title: Splice-correction strategies for treatment of X-linked agammaglobulinemia.
abstract: X-linked agammaglobulinemia (XLA) is a primary immunodeficiency disease caused by mutations in the gene coding for Bruton's tyrosine kinase (BTK). Deficiency of BTK leads to a developmental block in B cell differentiation; hence, the patients essentially lack antibody-producing plasma cells and are susceptible to various infections. A substantial portion of the mutations in BTK results in splicing defects, consequently preventing the formation of protein-coding mRNA. Antisense oligonucleotides (ASOs) are therapeutic compounds that have the ability to modulate pre-mRNA splicing and alter gene expression. The potential of ASOs has been exploited for a few severe diseases, both in pre-clinical and clinical studies. Recently, advances have also been made in using ASOs as a personalized therapy for XLA. Splice-correction of BTK has been shown to be feasible for different mutations in vitro, and a recent proof-of-concept study demonstrated the feasibility of correcting splicing and restoring BTK both ex vivo and in vivo in a humanized bacterial artificial chromosome (BAC)-transgenic mouse 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.
authors: Department of Laboratory Medicine, Clinical Research Center, Karolinska Institutet, Karolinska University Hospital, Novum Hälsovägen 7, 141 57, Huddinge, Sweden.
authors: Burcu
authors: B
authors: Bestas
authors: Janne J
authors: JJ
authors: Turunen
authors: K Emelie M
authors: KE
authors: Blomberg
authors: Qing
authors: Q
authors: Wang
authors: Robert
authors: R
authors: Månsson
authors: Samir
authors: S
authors: El Andaloussi
authors: Anna
authors: A
authors: Berglöf
authors: C I Edvard
authors: CI
authors: Smith
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D000361:Agammaglobulinemia / Q000235:genetics*; D017398:Alternative Splicing; D000818:Animals; D040181:Genetic Diseases, X-Linked / Q000235:genetics*; D006801:Humans; D009154:Mutation; D011505:Protein-Tyrosine Kinases / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D015398:Signal Transduction
chemical_list: D012333:RNA, Messenger; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C000625951:Btk protein, mouse
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