Splice-correction strategies for treatment of X-linked agammaglobulinemia

Curr Allergy Asthma Rep. 2015 Mar;15(3):510. doi: 10.1007/s11882-014-0510-0.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Agammaglobulinaemia Tyrosine Kinase
  • Agammaglobulinemia / genetics*
  • Alternative Splicing
  • Animals
  • Genetic Diseases, X-Linked / genetics*
  • Humans
  • Mutation
  • Protein-Tyrosine Kinases / genetics
  • RNA, Messenger / genetics
  • Signal Transduction

Substances

  • RNA, Messenger
  • Protein-Tyrosine Kinases
  • Agammaglobulinaemia Tyrosine Kinase
  • BTK protein, human
  • Btk protein, mouse

Supplementary concepts

  • Bruton type agammaglobulinemia