Beschreibung:
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<jats:title>Abstarct</jats:title>
<jats:p>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 <jats:italic>Idua-W402X</jats:italic> 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 <jats:italic>Idua-W402X</jats:italic> 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.</jats:p>
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<jats:title>Key messages</jats:title>
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<jats:p>Ataluren promotes readthrough of PTCs in a wide variety of contexts.</jats:p>
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<jats:p>Ataluren reduces glycosaminoglyan storage in MPS I-H cell and mouse models.</jats:p>
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<jats:p>Ataluren has a bell-shaped dose–response curve and a narrow effective range.</jats:p>
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