MT: Oligonucleotides: Therapies and Applications; nonsense mutations; oxadiazoles; precision medicine; primary immunodeficiency; translational readthrough; Molecular Medicine; Drug Discovery
Abstract :
[en] Nonsense mutations are among the genetic causes of LRBA (lipopolysaccharide-responsive beige-like anchor) deficiency, a rare autosomal-recessive immunodeficiency disorder. These mutations introduce premature stop codons, leading to the loss of LRBA protein expression. Following the recent market withdrawal of ataluren, the only approved translational readthrough-inducing drug (TRID), there is an urgent need for alternative therapeutic options. In this study, we investigated the efficacy of three 1,2,4-oxadiazole-based TRIDs-NV848, NV914, and NV930-using primary fibroblasts from a patient homozygous for the R1683X nonsense mutation. All compounds restored full-length LRBA protein with correct cytoplasmic localization, as confirmed by western blot and immunofluorescence, outperforming ataluren in readthrough efficiency. NV848 exhibited the strongest activity and uniquely increased LRBA mRNA levels, suggesting transcript stabilization. In contrast, NV930 and NV914 induced readthrough without stabilizing mRNA. Global proteomic profiling revealed minimal off-target effects for NV848, limited protein modulation by NV914, and widespread variations of 828 proteins by NV930, affecting pathways related to vesicular transport and mRNA splicing. However, network analysis revealed poor connectivity among differentially expressed proteins, with LRBA unrelated to any regulated cluster. These findings highlight the reported molecules as promising candidates for precision therapy in LRBA deficiency and shed light on the broader cellular impact of TRIDs.
Disciplines :
Immunology & infectious disease
Author, co-author :
Fiduccia, Ignazio; Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, Viale delle Scienze Parco d'Orleans II Ed. 17, 90128 Palermo, Italy
Vitale, Emanuele; Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, Viale delle Scienze Parco d'Orleans II Ed. 17, 90128 Palermo, Italy
Varrica, Riccardo; Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, Viale delle Scienze Parco d'Orleans II Ed. 17, 90128 Palermo, Italy
Ricci, Davide; Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, Viale delle Scienze Parco d'Orleans II Ed. 17, 90128 Palermo, Italy
Marino, Sefora; Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, Viale delle Scienze Parco d'Orleans II Ed. 17, 90128 Palermo, Italy
Zito, Antonino; Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, Viale delle Scienze Parco d'Orleans II Ed. 17, 90128 Palermo, Italy
Pace, Andrea; Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, Viale delle Scienze Parco d'Orleans II Ed. 17, 90128 Palermo, Italy
Colige, Alain ; Université de Liège - ULiège > GIGA > GIGA Cancer - Connective Tissue Biology
Moutschen, Michel ; Université de Liège - ULiège > GIGA > GIGA Immunobiology - Immunology & Infectious Diseases
Borutzki, Yasmin; Department of Analytical Chemistry, University of Vienna, 1090 Vienna, Austria
Bileck, Andrea; Department of Analytical Chemistry, University of Vienna, 1090 Vienna, Austria
Meier-Menches, Samuel M; Department of Analytical Chemistry, University of Vienna, 1090 Vienna, Austria
Lentini, Laura; Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, Viale delle Scienze Parco d'Orleans II Ed. 17, 90128 Palermo, Italy
Pibiri, Ivana ; Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, Viale delle Scienze Parco d'Orleans II Ed. 17, 90128 Palermo, Italy
MIUR - Ministero dell'Istruzione, dell'Università e della Ricerca EC - European Commission
Funding text :
The research leading to these results has received funding from the European Union - NextGenerationEU through the Italian Ministry of University and Research under PNRR-M4C2-I1.3 Project PE_00000019 \u201CHEAL ITALIA\u201D to I.P. and L.L. (University of Palermo), CUP B73C22001250006 and PRJ-0863 PRIN2022 to I.P. (University of Palermo), and CUP B53D23008390006. The views and opinions expressed are those of the authors only and do not necessarily reflect those of the European Union or the European Commission. Neither the European Union nor the European Commission can be held responsible for them.
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