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Lentivirus Mediated Correction of Artemis-Deficient Severe Combined Immunodeficiency.
Hum Gene Ther. 2017 01; 28(1):112-124.HG

Abstract

During B and T lymphocyte maturation, V(D)J recombination is initiated by creation of DNA double-strand breaks. Artemis is an exonuclease essential for their subsequent repair by nonhomologous end-joining. Mutations in DCLRE1C, the gene encoding Artemis, cause T-B-NK+ severe combined immunodeficiency (ART-SCID) and also confer heightened sensitivity to ionizing radiation and alkylating chemotherapy. Although allogeneic hematopoietic cell transplantation can treat ART-SCID, conditioning regimens are poorly tolerated, leading to early mortality and/or late complications, including short stature, endocrinopathies, and dental aplasia. However, without alkylating chemotherapy as preconditioning, patients usually have graft rejection or limited T cell and no B cell recovery. Thus, addition of normal DCLRE1C cDNA to autologous hematopoietic stem cells is an attractive strategy to treat ART-SCID. We designed a self-inactivating lentivirus vector containing human Artemis cDNA under transcriptional regulation of the human endogenous Artemis promoter (AProArt). Fibroblasts from ART-SCID patients transduced with AProArt lentivirus showed correction of radiosensitivity. Mobilized peripheral blood CD34+ cells from an ART-SCID patient as well as hematopoietic stem cells from Artemis-deficient mice demonstrated restored T and B cell development following AProArt transduction. Murine hematopoietic cells transduced with AProArt exhibited no increase in replating potential in an in vitro immortalization assay, and analysis of AProArt lentivirus insertions showed no predilection for sites that could activate oncogenes. These efficacy and safety findings support institution of a clinical trial of gene addition therapy for ART-SCID.

Authors+Show Affiliations

1 Department of Pediatrics, University of California School of Medicine and University of California San Francisco Benioff Children's Hospital , San Francisco, San Francisco, California.1 Department of Pediatrics, University of California School of Medicine and University of California San Francisco Benioff Children's Hospital , San Francisco, San Francisco, California.1 Department of Pediatrics, University of California School of Medicine and University of California San Francisco Benioff Children's Hospital , San Francisco, San Francisco, California.1 Department of Pediatrics, University of California School of Medicine and University of California San Francisco Benioff Children's Hospital , San Francisco, San Francisco, California.1 Department of Pediatrics, University of California School of Medicine and University of California San Francisco Benioff Children's Hospital , San Francisco, San Francisco, California.1 Department of Pediatrics, University of California School of Medicine and University of California San Francisco Benioff Children's Hospital , San Francisco, San Francisco, California.2 Departments of Microbiology, Immunology and Molecular Genetics and Pediatrics, University of California Los Angeles , Los Angeles, California.3 Department of Genetics, Cell Biology and Development, University of Minnesota , Minneapolis, Minnesota.1 Department of Pediatrics, University of California School of Medicine and University of California San Francisco Benioff Children's Hospital , San Francisco, San Francisco, California.4 Department of Medical and Molecular Genetics, Indiana University, and the Indiana University Viral Production Facility, Indianapolis, Indiana.5 Institute for Experimental Hematology, Hannover Medical School , Hannover, Germany.5 Institute for Experimental Hematology, Hannover Medical School , Hannover, Germany.2 Departments of Microbiology, Immunology and Molecular Genetics and Pediatrics, University of California Los Angeles , Los Angeles, California.6 Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, Division of Intramural Research, National Institutes of Health , Bethesda, Maryland.3 Department of Genetics, Cell Biology and Development, University of Minnesota , Minneapolis, Minnesota.1 Department of Pediatrics, University of California School of Medicine and University of California San Francisco Benioff Children's Hospital , San Francisco, San Francisco, California.1 Department of Pediatrics, University of California School of Medicine and University of California San Francisco Benioff Children's Hospital , San Francisco, San Francisco, California.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

