Lentiviral hematopoietic stem cell gene therapy for X-linked severe combined immunodeficiency.
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.
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.
Suk See
SS
De Ravin
Cancer Research Technology Program, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
Xiaolin
X
Wu
Laboratory of Immunoregulation, NIAID, NIH, Bethesda, MD 20892, USA.
Susan
S
Moir
Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA.
Sandra
S
Anaya-O'Brien
Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA.
Nana
N
Kwatemaa
Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA.
Patricia
P
Littel
Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA.
Narda
N
Theobald
Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA.
Uimook
U
Choi
Cancer Research Technology Program, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
Ling
L
Su
Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA.
Martha
M
Marquesen
Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA.
Dianne
D
Hilligoss
Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA.
Janet
J
Lee
Laboratory of Immunoregulation, NIAID, NIH, Bethesda, MD 20892, USA.
Clarissa M
CM
Buckner
Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA.
Kol A
KA
Zarember
Cancer and Inflammation Program, National Cancer Institute Frederick, Frederick, MD 21702, USA.
Geraldine
G
O'Connor
Cancer and Inflammation Program, National Cancer Institute Frederick, Frederick, MD 21702, USA.
Daniel
D
McVicar
Cancer Research Technology Program, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
Douglas
D
Kuhns
Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Robert E
RE
Throm
Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Sheng
S
Zhou
Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Luigi D
LD
Notarangelo
Texas Children's Hospital, Houston, TX 77030, USA.
I Celine
IC
Hanson
Department of Pediatrics, Benioff Children's Hospital, and University of California, San Francisco, San Francisco, CA, USA.
Mort J
MJ
Cowan
Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA.
Elizabeth
E
Kang
Laboratory of Immunoregulation, NIAID, NIH, Bethesda, MD 20892, USA.
Coleen
C
Hadigan
Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Michael
M
Meagher
Audentes Therapeutics, San Francisco, CA 94101, USA.
John T
JT
Gray
Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Brian P
BP
Sorrentino
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.
Harry L
HL
Malech
Lela
Kardava
D000293:Adolescent; D000328:Adult; D001402:B-Lymphocytes / Q000378:metabolism; D002648:Child; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006801:Humans; D053631:Interleukin Receptor Common gamma Subunit / Q000235:genetics; D007694:Killer Cells, Natural / Q000378:metabolism; D016086:Lentivirus / Q000235:genetics*; D008297:Male; D013601:T-Lymphocytes / Q000378:metabolism; D053632:X-Linked Combined Immunodeficiency Diseases / Q000235:genetics / Q000628:therapy*; D055815:Young Adult
C507941:IL2RG protein, human; D053631:Interleukin Receptor Common gamma Subunit