Lentiviral hematopoietic stem cell gene therapy for X-linked severe combined immunodeficiency
AuthorsDe Ravin, Suk S.
Buckner, Clarissa M.
Zarember, Kol A.
O'Connor, Geraldine M.
McVicar, Daniel W.
Throm, Robert E.
Notarangelo, Luigi D.
Hanson, I. Celine
Cowan, Mort J.
Gray, John T.
Sorrentino, Brian P.
Malech, Harry L.
AffiliationNational Institute of Allergy and Infectious Diseases; Frederick National Laboratory for Cancer Research; Laboratory of Immunoregulation; St. Jude Children’s Research Hospital; National Cancer Institute-Frederick; Boston Children’s Hospital, Harvard Medical School; Texas Children’s Hospital; Benioff Children's Hospital and University of California San Francisco; Audentes Therapeutics
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AbstractX-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 (gammac) of several interleukin receptors. Gamma-retroviral (gammaRV) 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 gammac 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.
CitationDe Ravin, S. S., et. al. (2016). Lentiviral hematopoietic stem cell gene therapy for X-linked severe combined immunodeficiency. Science Translational Medicine, 8(335), 335ra357. DOI:10.1126/scitranslmed.aad8856
JournalScience Translational Medicine
DescriptionThis document is the Accepted Manuscript version of a published work that appeared in final form in Science Translational Medicine. To access the final edited and published work see http://dx.doi.org/10.1126/scitranslmed.aad8856
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