Agammaglobulinemia: causative mutations and their implications for novel therapies

Abstract

Agammaglobulinemias are primary (inherited) immunodeficiencies characterized by the lack of functional B-cells and antibodies, and are caused by mutations in genes encoding components of the pre-B-cell or B-cell receptor, or their signaling pathways. The known genetic defects do not account for all agammaglobulinemic patients, suggesting that novel mutations underlying the disease remain to be found. While efficient, the current life-maintaining therapy with immunoglobulins and antibiotics is non-curative, prompting research into alternative treatment strategies that aim at rescuing the expression of the affected protein, thus giving rise to functional B-cells. These include gene therapy, which could be used to correct the defective gene or replace it with a functional copy. For a number of genetic defects, another alternative is to modulate the splicing of the affected transcripts. While these technologies are not yet ready for clinical trials in agammaglobulinemia, advances in genomic targeting are likely to make this option viable in the near future.

Keywords::

• agammaglobulinemia
• ARA
• B-cell
• gene therapy
• mouse models
• splicing
• XLA

Financial & competing interests disclosure

This work was supported by the Swedish Cancer Society, the Swedish Research Council, the Stockholm County Council (research grant ALF) and the Sigrid Jusélius Foundation (JJT). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• • Agammaglobulinemias are primary (inherited) immunodeficiencies characterized by the lack of functional B-cells and antibodies.

• • Mutations in 7 genes in the pre-BCR or BCR components or signaling pathway are currently known to cause agammaglobulinemia in humans.

• • Known genetic defects do not account for all patients, thus rare forms with novel disease genes are still likely to be found.

• • Knocking out genes involved in the B-cell development in mice provides an excellent tool to study the function of the corresponding proteins and provides information about putative human agammaglobulinemia genes.

• • Patients with agammaglobulinemia require lifelong treatment with immunoglobulin.

• • Curative treatment is possible in theory through gene therapy, by either replacing the affected gene with a functional copy, or by correcting the sequence in the original locus.

• • For a number of cases, splicing-based therapies offer an alternative way of correcting the gene expression.

• • Targeting the hematopoietic stem cell is an attractive option, but here the issues related to maintenance of these cells in an undifferentiated stage needs to be resolved first.