27611239

Citation

Punwani, Divya, et al. "Lentivirus Mediated Correction of Artemis-Deficient Severe Combined Immunodeficiency." Human Gene Therapy, vol. 28, no. 1, 2017, pp. 112-124.
Punwani D, Kawahara M, Yu J, et al. Lentivirus Mediated Correction of Artemis-Deficient Severe Combined Immunodeficiency. Hum Gene Ther. 2017;28(1):112-124.
Punwani, D., Kawahara, M., Yu, J., Sanford, U., Roy, S., Patel, K., Carbonaro, D. A., Karlen, A. D., Khan, S., Cornetta, K., Rothe, M., Schambach, A., Kohn, D. B., Malech, H. L., McIvor, R. S., Puck, J. M., & Cowan, M. J. (2017). Lentivirus Mediated Correction of Artemis-Deficient Severe Combined Immunodeficiency. Human Gene Therapy, 28(1), 112-124. https://doi.org/10.1089/hum.2016.064
Punwani D, et al. Lentivirus Mediated Correction of Artemis-Deficient Severe Combined Immunodeficiency. Hum Gene Ther. 2017;28(1):112-124. PubMed PMID: 27611239.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Lentivirus Mediated Correction of Artemis-Deficient Severe Combined Immunodeficiency. AU - Punwani,Divya, AU - Kawahara,Misako, AU - Yu,Jason, AU - Sanford,Ukina, AU - Roy,Sushmita, AU - Patel,Kiran, AU - Carbonaro,Denise A, AU - Karlen,Andrea D, AU - Khan,Sara, AU - Cornetta,Kenneth, AU - Rothe,Michael, AU - Schambach,Axel, AU - Kohn,Donald B, AU - Malech,Harry L, AU - McIvor,R Scott, AU - Puck,Jennifer M, AU - Cowan,Morton J, Y1 - 2016/09/07/ PY - 2016/9/10/pubmed PY - 2017/8/24/medline PY - 2016/9/10/entrez KW - Artemis KW - gene therapy KW - lentivirus KW - radiation sensitivity KW - severe combined immunodeficiency SP - 112 EP - 124 JF - Human gene therapy JO - Hum. Gene Ther. VL - 28 IS - 1 N2 - During B and T lymphocyte maturation, V(D)J recombination is initiated by creation of DNA double-strand breaks. Artemis is an exonuclease essential for their subsequent repair by nonhomologous end-joining. Mutations in DCLRE1C, the gene encoding Artemis, cause T-B-NK+ severe combined immunodeficiency (ART-SCID) and also confer heightened sensitivity to ionizing radiation and alkylating chemotherapy. Although allogeneic hematopoietic cell transplantation can treat ART-SCID, conditioning regimens are poorly tolerated, leading to early mortality and/or late complications, including short stature, endocrinopathies, and dental aplasia. However, without alkylating chemotherapy as preconditioning, patients usually have graft rejection or limited T cell and no B cell recovery. Thus, addition of normal DCLRE1C cDNA to autologous hematopoietic stem cells is an attractive strategy to treat ART-SCID. We designed a self-inactivating lentivirus vector containing human Artemis cDNA under transcriptional regulation of the human endogenous Artemis promoter (AProArt). Fibroblasts from ART-SCID patients transduced with AProArt lentivirus showed correction of radiosensitivity. Mobilized peripheral blood CD34+ cells from an ART-SCID patient as well as hematopoietic stem cells from Artemis-deficient mice demonstrated restored T and B cell development following AProArt transduction. Murine hematopoietic cells transduced with AProArt exhibited no increase in replating potential in an in vitro immortalization assay, and analysis of AProArt lentivirus insertions showed no predilection for sites that could activate oncogenes. These efficacy and safety findings support institution of a clinical trial of gene addition therapy for ART-SCID. SN - 1557-7422 UR - https://www.unboundmedicine.com/medline/citation/27611239/Lentivirus_Mediated_Correction_of_Artemis_Deficient_Severe_Combined_Immunodeficiency_ L2 - https://www.liebertpub.com/doi/full/10.1089/hum.2016.064?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -