Frank J. T. Staal

INTRODUCTION: X-linked agammaglobulinemia (XLA) is the most common primary immunodeficiency in man, and is caused by a single genetic defect. Inactivating mutations in the Bruton's tyrosine kinase (BTK) gene are invariably the cause of XLA,. XLA is characterized by a differentiation arrest at the pre-B cell stage, the absence of immunoglobulins and recurrent bacterial infections, making it an insidious disease that gradually disables the patient, and can result in death due to chronic lung disease. Current treatment involves prophylactic antibiotics and immunoglobulin infusions, which are non-curative. This disease is a good candidate for curative hematopoietic stem cell (HSC)-based gene therapy, which could correct the B cell and myeloid deficiencies. AREAS COVERED: This paper reviews the basic biology of BTK in B cell development, the clinical features of XLA, and the possibilities of gene therapy for XLA, covering the literature from 1995 to 2010. EXPERT OPINION: Work from various laboratories demonstrates the feasibility of using gene-corrected HSCs to complement the immune defects of Btk-deficiency in mice. We propose that it is timely to start clinical programs to develop stem cell based therapy for XLA, using gene-corrected autologous HSC.