Ataluren suppresses a premature termination codon in an MPS I-H mouse

• Type of Material: Article
• Authors: Dan Wang, University of Alabama Birmingham; Xiaojiao Xue, University of Alabama Birmingham; Gwen Gunn, Emory University; Ming Du, University of Alabama Birmingham; Amna Siddiqui, University of Alabama Birmingham; Marla Weetall, PTC Therapeut Inc; Kim M Keeling, University of Alabama Birmingham
• Language: English
• Date: 2022-07-20
• Publisher: SPRINGER HEIDELBERG
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2022
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1007/s00109-022-02232-0
• Title of Journal or Parent Work: JOURNAL OF MOLECULAR MEDICINE-JMM
• Volume: 100
• Issue: 8
• Start Page: 1223
• End Page: 1235
• Grant/Funding Information: This research was supported by grants from the National Institutes of Health grants R01 NS057412 (KMK) and R21 NS090928 (KMK), and the University of Pennsylvania Improved Therapies for MPS I Grant Program MPS I-11–001-01 (KMK).
• Keywords: STRATEGY; NONSENSE MUTATIONS; Science & Technology; TRANSLATION; MECHANISM; Genetics & Heredity; Mucopolysaccharidosis I-Hurler; Nonsense mutation; PTC suppression; Readthrough; Ataluren; Life Sciences & Biomedicine; Medicine, Research & Experimental; Research & Experimental Medicine; PTC124; AMINOGLYCOSIDES; BINDING; LUCIFERASE REPORTER; STABILIZATION; FIREFLY LUCIFERASE
• Research Categories: Chemistry, Biochemistry

Abstract

Abstarct: Suppressing translation termination at premature termination codons (PTCs), termed readthrough, is a potential therapy for genetic diseases caused by nonsense mutations. Ataluren is a compound that has shown promise for clinical use as a readthrough agent. However, some reports suggest that ataluren is ineffective at suppressing PTCs. To further evaluate the effectiveness of ataluren as a readthrough agent, we examined its ability to suppress PTCs in a variety of previously untested models. Using NanoLuc readthrough reporters expressed in two different cell types, we found that ataluren stimulated a significant level of readthrough. We also explored the ability of ataluren to suppress a nonsense mutation associated with Mucopolysaccharidosis I-Hurler (MPS I-H), a genetic disease that is caused by a deficiency of α-L-iduronidase that leads to lysosomal accumulation of glycosaminoglycans (GAGs). Using mouse embryonic fibroblasts (MEFs) derived from Idua-W402X mice, we found that ataluren partially rescued α-L-iduronidase function and significantly reduced GAG accumulation relative to controls. Two-week oral administration of ataluren to Idua-W402X mice led to significant GAG reductions in most tissues compared to controls. Together, these data reveal important details concerning the efficiency of ataluren as a readthrough agent and the mechanisms that govern its ability to suppress PTCs. Key messages: Ataluren promotes readthrough of PTCs in a wide variety of contexts.Ataluren reduces glycosaminoglyan storage in MPS I-H cell and mouse models.Ataluren has a bell-shaped dose–response curve and a narrow effective range.