Article (Scientific journals)
B cell-specific lentiviral gene therapy leads to sustained B-cell functional recovery in a murine model of X-linked agammaglobulinemia
Kerns, H. M.; Ryu, B. Y.; Stirling, B. V. et al.
2010In Blood, 115 (11), p. 2146-55
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Abstract :
[en] The immunodeficiency disorder, X-linked agammaglobulinemia (XLA), results from mutations in the gene encoding Bruton tyrosine kinase (Btk). Btk is required for pre-B cell clonal expansion and B-cell antigen receptor signaling. XLA patients lack mature B cells and immunoglobulin and experience recurrent bacterial infections only partially mitigated by life-long antibody replacement therapy. In pursuit of definitive therapy for XLA, we tested ex vivo gene therapy using a lentiviral vector (LV) containing the immunoglobulin enhancer (Eµ) and IgB (B29) minimal promoter to drive B lineage-specific human Btk expression in Btk/Teck-/- mice, a strain that reproduces the features of human XLA. After transplantation of EµB29-Btk-LV-transduced stem cells, treated mice showed significant, albeit incomplete, rescue of mature B cells in the bone marrow, peripheral blood, spleen, and peritoneal cavity, and improved responses to T-independent and T-dependent antigens. LV-teated B cells exhibited enhanced B-cell antigen receptor signaling and an in vivo selective advantage in the peripheral versus central B-cell compartment. Secondary transplantation showed sustained Btk expression, viral integration, and partial functional responses, consistent with long-term stem cell marking; and serial transplantation revealed no evidence for cellular or systemic toxicity. These findings strongly support pursuit of B lineage-targeted LV gene therapy in human XLA.
Disciplines :
Hematology
Author, co-author :
Kerns, H. M.
Ryu, B. Y.
Stirling, B. V.
Sather, B. D.
Astrakhan, A.
Humblet, Stéphanie ;  Université de Liège - ULiège > GIGA-R : Hématologie
Liggitt, D.
Rawlings, D. J.
Language :
English
Title :
B cell-specific lentiviral gene therapy leads to sustained B-cell functional recovery in a murine model of X-linked agammaglobulinemia
Publication date :
2010
Journal title :
Blood
ISSN :
0006-4971
eISSN :
1528-0020
Publisher :
American Society of Hematology, Washington, United States - District of Columbia
Volume :
115
Issue :
11
Pages :
2146-55
Peer reviewed :
Peer Reviewed verified by ORBi
Available on ORBi :
since 27 January 2012

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