Ataluren for the Treatment of Usher Syndrome 2A Caused by Nonsense Mutations

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.

Suppression of Nonsense Mutations by New Emerging Technologies

“…Several in silico studies and reporter cell-based assays have shed additional light on the mechanism of action of Ataluren and structurally similar molecules with read-through activity [ 57 , 58 , 59 ]. Ataluren is also shown to have a similar effect in Usher syndrome patient-derived cells expressing a nonsense mutation in the USH2A gene [ 7 ]. Usher syndrome causes deaf-blindness in humans.…”

“…For instance, Usher syndrome is an inherited retinal dystrophy (IRD) that is the principal cause of combined deafness and blindness. Nonsense mutations occur in 12% of Usher syndrome patients and have been described in different genes, such as the USH2A gene [ 6 , 7 ]. Some Hurler Syndrome patients, suffering from skeletal abnormalities and cognitive impairment, carry a nonsense mutation in the IDUA gene that prevents the production of a functional full-length IDUA protein in these patients [ 8 ].…”

“…For instance, aminoglycoside antibiotics such as Gentamicin have been used for PTC read-through [ 11 ]. Similarly, a small compound named Ataluren has also been tested to suppress nonsense mutations [ 7 , 12 , 13 ]. Both Gentamicin and Ataluren target the ribosome to induce the read-through of PTC and are fairly well developed.…”

Usher syndrome: clinical features, molecular genetics and advancing therapeutics

“…127 Further studies demonstrated PTC124 efficacy in restoring USH2A protein expression and primary ciliogenesis capability in USH2A patientderived fibroblasts with the c.9424G > T p.(Gly3142*) mutation. 128 Overall, TRIDs show promise as a safe and effective strategy to treat a range of Usher related nonsense mutations; however, these par ticular variants cause ~16% of USH2Arelated RP and 13% of all IRD cases. 128 An additional small molecule that has been of interest for Usher syndrome treatment, known as BioFocus 844 (BF844), was identified through cellbased high throughput screening as capable for stabilising the defective Clarin1 protein pro duced by the common CLRN1 missense variant p.(Asn48Lys).…”

Targeting Nonsense: Optimization of 1,2,4-Oxadiazole TRIDs to Rescue CFTR Expression and Functionality in Cystic Fibrosis Cell Model Systems

“…Nonsense mutations are found in about 11% of genetic disorders such as cystic fibrosis (CF) [ 17 ], Duchenne muscular dystrophy (DMD) [ 18 ], spinal muscular atrophy [ 19 , 20 ], neurofibromatosis [ 21 ], retinitis pigmentosa [ 22 , 23 , 24 ], lysosomal storage disease [ 13 , 25 , 26 ], Rett syndrome [ 27 ], Shwachman–Diamond syndrome [ 28 , 29 ], and Usher’s syndrome (USH) [ 30 ]. In this context and despite its limits, the translational readthrough of PTCs can represent a valuable pharmaceutical approach to target the specific genetic defect caused by nonsense mutations.…”