 |
| مُعرف محوري في PubMed: | PMC5428461 |
| DOI: | 10.1182/blood-2016-12-756734 |
| PMID: | 28351939 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1528-0020 |
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| DOI: | 10.1182/blood-2016-12-756734 |