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

De Ravin, Suk S.
; 
Wu, Xiaolin
; 
Moir, Susan
; 
Anaya-O'Brien, Sandra
; 
Kwatemaa, Nana
; 
Littel, Patricia
; 
Theobald, Narda
; 
Choi, Uimook
; 
Su, Ling
; 
Marquesen, Martha
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Affiliation
National 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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2016-04-20
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Biological Sciences
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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 (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.
Citation
De 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
Publisher
American Association for the Advancement of Science
Journal
Science Translational Medicine
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URI
http://hdl.handle.net/10034/617220
DOI
10.1126/scitranslmed.aad8856
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Article
Language
en
Description
This 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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1946-6242
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http://stm.sciencemag.org/content/8/335/335ra57.short
http://www.ncbi.nlm.nih.gov/pubmed/27099176