Promoting translational readthrough to augment fibrillin-1 (FBN1) deposition in Marfan syndrome fibroblasts: A proof-of-concept study.

Marfan syndrome (MFS) is a connective tissue disorder characterized by long bone overgrowth, enlargement of the aorta, ocular anomalies and other symptoms. Current treatment focuses on managing aortic aneurysms to avoid dissection or rupture. However, no cures are available. MFS is caused by one of >1,800 dominant pathogenic variants in FBN1, which encodes the extracellular matrix (ECM) protein fibrillin-1. A significant number of FBN1 variants result in premature termination codons (PTCs). Recently, small molecules were identified that can promote translational readthrough of PTCs and were evaluated in preclinical and clinical trials for several genetic disorders. Here, we show that the translational readthrough drugs ataluren and gentamicin ameliorated FBN1 deposition in some MFS patient-derived skin fibroblast lines harboring PTC variants in FBN1. In contrast, inhibitors of NMD were cytotoxic to the skin fibroblast lines that we analyzed. We conclude that promoting translational readthrough of PTC variants in FBN1 could result in a therapeutic benefit for MFS patients with specific PTCs in FBN1 and that its efficacy will likely depend on the PTC sequence context, the amino acids that are incorporated in FBN1 after PTC suppression and the overall increase of FBN1 deposition in the ECM.