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

Hdl Handle:
http://hdl.handle.net/10034/617220
Title:
Lentiviral hematopoietic stem cell gene therapy for X-linked severe combined immunodeficiency
Authors:
De Ravin, Suk S.; Wu, Xiaolin; Moir, Susan; Anaya-O'Brien, Sandra; Kwatemaa, Nana; Littel, Patricia; Theobald, Narda; Choi, Uimook; Su, Ling; Marquesen, Martha; Hilligoss, Dianne; Lee, Janet; Buckner, Clarissa M.; Zarember, Kol A.; O'Connor, Geraldine M.; McVicar, Daniel W.; Kuhns, Douglas; Throm, Robert E.; Zhou, Sheng; Notarangelo, Luigi D.; Hanson, I. Celine; Cowan, Mort J.; Kang, Elizabeth; Hadigan, Coleen; Meagher, Michael; Gray, John T.; Sorrentino, Brian P.; Malech, Harry L.
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.
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
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
Publication Date:
20-Apr-2016
URI:
http://hdl.handle.net/10034/617220
DOI:
10.1126/scitranslmed.aad8856
Additional Links:
http://stm.sciencemag.org/content/8/335/335ra57.short; http://www.ncbi.nlm.nih.gov/pubmed/27099176
Type:
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
EISSN:
1946-6242
Appears in Collections:
Biological Sciences

Full metadata record

DC FieldValue Language
dc.contributor.authorDe Ravin, Suk S.en
dc.contributor.authorWu, Xiaolinen
dc.contributor.authorMoir, Susanen
dc.contributor.authorAnaya-O'Brien, Sandraen
dc.contributor.authorKwatemaa, Nanaen
dc.contributor.authorLittel, Patriciaen
dc.contributor.authorTheobald, Nardaen
dc.contributor.authorChoi, Uimooken
dc.contributor.authorSu, Lingen
dc.contributor.authorMarquesen, Marthaen
dc.contributor.authorHilligoss, Dianneen
dc.contributor.authorLee, Janeten
dc.contributor.authorBuckner, Clarissa M.en
dc.contributor.authorZarember, Kol A.en
dc.contributor.authorO'Connor, Geraldine M.en
dc.contributor.authorMcVicar, Daniel W.en
dc.contributor.authorKuhns, Douglasen
dc.contributor.authorThrom, Robert E.en
dc.contributor.authorZhou, Shengen
dc.contributor.authorNotarangelo, Luigi D.en
dc.contributor.authorHanson, I. Celineen
dc.contributor.authorCowan, Mort J.en
dc.contributor.authorKang, Elizabethen
dc.contributor.authorHadigan, Coleenen
dc.contributor.authorMeagher, Michaelen
dc.contributor.authorGray, John T.en
dc.contributor.authorSorrentino, Brian P.en
dc.contributor.authorMalech, Harry L.en
dc.date.accessioned2016-07-19T14:13:59Z-
dc.date.available2016-07-19T14:13:59Z-
dc.date.issued2016-04-20-
dc.identifier.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.aad8856en
dc.identifier.doi10.1126/scitranslmed.aad8856-
dc.identifier.urihttp://hdl.handle.net/10034/617220-
dc.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.aad8856en
dc.description.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.en
dc.language.isoenen
dc.publisherAmerican Association for the Advancement of Scienceen
dc.relation.urlhttp://stm.sciencemag.org/content/8/335/335ra57.shorten
dc.relation.urlhttp://www.ncbi.nlm.nih.gov/pubmed/27099176en
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/en
dc.subjectGene therapyen
dc.subjectImmunodeficiencyen
dc.titleLentiviral hematopoietic stem cell gene therapy for X-linked severe combined immunodeficiencyen
dc.typeArticleen
dc.identifier.eissn1946-6242-
dc.contributor.departmentNational 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 Therapeuticsen
dc.identifier.journalScience Translational Medicineen
dc.date.accepted2016-04-20-
or.grant.openaccessYesen
rioxxterms.funderIntramural Research Program of NIAID, NIH,en
rioxxterms.identifier.projectExternally Funded - not through Chester Universityen
rioxxterms.versionAMen
rioxxterms.licenseref.startdate2016-10-20-
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