Ataluren, a New Therapeutic for Alpha-1 Antitrypsin-Deficient Individuals with Nonsense Mutations

• Published in: American journal of respiratory and critical care medicine Vol. 198; no. 8; pp. 1099 - 1102
• Main Authors: Reeves, Emer P, O'Dwyer, Ciara A, Dunlea, Danielle M, Wormald, Mark R, Hawkins, Padraig, Alfares, Mohammad, Kotton, Darrell N, Rowe, Steven M, Wilson, Andrew A, McElvaney, Noel G
• Format: Journal Article
• Language: English
• Published: United States American Thoracic Society 15.10.2018
• Subjects: Chromatography; Chronic obstructive pulmonary disease; Correspondence; Cystic fibrosis; Investigations; Muscular dystrophy; Mutation; Plasma; Proteins; Software; Stem cells; Ireland; Massachusetts
• ISSN: 1073-449X; 1535-4970
• DOI: 10.1164/rccm.201802-0338LE

After sequencing of all coding exons (II-V) of the SERPINA1 gene, the patient was identified as homozygous for the Q0bolton mutation, with two PTCs at amino acid 373 and 374 on exon V. Molecular dynamics simulations of Q0bolton-AAT suggested sufficient interactions to stabilize native-like protein structure, should it form during the early steps of protein folding. For Q0bolton-iPSC-hepatic cells, a significant 10-fold increase in AAT mRNA expression levels was observed compared with untreated cells (P < 0.05). [...]a significant 2-fold increase in the concentration of secreted Q0bolton-AAT protein was recorded with ataluren treatment (P < 0.001; Figure 2A). [...]for PTCs located more than 50 bp upstream of the most 3' exon-exon junction of the mRNA, nonsense-mediated decay is thought to eradicate the transcript (9). [...]this study demonstrates the potential use of ataluren to induce production and secretion of functional Q0bolton-AAT protein in vivo.