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, 8 (6), 540-6

New Approaches to Treatment of Primary Immunodeficiencies: Fixing Mutations With Chemicals


New Approaches to Treatment of Primary Immunodeficiencies: Fixing Mutations With Chemicals

Hailiang Hu et al. Curr Opin Allergy Clin Immunol.


Purpose of review: This review is to highlight the most current mutation-targeted therapeutic approaches and provide insights into new developments for treating primary immunodeficiencies.

Recent findings: Significant progress in mutation-targeted treatment was achieved in the past year with the identification and characterization of a translational read-through compound, PTC124. PTC124 demonstrates a new class of nontoxic bioavailable small drugs. Antisense oligonucleotide-mediated techniques such as splicing redirection, exon skipping, and mismatch repair have been successfully used to correct splicing, frameshift, and missense mutations, respectively. Delivery of antisense oligonucleotides to mammalian cells, including primary leukocytes and neurons, saw great progress during the past year. Recent advances for other approaches to correct frameshift and missense mutations are also considered.

Summary: Primary immunodeficiencies are monogenic disorders. The characterization and classification of disease-causing mutations facilitate the design and development of new mutation-targeted treatments. To date, using ataxia-telangiectasia (A-T) as a model primary immunodeficiency, the most promising advances have been with chemicals that read through various premature stop codons as well as with antisense oligonucleotides that mask aberrant splice sites. These principles can now be applied to other primary immunodeficiencies.


Figure 1
Figure 1. Distribution of mutations in primary immunodeficiencies
The percentage of each type of mutation is presented for individual PIDs. The gene responsible for the primary immunodeficiency disease and the total number of reported mutations are listed at the top and bottom of each pie-chart, respectively. ATM, ataxia–telangiectasia; WASP, Wiskott–Aldrich syndrome; BTK (Burton’s tyrosine kinase), X-Linked agammaglobulinemia; ADA, adenosine deaminase – severe combined immunodeficiency (SCID); CD40L, X-linked hyper-IgM; and CYBB, X-linked chronic granulomatous disease. PID, primary immunodeficiency.
Figure 2
Figure 2. Types of splicing mutations and correction with antisense morpholino oligonucleotides
(a) Type I refers to the classical splicing mutation that causes the deletion of an entire exon during pre-mRNA splicing. (b) Type II splicing mutations occur in the mid-intron and result in the insertion of a pseudoexon at the cDNA level. Blocking antisense morpholino oligonucleotides have been used to restore normal splicing. (c) Type III mutations lie within the coding region, resulting in the partial deletion of an exon. An antisense morpholino oligonucleotide has been used to block the mutation-generated 5′ splicing site. (d) Type IV mutations lie within the intron and lead to partial deletion of an exon. (e) Type V mutations disturb the lariat branch point and result in deletion of an exon.

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