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Lentiviral hematopoietic stem cell gene therapy for X-linked severe combined immunodeficiency.
Sci Transl Med. 2016 04 20; 8(335):335ra57.ST

Abstract

X-linked severe combined immunodeficiency (SCID-X1) is a profound deficiency of T, B, and natural killer (NK) cell immunity caused by mutations inIL2RGencoding the common chain (γc) of several interleukin receptors. Gamma-retroviral (γRV) gene therapy of SCID-X1 infants without conditioning restores T cell immunity without B or NK cell correction, but similar treatment fails in older SCID-X1 children. We used a lentiviral gene therapy approach to treat five SCID-X1 patients with persistent immune dysfunction despite haploidentical hematopoietic stem cell (HSC) transplant in infancy. Follow-up data from two older patients demonstrate that lentiviral vector γc transduced autologous HSC gene therapy after nonmyeloablative busulfan conditioning achieves selective expansion of gene-marked T, NK, and B cells, which is associated with sustained restoration of humoral responses to immunization and clinical improvement at 2 to 3 years after treatment. Similar gene marking levels have been achieved in three younger patients, albeit with only 6 to 9 months of follow-up. Lentiviral gene therapy with reduced-intensity conditioning appears safe and can restore humoral immune function to posthaploidentical transplant older patients with SCID-X1.

Authors+Show Affiliations

Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA. sderavin@niaid.nih.gov hmalech@niaid.nih.gov.Cancer Research Technology Program, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.Laboratory of Immunoregulation, NIAID, NIH, Bethesda, MD 20892, USA.Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA.Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA.Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA.Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA.Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA.Cancer Research Technology Program, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA.Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA.Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA.Laboratory of Immunoregulation, NIAID, NIH, Bethesda, MD 20892, USA.Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA.Cancer and Inflammation Program, National Cancer Institute Frederick, Frederick, MD 21702, USA.Cancer and Inflammation Program, National Cancer Institute Frederick, Frederick, MD 21702, USA.Cancer Research Technology Program, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.Texas Children's Hospital, Houston, TX 77030, USA.Department of Pediatrics, Benioff Children's Hospital, and University of California, San Francisco, San Francisco, CA, USA.Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA.Laboratory of Immunoregulation, NIAID, NIH, Bethesda, MD 20892, USA.Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.Audentes Therapeutics, San Francisco, CA 94101, USA.Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA. sderavin@niaid.nih.gov hmalech@niaid.nih.gov.No affiliation info available

Pub Type(s)

Clinical Trial, Phase I
Clinical Trial, Phase II
Journal Article
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

27099176

Citation

De Ravin, Suk See, et al. "Lentiviral Hematopoietic Stem Cell Gene Therapy for X-linked Severe Combined Immunodeficiency." Science Translational Medicine, vol. 8, no. 335, 2016, pp. 335ra57.
De Ravin SS, Wu X, Moir S, et al. Lentiviral hematopoietic stem cell gene therapy for X-linked severe combined immunodeficiency. Sci Transl Med. 2016;8(335):335ra57.
De Ravin, S. S., Wu, X., Moir, S., Anaya-O'Brien, S., Kwatemaa, N., Littel, P., Theobald, N., Choi, U., Su, L., Marquesen, M., Hilligoss, D., Lee, J., Buckner, C. M., Zarember, K. A., O'Connor, G., McVicar, D., Kuhns, D., Throm, R. E., Zhou, S., ... Kardava, . (2016). Lentiviral hematopoietic stem cell gene therapy for X-linked severe combined immunodeficiency. Science Translational Medicine, 8(335), 335ra57. https://doi.org/10.1126/scitranslmed.aad8856
De Ravin SS, et al. Lentiviral Hematopoietic Stem Cell Gene Therapy for X-linked Severe Combined Immunodeficiency. Sci Transl Med. 2016 04 20;8(335):335ra57. PubMed PMID: 27099176.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Lentiviral hematopoietic stem cell gene therapy for X-linked severe combined immunodeficiency. AU - De Ravin,Suk See, AU - Wu,Xiaolin, AU - Moir,Susan, AU - Anaya-O'Brien,Sandra, AU - Kwatemaa,Nana, AU - Littel,Patricia, AU - Theobald,Narda, AU - Choi,Uimook, AU - Su,Ling, AU - Marquesen,Martha, AU - Hilligoss,Dianne, AU - Lee,Janet, AU - Buckner,Clarissa M, AU - Zarember,Kol A, AU - O'Connor,Geraldine, AU - McVicar,Daniel, AU - Kuhns,Douglas, AU - Throm,Robert E, AU - Zhou,Sheng, AU - Notarangelo,Luigi D, AU - Hanson,I Celine, AU - Cowan,Mort J, AU - Kang,Elizabeth, AU - Hadigan,Coleen, AU - Meagher,Michael, AU - Gray,John T, AU - Sorrentino,Brian P, AU - Malech,Harry L, AU - Kardava,Lela, PY - 2015/11/16/received PY - 2016/03/03/accepted PY - 2016/4/22/entrez PY - 2016/4/22/pubmed PY - 2017/12/8/medline SP - 335ra57 EP - 335ra57 JF - Science translational medicine JO - Sci Transl Med VL - 8 IS - 335 N2 - X-linked severe combined immunodeficiency (SCID-X1) is a profound deficiency of T, B, and natural killer (NK) cell immunity caused by mutations inIL2RGencoding the common chain (γc) of several interleukin receptors. Gamma-retroviral (γRV) gene therapy of SCID-X1 infants without conditioning restores T cell immunity without B or NK cell correction, but similar treatment fails in older SCID-X1 children. We used a lentiviral gene therapy approach to treat five SCID-X1 patients with persistent immune dysfunction despite haploidentical hematopoietic stem cell (HSC) transplant in infancy. Follow-up data from two older patients demonstrate that lentiviral vector γc transduced autologous HSC gene therapy after nonmyeloablative busulfan conditioning achieves selective expansion of gene-marked T, NK, and B cells, which is associated with sustained restoration of humoral responses to immunization and clinical improvement at 2 to 3 years after treatment. Similar gene marking levels have been achieved in three younger patients, albeit with only 6 to 9 months of follow-up. Lentiviral gene therapy with reduced-intensity conditioning appears safe and can restore humoral immune function to posthaploidentical transplant older patients with SCID-X1. SN - 1946-6242 UR - https://www.unboundmedicine.com/medline/citation/27099176/Lentiviral_hematopoietic_stem_cell_gene_therapy_for_X_linked_severe_combined_immunodeficiency_ L2 - http://stm.sciencemag.org/cgi/pmidlookup?view=short&pmid=27099176 DB - PRIME DP - Unbound Medicine ER -