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Sci Transl Med. 2016 Apr 20;8(335):335ra57. doi: 10.1126/scitranslmed.aad8856.

Lentiviral hematopoietic stem cell gene therapy for X-linked severe combined immunodeficiency.

Author information

1
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.
2
Cancer Research Technology Program, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
3
Laboratory of Immunoregulation, NIAID, NIH, Bethesda, MD 20892, USA.
4
Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA.
5
Cancer and Inflammation Program, National Cancer Institute Frederick, Frederick, MD 21702, USA.
6
Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
7
Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
8
Texas Children's Hospital, Houston, TX 77030, USA.
9
Department of Pediatrics, Benioff Children's Hospital, and University of California, San Francisco, San Francisco, CA, USA.
10
Audentes Therapeutics, San Francisco, CA 94101, USA.

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.

PMID:
27099176
PMCID:
PMC5557273
DOI:
10.1126/scitranslmed.aad8856
[Indexed for MEDLINE]
Free PMC Article

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