In the in vivo part, ASOs are injected either i.v. model. This review summarizes the advances in splice correction, as a personalized medicine for XLA, and outlines the promises and challenges of using this technology as a curative long-term treatment option. gene result in a developmental block in the bone marrow at the stage where the transition between pro-B and pre-B cells takes place. In XLA, precursor B cells are present, but they fail to differentiate [6, 7]. Hence, the amount of peripheral B cells is low, and they are of an immature phenotype , resulting in the absence of antigen-specific Ig production . Female carriers are healthy, as the B lymphocytes with the X chromosome expressing the wild-type BTK are specifically selected for; in fact, only a single female with XLA has been definitively reported . Mouse models Rabbit Polyclonal to ACOT8 have been extensively used to study the mechanisms of Indirubin-3-monoxime the immunodeficiency, and dysfunction of the mouse Btk was also identified as the underlying defect in mice affected by X-linked immunodeficiency (XID) [11C13]. This was subsequently confirmed by mouse models with engineered knockouts (KO), which have essentially the same phenotype as Indirubin-3-monoxime the XID mice [14C16]. These mice have a 50?% reduction in the number of splenic B cells and reduced levels of secretory IgM and IgG3 and impaired responses to certain T cell-independent antigens . In humans, the point mutation found in XID mice causes classical XLA; Btk deficiency therefore results in a less severe phenotype in mice . XLA patients are vulnerable to bacterial and enteroviral infections. Encapsulated bacteria such as and are the most typical causes of bacterial infections [19C23]. Clinically, XLA patients display infections in the upper and lower respiratory and gastrointestinal tract . Currently, there is no curative therapy for XLA, and the treatment instead consists of immunoglobulin substitution and frequent administration of antibiotics. This is suboptimal , since the patients quality of life is reduced owing to recurrent infections [20, 26, 23, 24]. Some attempts have been made to treat XLA patients by stem cell transplantation, but the results have not been satisfactory due to transplantation complications . Therefore, alternative strategies such as gene therapy remain valid [1, 17]. In this review, we will briefly discuss one such putative XLA therapy, splice-correction, and its possible future applications. BTK Belongs to a Family of Kinases and Signals Downstream of the B Cell Receptor BTK is expressed from Indirubin-3-monoxime a 37.5-kb gene that contains 19 exons and has a molecular weight of 77?kDa [28C31]. It belongs to the TEC family of non-receptor kinases (TFKs), consisting of additional four members: TEC, BMX, ITK, and TXK/RLK . Among those, BTK and ITK are the only members definitively associated with human disease . While BTK deficiency causes XLA, mutations inactivating ITK result instead in susceptibility to severe Epstein-Barr virus infections (reviewed in ). ITK is also involved in the formation of a fusion gene causing T cell lymphomas [35C38]. BTK Indirubin-3-monoxime is expressed in myeloid cells and in B lineage cells with the important exception of mature plasma cells [39C41]. Although the phenotypic alterations caused by mutations are predominantly limited to the B cell lineage, there have been reports of other affected cell lineages as well [42, 43]. Similar to other TFKs, BTK has unique domains that are important for downstream signaling . These are from the N terminus: pleckstrin homology (PH), Tec homology (TH), Src homology 3 (SH3), SH2, and the catalytic kinase domain . Upon BCR stimulation, BTK translocates to the plasma membrane, where it is phosphorylated at Y551 of the kinase domain by SRC.