A precision medicine approach to primary immunodeficiency disease: Ataluren strikes nonsense mutations once again

Primary immunodeficiency diseases (PIDs) are associated with multiple genetic alterations including mutations of the lipopolysaccharide responsive Beige anchor (LRBA) gene. Nonsense mutations in the LRBA gene resulting in premature termination codons cause the loss of LRBA protein expression in PID. We evaluated the impact of a translational readthrough-inducing drug (TRID) ataluren as a nonsense suppression therapy in a PID patient with a homozygous stop codon mutation in exon 30 of LRBA. A precision medicine approach allowed us to pass from “in silico” to “in vitro” to the “bedside”: following the in vitro treatment of patient-derived primary fibroblasts with ataluren, we observed a restoration of the LRBA protein expression and localization. In silico predictions suggested LRBA retained function after readthrough. Based on the successful experimental and computational results we treated the patient with ataluren resulting in an improvement of his clinical symptoms and quality of life. Importantly, the clinical symptoms were associated with a recovery of LRBA expression in liver biopsies post-treatment compared with pre-treatment. Our results provide proof of concept demonstrating that ataluren can rescue LRBA expression in PID. This work highlights the potential for personalized precision medicine approaches to be exploited for different genetic diseases due to premature termination codons.