In:
Blood, American Society of Hematology, Vol. 115, No. 11 ( 2010-03-18), p. 2146-2155
Abstract:
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 Igβ (B29) minimal promoter to drive B lineage–specific human Btk expression in Btk/Tec−/− 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-treated 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.
Type of Medium:
Online Resource
ISSN:
0006-4971
,
1528-0020
DOI:
10.1182/blood-2009-09-241869
Language:
English
Publisher:
American Society of Hematology
Publication Date:
2010
detail.hit.zdb_id:
1468538-3
detail.hit.zdb_id:
80069-7
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