Abstract
The identification of genetic defects that underlie inherited retinal diseases (IRDs) paves the way for the development of therapeutic strategies. Nonsense mutations caused approximately 12% of all IRD cases, resulting in a premature termination codon (PTC). Therefore, an approach that targets nonsense mutations could be a promising pharmacogenetic strategy for the treatment of IRDs. Small molecules (translational read-through inducing drugs; TRIDs) have the potential to mediate the read-through of nonsense mutations by inducing expression of the full-length protein. We provide novel data on the read-through efficacy of Ataluren on a nonsense mutation in the Usher syndrome gene USH2A that causes deaf-blindness in humans. We demonstrate Ataluren´s efficacy in both transiently USH2AG3142*-transfected HEK293T cells and patient-derived fibroblasts by restoring USH2A protein expression. Furthermore, we observed enhanced ciliogenesis in patient-derived fibroblasts after treatment with TRIDs, thereby restoring a phenotype that is similar to that found in healthy donors. In light of recent findings, we validated Ataluren´s efficacy to induce read-through on a nonsense mutation in USH2A-related IRD. In line with published data, our findings support the use of patient-derived fibroblasts as a platform for the validation of preclinical therapies. The excellent biocompatibility combined with sustained read-through efficacy makes Ataluren an ideal TRID for treating nonsense mutations based IRDs.
Highlights
Inherited retinal degenerations (IRDs) are rare genetic diseases of the retina that are characterized by vision loss or blindness
We analysed the relative abilities of Ataluren and Gentamicin to induce the translational read-through of a specific nonsense mutation (c.9424G>T; p.G3142*) in the USH2A gene
The long USH2A isoform b is a transmembrane protein composed of a signal peptide, a large extracellular domain with several functional subdomains, such as FN3 domains, a laminin G-like domain (LamGL), several laminin-type EGF-like modules (EGF-LAM) and two laminin G domains (LamG), a transmembrane domain, and the intracellular cytoplasmic tail domain containing a PDZ-binding motif (PBM) (Figure 2A)
Summary
Inherited retinal degenerations (IRDs) are rare genetic diseases of the retina that are characterized by vision loss or blindness. More than 50 genes have been associated with the non-syndromic forms of RP, in which only the retina is affected. RP belongs to major causes of visual impairment and blindness in young patients, being a spectrum of orphan diseases. The classical approach is gene augmentation that utilizes viral vectors, such as adeno-associated viral vectors (AAVs) or lentiviruses for the transfer of the wild type cDNA of the affected gene. Clinical trials using gene augmentation therapy led to promising results in a subgroup of Leber congenital amaurosis (LCA) that is caused by mutations in the RPE65 gene [5]. In 2018, the AAV-based drug LUXTURNATM has been FDA-approved as a prescription gene therapy for patients with IRD and it is approved in Europe. The size of the coding sequences that exceed the cargo capacity of the currently applied viruses, e.g. IRDs caused by mutations in USH2A, hampered gene augmentation for several IRDs [2,6]
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