New approaches to treatment of primary immunodeficiencies: fixing mutations with chemicals.

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.