B cell-specific lentiviral gene therapy leads to sustained B-cell functional recovery in a murine model of X-linked agammaglobulinemia.
|Title||B cell-specific lentiviral gene therapy leads to sustained B-cell functional recovery in a murine model of X-linked agammaglobulinemia.|
|Publication Type||Journal Article|
|Year of Publication||2010|
|Authors||Kerns HM, Ryu BY, Stirling BV, Sather BD, Astrakhan A, Humblet-Baron S, Liggitt D, Rawlings DJ|
|Date Published||2010 Mar 18|
|Keywords||Agammaglobulinemia, Animals, Antigens, CD79, B-Lymphocytes, Bone Marrow Cells, Bone Marrow Transplantation, Cell Line, Cell Lineage, Disease Models, Animal, Gene Therapy, Genetic Diseases, X-Linked, Genetic Vectors, Humans, Immunoglobulin Heavy Chains, Lentivirus, Mice, Mice, Inbred C57BL, Organ Specificity, Protein-Tyrosine Kinases, Recovery of Function|
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 (Emu) and Igbeta (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 EmuB29-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.